ASSAYS FOR COMPOUNDS WHICH INCREASE PHOSPHOLIPASE A2 ACTIVITY

Abstract: A method of identifying a compound which increases the activity of a phospholipase A2 towards a given phospholipid substrate the method comprising determining whether the activity of phospholipase A2 towards the given substrate is increased in the presence of a compound compared to its activity in the absence of the same compound. A method of identifying a compound which increases the production or expression of phospholipase A2 in a cell the method comprising determining directly or indirectly whether the production or expression of phospholipase A2 in a cell is increased in the presence of a compound compared to its production or expression in the absence of the same compound. A method of treating a psychiatric or neurological disorder such as depression in a patient the method comprising administering an effective dose of a compound which increases the release of docosahexaenoic acid from brain membrane phospholipids. A method of identifying a compound which mimics the effect of docosahexaenoic acid on the glucocorticoid receptor the method comprising contacting the glucocorticoid receptor with a compound and determining whether the compound has substantially the same effect as docosahexaenoic acid on the glucocorticoid receptor.

Description: ASSAYS FOR COMPOUNDS WHICH INCREASE PHOSPOLIPASE A2 ACTIVITY The present invention relates to assays for compounds, in particular to assays for compounds which are useful in treating depression and related psychiatric disorders (including anxiety and schizophrenia), and their use in such treatment. In addition, the present invention also relates to the use of docosahexaenoic acid, and compounds which mimic the effect of docosahexaenoic acid, for the treatment of depression and related psychiatric disorders. Depression is one of the most prevalent psychiatric conditions in the industrial world. In the United States and the UK the point of prevalence is considered to be 13-20% (Boyd and Weissman, 1981). There is a strong link between depression and suicide. Depression is diagnosable in 40-70% of suicidal patients and 15% of patients with a mood disorder eventually commit suicide (see review by Schifano, 1994). Non-fatal suicide behaviour is observed in 20-40% of patients. In addition, there are very high costs to society of this disease in terms of mortality (for example suicides, fatal accidents due to impaired concentration, and death due to illnesses which can be a sequelae), morbidity (for example attempted suicide, accidents, illness, poor employment prospects and substance abuse), and societal cost (for example dysfunctional families, absenteeism and unemployment). Traditionally, research has focused on the brain serotonergic and noradrenergic systems because in the 1960s it was proposed that depression results from a deficit in serotonin (5-HT) and/or noradrenaiine function (Schildkraut 1965; Lapin and Oxenkrug, 1969). Although this hypothesis still remains valid, and current pharmacotherapy is directed at modulating these two systems, existing drugs to treat depression are unsatisfactory for three key reasons: 1. Antidepressant drugs are only effective in approximately 70% of patients, leaving a significant proportion (~30%) resistant to current therapy (US Department of Health and Human Services, 1993). Of those who do respond to drug treatment, many are not in full remission (at least 50% decrease in symptoms assessed on a standard psychiatric rating scale). 2. All existing antidepressant drugs are relatively slow in producing their clinical effects, requiring administration for 4 weeks or longer to attain their maximal efficacy (Frazer, 1994). 3. The incidence and severity of side effects is also a problem, especially with the older tricyclic drugs (for example toxicity in overdose, sedation, dry mouth and blurred vision may occur) whereas second generation antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) can produce dizziness, nausea, gastrointestinal disturbance, headache, sleep disturbance and sexual dysfunction (Frazer, 1994). Electroconvulsive Therapy (ECT) is the only treatment for depression that is both rapid in onset and effective in treatment-resistant patients (Paykel and Hale, 1986; Segman et al, 1994). However, its use is limited for a number of reasons. Primarily these are due to the short-term memory loss and the intense social stigma associated with the use of ECT. Furthermore, it is restricted to use in hospitals (usually ones with academic departments of psychiatry) because it is usually given under anaesthesia with muscle relaxants (eg see Segman et al, 1994) to prevent some of its distressing side-effects, although in the past it has been given without neuromuscular blockade or anaesthetic. ECT is especially useful when rapid onset of clinical effect is essential (eg high suicide risk) and patients are refractory to a number of antidepressant drugs. Although the mode of action of ECT has remained elusive, its beneficial effects are believed to be due to the neural activity associated with the convulsive seizure, rather than the passage of electricity through the body, because similar beneficial effects can be produced with chemical convulsants such as bicuculline (Siesjό et al, 1982) or fluorothyl (Green, 1980). If the mechanism of therapeutic action of ECT could be unravelled, we believe that it would be possible to find new antidepressant drugs with the powerful efficacy of ECT in treatment-resistant patients. It would be desirable for such a drug to produce its effects without inducing a convulsion or causing short term memory loss. The primary predicted advantages of such a therapy would be rapid onset of action and efficacy. Despite extensive research, the exact mechanism of action of ECT is unclear, but it may be explored following administration of electroconvulsive shock (ECS) to animals. ECS and antidepressants have a number of common effects on monoaminergic systems. For example, both types of treatment generally down- regulate α 2 adrenoceptors, $■_ adrenoceptors (Green et al, 1984) and 5-HT 1A receptors (Martin et al, 1992). However, there are two receptors that are affected in opposite ways by ECS and antidepressant drugs, these are 5-HT ∑A and dopamine D- . receptors. Antidepressant drugs generally cause a down regulation of 5-HT^ receptors (Peroutka and Snyder, 1980), but ECS causes an up-regulation of these receptors (Green et al, 1983; Martin et al, 1991). Similarly, D receptors are not affected by antidepressant drugs (Martin et al, 1988) but D-, function is enhanced by ECS (Martin et al, 1990). It is unlikely that these changes are induced by alterations in extracellular monoamine levels because the effects of ECS on α 2 adrenoceptors persist in the absence of serotonergic or noradrenergic neurones (Heal et al, 1991) and its effects on βi adrenoceptors persist in the absence of noradrenergic neurones (Dooley et al, 1987). Basan & Rakowski (1970) reported that a single ECS induces a rapid, short- lasting increase in brain free fatty acids (FFAs). There is evidence that FFAs modulate a number of cellular functions (Sumida et al 1993; Meires, 1994). We have now shown that docosahexaenoic acid (DHA [22:6 ω-3]) is the likely mediator of the antidepressant actions of repeated ECT. The action of phospholipase A 2 on brain membrane phospholipids is the likely source of DHA. Phospholipases as a class of enzymes have been reasonably well characterized and, in particular, phospholipase A 2 (PLA 2 ) is known to be a superfamily of enzymes some of which are involved in signal transduction (see for example Dennis, 1997). Similarly, the role of fatty acids in signal transduction is reviewed in Sumida et al, 1993a. Vallette et al, 1995 suggest that arachidonic acid and DHA may be playing a role in modulating the intracellular steroid hormone signalling pathway to co-regulate a glucocorticoid-sensitive promoter. Sumida et al, 1993b suggest that unsaturated fatty acids such as DHA interact with the rat liver glucocuricoid receptor and that their site of action is on a fragment of the receptor containing the hormone-binding domain and some sequences C-terminal of the DNA-binding domain. Fatty acids have been shown to induce the gene for the adipocyte fatty acid binding protein aP2 (Grimaldi et al, 1992) and to activate a chimaera of the clofibric acid-activated receptor and the glucocorticoid receptor (Gόttlicher et al, 1992). The molecular cloning of various forms of PLA 2 is described in Sharp et al, 1991 ; Clark et al, 1991 ; Larson et al, 1998; Ma et al, 1999, US 5,466, 595; US 5,328, 842; US 5,554,511 (which is a divisional of US 5,466,595); US 5,354,677; US 5,322,776; and WO 96/03512 (which is related to US 5,466,595). Methods for screening for inhibitors are described in WO 93/03512 and it is suggested that such inhibitors may have anti-inflammatory activity mediated by the arachidonic acid cascade. Further PLA 2 -encoding polynucleotides are described in WO 95/02328, and WO 95/05479 relates to new substrates for cytosolic PLA 2 which may be useful in the measurement of enzyme activity. WO 97/04127 relates to a putative diagnostic test for schizophrenia by analysing allelic variations in the cytosolic PLA 2 gene, and EP 0 599 576 relates to the use of combinations of gamma-linoleic acid, arachidonic acid and DHA in treating schizophrenia. Objects of the invention are to provide screening assays for compounds which are useful as drugs to treat psychiatric or neurological disorders, including depression and anxiety, or at least which are useful as lead compounds for development into such drugs; and to provide for methods of treatment of psychiatric or neurological disorders including depression. Docosahexaenoic acid has been identified by us as the likely mediator of the antidepressant actions of repeated ECT. Since ECS up-regulates 5-HT^ binding (Martin et al, 1991), expression (Butler et al, 1993) and function (Green et al, 1983), we have used this as a marker of an ECS like effect. Repeated ECS causes a significant release of free fatty acids, including DHA (Figure 1). Repeated administration of ECS (5 times over 10 days) causes a significant increase in 5-HT 2 receptor binding B of 11-13% in frontal cortex and 30-46% in hippocampus (Martin et al, 1991); this effect can be mimicked by DHA (200 pmol i.c.v. (intracerebroventricular route) 5 times over 10 days), causing approximately a 40% increase in 5-HT 2 binding B maχ ex vivo (Figure 2). A larger effect of DHA treatment is seen on 5-HT 2 -mediated function in vivo: 200 pmol or 400 pmol DHA given i.c.v. 5 times over 10 days increases the frequency of 5-methoxy-N,N-dimethyltryptamine (5- MeO-DMT)-induced headtwitches in C57 B1J6 mice by 65 and 100% of controls, respectively, the higher dose of DHA producing an effect indistinguishable from ECS (Figure 3a). Of the other fatty acids, arachidonic acid (AA; 20:4 ω-6 ) had no effect, and the effects of oleic acid (OA; 18:1 ω-9) were inconsistent (Figure 3b). In addition, DHA application (400 pmol, i.c.v. 5 times over 10 days) has a significant antidepressant effect in the Porsolt forced-swim test, comparable to that caused by a similar ECS treatment regimen (Figure 4). By contrast, i.c.v. administration of a mixture containing 200 pmol each of DHA, AA and OA was without effect (Figure 4). In further support of our work is the finding that the level ofα-linolenic acid, the essential fatty acid precursor of DHA, is significantly lower in serum cholesteryl esters of patients with major or minor depression compared with healthy controls (Maer et a/, 1996). In conclusion, these data demonstrate that many of the beneficial effects of ECT can be mimicked by treatment with DHA. Furthermore, they also indicate that mechanisms to release DHA from membrane phospholipids, thereby elevating the level of free DHA in the brain, may provide alternative means to treat depression and other psychiatric illnesses and disorders of the nervous system. These approaches will have similar efficacy to ECT (ie rapid onset of action, and efficacy in treatment- resistant patients). A first aspect of the invention provides a method of identifying a compound which increases the activity of a phospholipase A 2 towards a given phospholipid substrate the method comprising determining whether the activity of phospholipase A 2 towards the given substrate is increased in the presence of a compound compared to its activity in the absence of the same compound. A second aspect of the invention provides a method of identifying a compound which increases the production or expression of phospholipase A in a cell the method comprising determining directly or indirectly whether the production or expression of phospholipase A 2 in a cell is increased in the presence of a compound compared to its production or expression in the absence of the same compound. Our work shows that DHA is the likely mediator of the beneficial, antidepressant effects of ECT, and activation of a phospholipase enzyme, or increased production or expression of the enzyme, to stimulate release of endogenous DHA is believed to be able to bring about these beneficial effects. Although not bound by any theory in relation to the invention, the rationale behind activation of a phospholipase enzyme to bring about release of DHA is discussed below. Membrane lipids fall into four major groups: triglycerides, phosphoglycerides, sphingolipids and glycolipids. Phosphoglycerides form the predominant lipid class. A phosphoglyceride (or phospholipid) comprises two fatty acid groups attached at the first (sn-1) and second (sn-2) carbon atoms of glycerol, with a phosphate group attached at the third (sn-3) carbon atom linked to one of four possible polar head groups: serine, ethanolamine, choline or inositol. Hence, dependent on the polar head group, phospholipids are subdivided into the classes: phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylcholine (PC) or phosphatidyl-inositol (PI). Each class of phospholipid can be further divided, depending on the fatty acids incorporated at the sn-1 and sn-2 positions. However, some generalisations exist: saturated fatty acids (eg palmitic [16:0] or stearic acid [18:0]) or monounsaturated fatty acids (eg OA) are generally incorporated at sn-1 , while longer, polyunsaturated acids are incorporated at sn-2. In addition, particular polyunsaturated fatty acids tend to be associated with particular polar head groups. Thus, in the brain phospholipid pool, AA is incorporated predominantly in PI and PC, while DHA is incorporated into PS and PE (Salem et al, 1986). Once incorporated into phospholipids, fatty acids can be released by the hydrolysing activity of phospholipases. Phospholipases have been grouped into four major classes, dependent upon where they cleave the phosphoglyceride molecule. Phospholipases A-_ (PLA^ and A 2 (PLA 2 ) remove the acids at the sn-1 and sn-2 positions respectively, directly generating free fatty acid and lyso- phosphatidylglycerol. Phospholipase B (PLB) enzymes combine PIJV, and PLA 2 activity. Phospholipase C (PLC) cleaves at the sn-3 position to generate 1 ,2,diacylglycerol (DAG) and phosphorylated head group. Due to the PI and PC substrate specificity of this group of enzymes, usually phosphoinositol or phosphocholine are released. The free fatty acids must subsequently be released from DAG by diacylglycerol lipase. Phospholipase D (PLD) cleaves the polar head group from the phosphate at the sn-3 position, to generate phosphatidic acid (PA; diacyglycerol-3-phosphate), and free head group. Usually, this is free choline, due to the PC specificity of the enzyme (Liscovitch 1991 ; Wantet al, 1991 ; Thompson et al, 1993). Release of free fatty acids from PA requires the subsequent, sequential activity of phosphatidic acid dephosphoryiase and diacylglycerol lipase. Thus, in order to release directly free fatty acids from brain membrane phospholipids, it is necessary to activate a PLA 2 or PLB enzyme. However, in the context of the present invention non-specific release of free fatty acids is not necessarily beneficial. Release of AA leads to generation of thromboxanes and prostaglandins, which are potent inflammatory mediators. It is therefore desirable not to activate phospholipases which will release AA. Consequently, it is desirable to cause preferential release of DHA from the brain phospholipid pool by activating a phospholipase with either : (a) selectivity for DHA at the sn-2 position, or (b) with selectivity for phosphoserine or phosphoethanolamine at the sn-3 position, to define a substrate with a suitably high proportion of DHA at the sn-2 position. Isoforms of PLA 2 are known which have these characteristics and, in any case with molecular genetic approaches, further isoforms of PLA 2 with these desirable characteristics may be found. Biochemical characterisation and molecular genetic analysis of enzymes with PLA 2 activity has revealed many isoforms, that can be grouped into two major classes: small molecular weight (14kD) secreted isoforms (cPLA 2 ) and larger molecular weight (40-110kD) cytosolic isoforms (cPLA 2 ). These major divisions are further subdivided, based on substrate specificities, co-factor requirements, and mechanism of activation. A comprehensive review of all PLA 2 isoforms for which protein or DNA sequence data are available is given in Dennis (1997). Of these sequenced isoforms, a particularly preferred isoform, with the required substrate specificity to release DHA preferentially is the 85kDa type VI calcium-independent cPLA . Three rodent isoforms have been cloned and shown to be homologous (hamster: Jones and Tang 1995, Tang et al, 1997; mouse: Balboa et al, 1997; rat: Ma et al, 1997) although a fourth, biochemically characterised rodent macrophage isoform (Ackerman et al, 1994) is also believed to be homologous (Balboa et at, 1997). The human homologue of this type VI calcium-independent cPLA 2 enzyme has also been sequenced and shown to exist in two isoforms (Larsson et al, 1998; Ma et al, 1999). The short isoform (85 kD) is highly homologous (approximately 95% identity) to the rodent isoforms (Ma et al, 1999), whereas the long isoform (88 kD) includes an additional 54 amino acids not present in the rodent isoforms (Larsson et al, 1998), which confer activation of the enzyme by adenosine triphosphate (ATP) (Ma et al, 1999). However, there are additional isoforms that have been characterised biochemically, but not yet sequenced at the protein or DNA level. Some of these also have the required substrate specificity that will preferentially release DHA. These include the 14kD soluble cytosolic PLA 2 isoform, with PE selectivity and pH optimum of 8.5, isolated from gerbil brain byRordorf et al, (1991); the 110kDa calcium-independent PLA 2 with PE selectivity, isolated from bovine brain by Hirashima et al (1992); the 60kDa calcium-dependent cytosolic PLA 2 with an alkaline pH optimum and PE selectivity, purified from rat kidney by Hara al (1995); and the PS hydrolysing calcium dependent cytosolic PLA 2 , with a neutral/acid pH optimum, purified from rat mast cells (Murakami et al, 1992), provided these latter two isoform are also present in brain. All of these references, and in particular the teachings within them which relate to the identification and acquisition of the PLA 2 enzymes, are incorporated herein by reference. Thus, five cytosolic isoforms of PLA 2 have been identified to date with the appropriate substrate specificity to release selectively DHA. The various classes of sequenced PLA 2 , isoforms, and the biochemically characterised isoforms of particular interest in relation to the practice of this invention are shown in Table 1 Legend for Table Classification of Phospholipase A2 isoforms based on protein and DNA sequence homology, after Dennis 1997. Molecular weight, tissue location, function, selectivity and calcium requirements for activity have been indicated. Some additional partially purifiedisoforms, identified by biochemical characteristics but not yet sequenced, are also represented (Type not indicated). Non-mammalian isoforms have been omitted. PAF: platelet activating factor; PC:phosphatidylcholine; PE: phosphatidylethanolamine; PI: phosphatidylinositol; PS: phosphatidylserine; 18:2 ω-6: linoleic acid; 20:4 ω-6: arachidonic acid. The preferred isoform for screening, for which the DNA and/or protein sequence is known, is the human cicPLA 2 based on its ability to cleave fatty acid from the sn-2 position of PE (Larsson et al, 1998; Ma et al, 1999). In addition, preferred isoforms for which the DNA and/or protein sequence are not yet known, are, in order of preference, the 14kD rat mast cell isoform (Murakami et al, 1992), the 110kD bovine brain form (Hirashima et al, 1992), the 14 kD gerbil brain form (Rordorf et al, 1991) and the 60kD rat kidney form (Hara et al, 1995). Furthermore, other splice variants and homologues of the human cicPLA 2 identified by Larsson et al, (1998) and Ma et al, (1999), with improved substrate selectivity (namely, cleavage of DHA from the sn-2 position of PE or PS) would also be preferred for the screen. In relation to the first aspect of the invention by "increasing the activity of phospholipase A 2 towards a given phospholipid substrate" we mean that the activity is increased in the presence of the test compound compared to the absence of the test compound (under otherwise identical conditions) at least 1.2-fold, more preferably at least 2-fold, still more preferably at least 5-fold and most preferably at least 10-fold. Any suitable assay can be used to measure the activity of phospholipase A 2 . Suitable assays are known in the art such as those described, for example, in WO 96/03512 (although in that case the assays were used to identify compounds which inhibit phospholipase activity). It is possible to carry out the assays, using any suitable form of phospholipase A 2 . For example, phospholipase A 2 may be purified from brain tissue or it may be purified from cell culture (ie from cells in culture which naturally express the phospholipase A 2 ). Alternatively, and preferably, the phospholipase A 2 used in the method of the invention may be produced by recombinant DNA technology, for example by expressing a cDNA encoding the enzyme in a suitable host cell system. It will be appreciated that the PLA 2 for use in the assay of the invention need not necessarily be identical to a naturally-occurring PLA 2 (although such PLA 2 s may be preferred). For example, the PLA 2 may be a fusion protein between PLA 2 and a further polypeptide. In particular, the PLA 2 may be a fusion between PLA 2 and a polypeptide which makes the fusion protein more readily purifiable. Typically, the fusion protein will contain a portion which has the PLA 2 activity (and which may be substantially the same as a natural PLA 2 molecule) and a portion that can bind to an affinity ligand. For example, fusions between PLA 2 and anoligo-histidine peptide can be purified using Ni 2+ affinity chromatography; fusions between PLA 2 and a Myc epitope can be purified using anti-Myc antibody; and fusions between PLA 2 and glutathione-S-transferase can be purified using glutathione affinity chromatography. It will be appreciated that the fusions may be at the N- or C-terminus or both. It will also be appreciated that the PLA2 useful in the assay may be a truncated form of the natural PLA 2 or it may be a variant form of the PLA 2 . By "variants" we include deletions, insertions, and substitutions, either conservative or non-conservative, where such changes do not substantially change the PLA 2 activity of the enzyme. By "conservative substitutions" is intended combinations such as Gly, Ala; Val, lie, Leu; Lys, His, Arg; and Phe, Tyr. Such variants may be made using thewell known methods of protein engineering and site-directed mutagenesis. In order to produce PLA 2 suitable for use in the screening assays, the DNA or RNA, encoding the PLA 2 or a suitable variant thereof (as the case may be) is then expressed in a suitable host to produce a polypeptide. Thus, the DNA encoding the polypeptide may be used in accordance with known techniques, appropriately modified in view of the teachings contained herein, to construct an expression vector, which is then used to transform an appropriate host cell for the expression and production of the polypeptide of the invention. Such techniques include those disclosed in US Patent Nos. 4,440,859 issued 3 April 1984 to Rutter et al, 4,530,901 issued 23 July 1985 to Weissman, 4,582,800 issued 15 April 1986 to Crowl, 4,677,063 issued 30 June 1987 to Mark et al, 4,678,751 issued 7 July 1987 to Goeddel, 4,704,362 issued 3 November 1987 to Itakura et al, 4,710,463 issued 1 December 1987 to Murray, 4,757,006 issued 12 July 1988 to Toole, Jr. et al, 4,766,075 issued 23 August 1988 to Goeddel et al and 4,810,648 issued 7 March 1989 to Stalker, all of which are incorporated herein by reference. The DNA encoding the polypeptide may be joined to a wide variety of other DNA sequences for introduction into an appropriate host. The companion DNA will depend upon the nature of the host, the manner of the introduction of the DNA into the host, and whether episomal maintenance or integration is desired. Generally, the DNA is inserted into an expression vector, such as a plasmid, in proper orientation and correct reading frame for expression. If necessary, the DNA may be linked to the appropriate transcriptional and translational regulatory control nucleotide sequences recognised by the desired host, although such controls are generally available in the expression vector. The vector is then introduced into the host through standard techniques. Generally, not all of the hosts will be transformed by the vector. Therefore, it will be necessary to select for transformed host cells. One selection technique involves incorporating into the expression vector a DNA sequence, with any necessary control elements, that codes for a selectable trait in the transformed cell, such as antibiotic resistance. Alternatively, the gene for such selectable trait can be on another vector, which is used to co-transform the desired host cell. Host cells that have been transformed by the recombinant DNA are then cultured for a sufficient time and under appropriate conditions known to those skilled in the art in view of the teachings disclosed herein to permit the expression of the polypeptide, which can then be recovered. Many expression systems are known, including bacteria (for example E. coli and Bacillus subtilis), yeasts (for example Saccharomyces cerevisiae), filamentous fungi (for example Aspergillus), plant cells, animal cells and insect cells. The vectors include a prokaryotic replicon, such as the ColE1 ori, for propagation in a prokaryote, even if the vector is to be used for expression in other, non-prokaryotic, cell types. The vectors can also include an appropriate promoter such as a prokaryotic promoter capable of directing the expression (transcription and translation) of the genes in a bacterial host cell, such asE. coli, transformed therewith. A promoter is an expression control element formed by a DNA sequence that permits binding of RNA polymerase and transcription to occur. Promoter sequences compatible with exemplary bacterial hosts are typically provided in plasmid vectors containing convenient restriction sites for insertion of a DNA segment of the present invention. Typical prokaryotic vector plasmids are pUC18, pUC19, pBR322 and pBR329 available from Biorad Laboratories, (Richmond, CA, USA) and pTrc99A and pKK223-3 available from Pharmacia, Piscataway, NJ, USA. A typical mammalian cell vector plasmid is pSVL available from Pharmacia, Piscataway, NJ, USA. This vector uses the SV40 late promoter to drive expression of cloned genes, the highest level of expression being found in T antigen-producing cells, such as COS-1 cells. An example of an inducible mammalian expression vector is pMSG, also available from Pharmacia. This vector uses the glucocorticoid-inducible promoter of the mouse mammary tumour virus long terminal repeat to drive expression of the cloned gene. Useful yeast plasmid vectors are pRS403-406 and pRS413-416 and are generally available from Stratagene Cloning Systems, La Jolla, CA 92037, USA. Plasmids pRS403, pRS404, pRS405 and pRS406 are Yeast Integrating plasmids (Yips) and incorporate the yeast selectable markers HIS3, TRP1, LEU2 and URA3. Plasmids pRS413-416 are Yeast Centromere plasmids (YCps) A variety of methods have been developed to operably link DNA to vectors via complementary cohesive termini. For instance, complementary homopolymer tracts can be added to the DNA segment to be inserted to the vector DNA. The vector and DNA segment are then joined by hydrogen bonding between the complementary homopolymeric tails to form recombinant DNA molecules. Synthetic linkers containing one or more restriction sites provide an alternative method of joining the DNA segment to vectors. The DNA segment, generated by endonuclease restriction digestion as described earlier, is treated with bacteriophage T4 DNA polymerase or E. coli DNA polymerase I, enzymes that remove protruding, 3'- single-stranded termini with their 3'-5'-exonucleolytic activities, and fill in recessed 3'- ends with their polymerizing activities. The combination of these activities therefore generates blunt-ended DNA segments. The blunt-ended segments are then incubated with a large molar excess of linker molecules in the presence of an enzyme that is able to catalyze the ligation of blunt-ended DNA molecules, such as bacteriophage T4 DNA ligase. Thus, the products of the reaction are DNA segments carrying polymeric linker sequences at their ends. These DNA segments are then cleaved with the appropriate restriction enzyme and ligated to an expression vector that has been cleaved with an enzyme that produces termini compatible with those of the DNA segment. Synthetic linkers containing a variety of restriction endonuclease sites are commercially available from a number of sources including International Biotechnologies Inc, New Haven, CN, USA. A desirable way to modify the DNA encoding the polypeptide of the invention is to use the polymerase chain reaction as disclosed by Saiki et al (1988) Science 239, 487-491. In this method the DNA to be enzymatically amplified is flanked by two specific oligonucleotide primers which themselves become incorporated into the amplified DNA. The said specific primers may contain restriction endonuclease recognition sites which can be used for cloning into expression vectors using methods known in the art. Other suitable DNA manipulation and expression techniques are described in Sambrook et al (1989) "Molecular Cloning, a laboratory manual", cold Spring Hargbor Press, Cold Spring Harbor, New York, USA. Although it may be desirable to carry out the assay method of the invention using isolated phospholipase A 2 , it may also be convenient to carry out the assay using cells which express a particular phospholipase A 2 as the predominant phospholipase activity. Such cells may be naturally-occurring cells which over- express a phospholipase A 2 or cells which do so in culture, or they may be genetically-engineered cells which over-express the phospholipase A 2 of interest. It is possible that "super-activation" of PLA 2 can be screened. Since the PLA 2 assays can be used to measure hydrolysis rate, superactivation is observed if the hydrolysis rate of the substrate by the PLA 2 is faster in the presence of activator compound than in its absence. A precedent exists: activator substances/cofactors required to enhance calcium-independent PLA 2 activity include, for example, adenosine triphosphate (ATP) (Ackerman et al, 1994; Ma et al 1999) and the detergent Triton X-100 (Hirashima et al, 1992; Ackerman et al, 1994). Alternatively, the assay can be used to seek activators of PLA 2 , by testing for their ability to overcome inhibition. In this case, the control sample and testsample contain an inhibitor of PLA 2 and a compound is selected which can overcome the inhibition. A range of inhibitor substances may be used in this embodiment of the assay. Some of these are specific to cytosolic isoforms, but do not distinguish between isoforms, eg bromophenacylbromide or methyl-arachidonyl- fluorophosphonate (MAFP). Others are specific for the calcium independent isoform, eg palmitoyl trifluoromethyl-ketone (PACOCF 3 ), arachidonyl trifluoromethyl-ketone (AACOCF 3 ) (and other trifluoromethyl-ketone derivatives) or bromoenol lactone (BEL) (Ackermann et al, 1994; Ma et al 1999). However, if an inhibitor is used to somewhat reduce PLA 2 activity, there are two assay considerations; firstly, compounds overcoming the effect of the inhibitor binding at the active site of the enzyme are unlikely to have a superactivator effect; and secondly, it is important not to use irreversible, 'suicide substrate' type inhibitors, such as BEL. In this embodiment of the assay, compounds are sought which activate the PLA 2 , probably by identifying compounds which act at an allosteric site to potentiate the catalytic activity. The type of compounds sought by this approach are unlikely to bind at the catalytic site, because they would then tend to compromise catalytic activity. Nevertheless, any compound able to increase PLA 2 activity by whatever mechanism, may be useful in this approach. Assay formats, such as high-throughput screening assays, may be made by the person skilled in the art without inventive effort using the enzymes and substrates as disclosed herein. Particularly preferred phospholipid substrates for the phospholipase A 2 are those which have DHA at the sn-2 position and also, preferably, have phosphoserine or phosphoethanolamine at the sn-3 position of the phospholipid substrate. In relation to the second aspect of the invention, the production or expression of phospholipase A 2 can be measured in a cell using any suitable method. For example, it may be measured by measuring the amount of protein or mRNA in the cell (using, for example, the well known methods of immuno assays such as an enzyme-linked immuno sorbent assay (ELISA) for detecting amounts of a protein and using, for example, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to measure amounts of mRNA). Also, it may be measured by assaying phospholipase A activity as herein disclosed. Western blotting (with polyacrylamide gel separation before protein transfer and subsequent blotting, or by direct dot-blotting) may also be used to determine the level of protein expression. Northern blotting, (after agarose gel separation, or by direct Northern slot/dot blotting of crude mRNA extracts) may also be used to measure mRNA expression level. Typically, the celt which is used in the assay method of the second aspect of the invention is one which naturally expresses the phospholipase A 2 . Examples include rat or human mast cells, CHO cells, glioblastoma cells, neuroblastoma cells, HEK 293 (kidney) cells, or any cells obtained from a tissue expressing the appropriate isoform and grown in primary culture. The source clearly depends on the isoform to be used. However, suitable genetically engineered cells which express the phospholipase A 2 may be used (and may be produced by any suitable methods such as those herein disclosed). In addition, levels of protein or mRNA expression could be tested, using any of the methods listed, in brain or other tissue removed from an experimental animal following a suitable period of / ' π vivo treatment with test compound. As an alternative to measuring changes in the expression and production of phospholipase A 2 directly, it is possible to use indirect methods. In one particular embodiment, the promoter of the gene encoding the phospholipase A 2 is linked operably to a reporter gene. In this case the change of level of expression or production of the reporter gene product will be assessed instead of the change in the level of expression or production of the phospholipase A 2 . Suitable reporter genes include β-galactosidase (which can be detected using colourless substrates which are converted to coloured products by action of the enzyme), chloramphenicol acetyl transferase (which can be detected using suitable radioactive substrates) and luciferase (which can be detected by the- fact that it can emit light under appropriate circumstances). Other suitable reporter genes are well known in the art, such as green fluorescent protein, or recombinant fusion products thereof (which are intrinsically fluorescent if provided with a suitable excitatory wavelength of light); aequorin (which catalytically generates a fluorescent product); or the Gal 4 transcription factor (which can be used to enhance expression of any other reporter gene in a two step process). The host cell for the promoter/reporter gene construct is any suitable host cell in which the promoter is functional, but it is preferred that the host cell is a cell in which the phospholipase A 2 enzyme is naturally expressed. Suitable cells include rat or human mast cells, CHO cells, glioblastoma cells, neuroblastoma cells and HEK293 (kidney) cells. By "increases the production or expression of phospholipase A 2 " we mean that the level of phospholipase A 2 is increased by at least 1.2-fold, preferably at least 2-fold, more preferably at least 5-fold and most preferably at least 10-fold. It will be appreciated that the methods of the invention are used as screening assays for compounds with the desirable properties. The compounds to be tested are any suitable compounds. In particular, the compounds may be organic molecules which have a molecular mass of less than 5000. Compounds are, preferably, soluble in water or aqueous vehicles, less preferably in biologically- compatible organic solvents such as ethanol, dimethylsulphoxide or digol, and least preferably in biologically-incompatible solvents nevertheless compatible with the assay method. The compounds selected in the assay need not be completely selective for a particular isoform of phospholipase A 2 but it is desirable that they are selective for PLA 2 s which act on phospholipids that contain DHA. It will be appreciated that the phospholipase A 2 used in the methods of the invention preferably has selectivity for the sn-2 position of the phospholipid substrate. It is particularly preferred if the phospholipase A 2 has selectivity for phosphoserine or phosphoethanolamine at the sn-3 position of the phospholipid substrate. Preferably, the phospholipase A 2 for use in the methods of the invention is a phospholipase as described in Table 1 , in particular those described in any of Murakami et al, 1992; Hara et al, 1995; Hirashima et a/, 1992; Rordorf et al, 1991; Jones and Tang 1995; Ma et al, 1997, Tang et al, 1997; Balboa et al, 1997; Larsson et al, 1998; Ma et al, 1999. While a suitable phospholipase A 2 from any suitable animal species may be used, it is desirable that the compound identified is able to activate a human phospholipase A 2 . A further aspect of the invention provides a method of selecting a drug, or a lead compound for producing a drug, useful in treating a psychiatric or neurological disorder such as depression the method comprising selecting a compound which increases the activity of phospholipase A 2 as defined in the first aspect of the invention or which increases the production or expression of phospholipase A 2 as defined in the second aspect of the invention. It is believed that the drugs found using the screening methods of the invention may be useful in a range of psychiatric disorders including depression, anxiety and schizophrenia, or in a range of neurological disorders including stroke, epilepsy and other neurodegenerative disorders. It will be appreciated that the assay methods are particularly suited to identifying drugs or a lead compound for producing a drug which may be useful for treating the approximately 30% of patients resistant to conventional antidepressant drug therapy, as mentioned above. While the compounds which are identified using the first and second aspects of the invention are useful in that they activate phospholipase A 2 or increase its production or expression in a cell, it is desirable to further select compounds as a drug-like or lead compound for producing a drug on the basis of other desirable properties. The term "drug" or "drug-like compound" is well known to those skilled in the art, and may include the meaning of a compound that has characteristics that may make it suitable for use in medicine, for example as the active ingredient in a medicament. Thus, for example, a drug-like compound may be a molecule that may be synthesised by the techniques of organic chemistry, less preferably by techniques of molecular biology or biochemistry, and is preferably a small molecule, which may be a less than 5000 daltons molecular weight, it may be water-soluble. A drug-like compound may additionally exhibit features of selective interaction with a particular protein or proteins and be bioavailable and/or able to gain access to the brain, penetrate target cellular membranes, but it will be appreciated that these features are not essential. Conveniently, the compound which is selected is one which, upon administration to a mammal, is able to reach the brain which is the site of action. Thus, it is particularly preferred if the drug-like compound or lead-compound need to pass through the blood-brain barrier. The terms "lead compound" is similarly well known to those skilled in the art, and may include the meaning that the compound, whilst not itself suitable for use as a drug (for example because it is only weakly potent against its intended target, non- selective in its action, unstable, poorly soluble, difficult to synthesise or has poor bioavilability) may provide a starting-point for the design of other compounds that may have more desirable characteristics. Suitably, the drug or lead compound is selected on the basis of further desirable properties. It is particularly preferred if the compound is selected on the basis that it activates DHA release in a brain homogenate which homogenate comprises phospholipase A 2 enzymes and brain membrane phospholipids. It is particularly preferred that the drug or lead compound is further selected on the basis that it does not activate AA release in a human homogenate which homogenate comprises phospholipase A 2 enzymes and brain membrane phospholipids. The release of AA is undesirable since it may lead to undesirable inflammation and/or neurotoxicity in the patient. It will be appreciated that the release of DHA and the release of AA may be measured in the same assay, for example by using radiolabelled phospholipids and by separating DHA from AA. It is particularly preferred if the compound is selected on the basis that it mimics the effect of ECS in an animal. For example, it is preferred if a compound is selected on the basis that it elicits in an animal a time-course of response which is substantially similar to the time-course with ECS. Such an effect, and thetimecourse for this effect, may be recognised by a potentiation of 5-methoxy-NN- dimethyltryptamine induced headtwitches, or of prolongation of swimming time in the Porsolt swim test (Porsolt et al, 1977), preferably in C57 BLJ6 mice, following drug administration 5 times over 10 days. However, efficacy in any other recognised animal model of depression or other psychiatric or neurological disorder, and any other treatment regime may be used. Preferably, efficacy should be apparent within 7 days. It is also particularly preferred if the compound is selected on the basis that, upon administration to an animal it is non-convulsive and does not lead to short-term memory loss. What constitutes seizures/convulsions is well known to those familiar with laboratory animal behaviour. Short term memory loss is preferably evaluated using the Morris water maze (Morris, 1984) or passive avoidance tests well known to those skilled in the art. A further aspect of the invention provides a method of treating a psychiatric or neurological disorder in a patient the method comprising administering an effective dose of a compound which increases the release of docosahexaenoic acid from brain membrane phospholipids. By psychiatric or neurological disorder we include depression, anxiety, schizophrenia, stroke, epilepsy and other neurodegenerative disorders. It is particularly preferred if the method is used to treat depression and/or anxiety. Preferably, the compound is one which activates phospholipase A 2 . More preferably, the compound is one which does not substantially increase the release of arachidonic acid from brain membrane phospholipids. Suitably, the compound is one which is obtainable using the assay methods of the invention. The compounds are typically made into pharmaceutical formulations. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (compound for use in the methods of the invention) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (eg povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcelluiose in varying proportions to provide desired release profile. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier. Formulations suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose or an appropriate fraction thereof, of an active ingredient. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. Any suitable route of administration may be used, including oral, rectal, intramuscular, intravenous, intraperitoneal, topical and so on. It is preferred if the compound is administered orally. The aforementioned compounds or a formulation thereof may be administered by any conventional method including oral and parenteral (eg subcutaneous or intramuscular) injection. The treatment may consist of a single dose or a plurality of doses over a period of time. Whilst it is possible for a compound for use in the treatment methods of the invention to be administered alone, it is preferable to present it as a pharmaceutical formulation, together with one or more acceptable carriers. The carrier(s) must be ^acceptable * * in the sense of being compatible with the compound of the invention and not deleterious to the recipients thereof. Typically, the carriers will be water or saline which will be sterile and pyrogen free. A still further aspect of the invention provides use of a compound which increases the release of docosahexaenoic acid from brain membrane phospholipids in the manufacture of a medicament for treating a psychiatric or neurological disorder. Preferably the disorder is depression and/or anxiety. A further aspect of the invention provides a method of treating apyschiatric or neurological disorder in a patient the method comprising administering an effective amount of docosahexaenoic acid or a compound that mimics the anti-depressant effect of docosahexaenoic acid, provided that if the method is for treating schizophrenia docosahexaenoic acid is not used in combination with arachidonic acid. Preferably, the disorder is depression and/or anxiety. A compound which mimics the anti-depressant effects of DHA is particularly useful. A still further aspect of the invention provides use of docosahexaenoic acid or a compound that mimics the anti-psychiatric or neurological disorder effect of docosahexaenoic acid in the manufacture of a medicament for treating a psychiatric or neurological disorder, provided that if the medicament is for treating schizophrenia docosahexaenoic acid is not used in combination with arachidonic acid. Preferably the disorder is despression. A compound which mimics the antidepressant effects of DHA is particularly useful. While it is contemplated that activating a specific PLA 2 isoform to release DHA, or bringing about some of the beneficial effects of ECT (such as up-regulations of 5-HT 2 binding and function) is useful, it is also contemplated that DHA release leads to changes in gene expression. We believe that DHA may mediate changes in gene expression and, in particular, that changes in gene expression mediated by DHA are via the activation of the glucorticoid receptor. There is considerable evidence which supports the view that the receptor for DHA is a member of the steroid hormone nuclear receptor family of transcription factors. Thus, DHA allosterically inhibits dexamethasone binding to glucocorticoid receptors in rat liver cytosol extracts (Sumida et al, 1993b) and increases dexamethasone-induced luciferase reported expression (Valette et al, 1995). Other fatty acids have been reported to activate gene transcription via the peroxisome proliferator-activated receptor (PPAR) nuclear receptor (Gόttlicher et al, 1992) and the aP2 gene in adipocytes is activated by fatty acids binding to a homologue of hNUC-1 nuclear receptor (Grimaldi et al, 1992). Since all of these effects of FFAs are mediated via steroid hormone nuclear receptors, it is important to note that the glucocorticoid receptor, a member of this superfamily of receptors, has been implicated in modulating δ-HT^ receptor expression. For example, hydrocortisone increases 5-HT 2 function (Buckett and Luscombe 1984) and dexamethasone increases 5-HT 2 binding in rat cortex (Kuroda et al, 1993). Additionally, 5-HT 2 binding is reduced in a "depressed" transgenic mouse in which glucocorticoid receptor expression is reduced by an antisense mRNA construct (Pepin et al, 1992a), while the tricyciic antidepressant, desipramine, increases brain glucocorticoid receptor mRNA level in the same transgenic mouse line (Pepin et al, 1992b). Finally, an elegant study has shown that 5-HT 2 promoter- luciferase reported expression is increased by dexamethasone in Neuro 2a cells (Garlow and Ciaranello, 1995). Thus, by a compound which mimics the anti-depressant effects of DHA we include, in particular, compounds which have substantially the same effect on the glucorticoid receptor as does DHA. Such compounds include ones which are able to bind to the glucocorticoid receptor and modulate the expression of the same genes that are activated by the glucocorticoid receptor when DHA is bound thereto. The glucocorticoid receptor can bind to DNA and either activate gene expression or inhibit it, depending on the location of the glucocorticoid response element with respect to the RNA polymerase binding site in the gene promotor. Specifically, corticosteroids can upregulate expression of the 5-HT 2A receptor in the hippocampus, while simultaneously downregulating expression of the 5-HT A receptor (an effect also seen with ECT). Typically, activation of these genes is assessed. A further aspect of the invention therefore includes a method of identifying a compound which mimics the effect of docosahexaenoic acid on the glucocorticoid receptor the method comprising contacting the glucocorticoid receptor with a compound and determining whether the effect of the compound is substantially the same as docosahexaenoic acid. It will be appreciated that the method may be used in order to identify compounds which are drugs or drug-like compounds or lead compounds which are useful in relation to the treatment of depression. It is also contemplated that drugs that mimic the effect of DHA may also be useful in treating other CNS disorders such as psychoses, stroke (cerebral ischaemia), head trauma, and neurodegenerative conditions. By "contacting the glucocorticoid receptor with a compound" we specifically include the possibility of contacting the glucocorticoid receptor with a compound indirectly in the sense that, typically, the glucocorticoid receptor is comprised within a cell and the compound is contacted with the cell. Conveniently, the effect of the compound is measured by determining what effect it has on the ability of the glucocorticoid receptor to modulate the expression of a gene. Many genes contain promoters which can be modulated by binding of the glucocorticoid receptor (when it itself has been activated for example by the binding of an activator such as DHA). Thus, it is particularly convenient to comDare tne effect that a test compound has on the activation of gene expression (of a gene which has a response element which is responsive to glucocorticoid receptor) to the effect that DHA has an activation of expression of the same gene. Although a cell may contain a natural genetic system in which a gene is present which contains a response element which responds to glucocorticoid receptor, and the activation of expression (by DHA or by the test compound) can be measured by measuring expression of the gene (for example, by measuring expression of its product), it is particularly desirable if the response element is operably linked to a promoter which in turn is operatively linked to a reporter gene. Thus, it is preferred if the cell used in the assay comprises a nucleic acid comprising a glucocorticoid response element operatively linked to a promoter which is operatively linked to a reporter gene. The expression of the reporter gene can be taken as a measure of the activation of the glucocorticoid receptor by the test compound (or DHA) as the case may be. As noted above in relation to earlier aspects of the invention, reporter genes such as β-galactosidase, chloramphenicol acetyltransferase and luciferase are known in the art. Luciferase is a particularly preferred reporter gene because of the sensitivity associated with light emission. A particularly preferred response element and promoter for use in expression of a reporter gene in the assay method are the response element and promoter from the 5-HT^ receptor gene. These elements from the rat 5-HT^ receptor gene are described in Garlow and Ciaranello (1995) Mol. Bain Res. 31, 201-209, incorporated herein by reference, and, indeed, the response element and promoter are described in operative linkage to a luciferase reporter gene. The human 5-HT 2A gene promoter has been cloned by Zhu et al, (1995). Four transcription initiation sites have been identified in the human gene, starting at bases: -1157, -1137, -1 127 and -496 (base +1 = A of ATG translation initiation). The transcription initiation sites at -1157, -1127 and —496 are used in brain. DNasel footprinting experiments reveal transcription factor binding sites at bases -1248 to - 1219 (upstream of the first three initiation sites), at -1109 to -891 , and at -810 to - 795 (downstream of the first three initiation sites but upstream of site 4). The transcription factor Sp1 binds to the 3' end of the firstof these footprinted sites, but its 5' end has no known transcription factor binding site and most therefore be protected by a novel transcription factor. The second footprint site contains no known transcription factor binding sites and must similarly be protected by unknown transcription factors, while the third site centres on a basic helix-loop-helix transcription factor (E-box) binding site. Transcription initiation sites 1-3 are most commonly used, and repress transcription from site 4. However, in the absence of the upstream repressor(s), site 4 is the most effective promoter. Examination of this published promoter sequence reveals a glucocorticoid receptor response element located at bases -122 to -107. However, any footprinting/DNasel protection at this site was not tested. Without being bound by any particular theory as the mechanism of the invention, as described in Figure 1 it is believed that DHA activates 5-HT2 A gene expression. Thus, a compound which acts in substantially the same way in activating 5-HT^ gene expression as does DHA may be identified by the screening assay of the invention and may be useful in the way described. It will be appreciated that the compounds identified as mimicking DHA are potential drug-like compounds or lead compounds and, as such, it is desirable for them to be selected further as suitable compounds for administration to a patient with depression or other ailment in the way described earlier. In particular, it is preferred if compounds are selected which, as well as mimicking the effect of DHA on the glucocorticoid receptor, also have similar effects as DHA when tested against other parameters which are indicative of activity against a psychiatric or neurological disorder, such as antidepressant activity. In addition, as described above, it is preferred if compounds are selected which have other desirable properties for use as drugs. Further aspects of the invention include the use of the screening methods of the invention for identifying drugs or drug-like compounds or lead compounds which are useful in (or useful in making drugs that are useful in) treating depression or other CNS ailments including psychoses, stroke, head trauma, and neurodegenerative diseases. The invention will now be described in detail with reference to the following Figure and Examples. Figure 1 shows (a) the effect of a single ECS and the fifth ECS on mouse whole brain DHA levels and (b) the effect of a single ECS and the fifth ECS on mouse whole brain AA levels. Figure 2 shows the effect of DHA (200 pmol i.c.v.) on mouse cortical 5-HT 2 receptor binding ex vivo. Figure 3 shows (a) the effects of DHA i.c.v. on 5-HT 2 receptor function in vivo and (b) the effects of AA and OA (200 pmol) i.c.v. on 5-HT 2 receptor function in vivo. Figure 4 shows the effects of ECS, DHA (400 pmol i.c.v.) and a combination of DHA, AA and OA (200 pmol each, i.c.v.) on escape behaviours in the Porsolt forced swim test. Figure 5 describes a mechanism by which DHA activates 5-HT^ receptor gene expression. Example 1 : Isolation and Purification of PLA 2 /PLB isoforms Isolation from crude whole brain extracts Phospholipase enzyme is extracted from whole brain (eg Hirashima et al, 1992; Bonventre and Koroshetz, 1993) by homogenisation of up to 1kg brain tissue, followed by centrifugation separation into cytosolic (100,000 x g supernatant), synaptosomal and microsomal fractions. Cytosolic and other fractions are partially purified by an initial DEAE toyopearl column chromatography step. Alternatively, crude fractions are treated with 40-45% ammonium sulphate to precipitate most proteins, then extracted/redissolved in 1 M potassium chloride and partially purified by Superose gel filtration chromatography (Rordorf et al, 1991 ; Bonventre and Koroshetz, 1993). Partially purified enzymes are further purified using a variety of size exclusion affinity chromatography methods (eg Ultrogel AcA 54 column, Octyl- Sepharose column, Phenyl toyopearl column). Chromatography methods of particular advantage for isolating a PLA 2 enzyme with the preferred substrate specificity described by the invention, namely a phosphatidylserine or ethanolamine hydrolysing enzyme preferentially releasing DHA from the sn-2 position, are bound substrate affinity columns (eg sn-1 acyl, sn-2 docosahexaenoyl phosphoserine/ethanoiamine, Affigel 10 columns (after Hirashima et al 1992)) or bound cofactor affinity columns (eg adenosine triphosphate-agarose affinity columns (Ackerman et al 1994) or bound heparin columns [Jones and Tang 1995]). Final purification to homogeneity is achieved with HRLC MA 7Q, hydroxyapatite, or Mono P 5/20 columns. Purification of 1 ,000 to 10,000 fold is achieved, with a yield of approximately 5%. Isolation following endogenous expression in cell lines Extraction of native enzyme constitutively expressed in a characterised cell line, possibly neural/glial origin, from human (eg MRC5, HEK 298, HeLa, Ntera2) or other mammalian species (eg monkey COS, hamster CHO or BHK, mouse 3T3 or NB41A3 neuroblastoma, rat C6 glioma, etc), is achieved by a similar protocol to that used for extraction of phospholipase A 2 /B from whole brain, except that approximately 10 11 to 10 12 cells (approximately 1kg cells, by weight) is required to provide sufficient material to purify the enzyme to homogeneity for microsequencing. Isolation of enzyme from genetically modified cells, either of vertebrate or other (eg insect) origin The selected DHA releasing phospholipase enzyme, most probably the human isoform, is expressed in a variety of cells by transfection with a synthetic DNA construct containing the coding sequence for the selected enzyme linked to regulatory DNA sequence (s) required for heterologous expression. Most vertebrate cell lines are suitable for this process, though expression using baculovirus in insect cell lines has also proven suitable (Ma et al, 1999). The synthetic DNA constructs used is either epi-chromosomal (transient transfections) or stably integrated into chromosomal DNA. A requirement of the host cells is that they must be capable of post-translational enzyme glycosylation and other modifications required for the phospholipase to gain activity equivalent to levels in native tissue. The phospholipase enzyme is purified from the genetically modified cells using similar techniques to those used for extraction of endogenously expressed enzyme from cell lines. Affinity isolation of recombinant protein As an alternative to extraction and purification of protein from genetically modified cells expressing heterologous phospholipase enzyme, recombinant enzymes(s) are created, incorporating a 'tagging' poly-histidine or similar linker sequence into the genetic construct encoding the phospholipase enzyme. These constructs must be expressed in eukaryotic cells if enzyme glycosylation and other post-translational modifications are required, but may also be expressed in suitable prokaryotic cells such as Eshericia coli. A typical extraction is described in Witmeret al. (1995), in which approximately 60 g bacteria were lysed by sonication and soluble proteins extracted/precipitated with 45% ammonium sulphate. Dialysis was used to remove the ammonium sulphate, and was followed by an initial ion exchange chromatography purification step with a Pharmacia HiLoad 26.10 Q sepharose column. This was followed by purification of the pooled active fractions on a metal chelate resin affinity column, pre-charged with zinc chloride. Under such conditions the poly-histidine tagging sequence of the recombinant enzyme interacts with the divalent ions attached to the affinity column; imidazole steps up to 1 M were used to elute the purified protein. Further purifications steps were also used to provide a stable enzyme stock, including concentration with CentriPrep 30 units and eiution from a Pharmacia Mono Q HR 5/5 column. Example 2: Assay of DHA-liberating phospholipase activity and its activation by pharmaceutical compounds The purpose of any assay used to measure phospholipase activity according to the invention is to identify compounds that activate hydrolysis of a phospholipid substrate by a normally inactive enzyme, or to enhance the hydrolytic activity of a constitutively active enzyme. The principle of the assay is to form a mixture of a phospholipid substrate containing DHA at the sn-2 position and an appropriate base (ethanolamine or serine) at the sn-3 position, candidate activator compound, and phospholipase enzyme capable of selectively releasing DHA from the substrate when activated. There are a variety of methodologies by which phospholipid hydrolysis is monitored, as described in Reynolds et al (1991). The two principal methods are detailed below. 5, 5'-dithiobis(2-nitrobenzioc acid)(DTNB) methodology This assay methodology utilises hydrolysis of a thio-ester-linked fatty acid from the sn-2 position of the substrate, in the presence of a thiol-sensitive chromophore, (such as 5,5'-dithiobis(2-nitrobenzioc acid) (DTNB)), to spectrophotometrically monitor the generation of the yellow chromophore (2-nitro-5- thiobenzoic acid) as free thiols are generated by the phospholipase enzyme activity (Yu and Dennis 1991). Micelles of an appropriate phospholipid substrate, such as sn-1-stearoyl, sn-2-thio- docosahexaenoyl phosphatidylethanoiamine (this compound is not commercially available but a suitable crude substrate may be obtained by extracting phospholipids from brain, testis, and particularly the retina, all of which have particularly high concentrations of DHA-containing phospholipids. Indeed, much of the retinal rod outer segment membrane phospholipid is comprised of di-(sn-1 , sn-2)- docosahexaenoyl phospholipid; substrates are restricted to the non-ideal dicaprylthiophosphatidylcholine, the sn-1-stearoyl, sn-2-thio-arachidonyl- phosphatidylcholine, or its alternative sn-3 substituted phosphatidylethanoiamine (available from Cayman Chemical Company, Ann Arbor, Ml 48108, USA), are mixed with Triton X-100 and bovine serum albumin in a Tris-based buffer at a pH optimal for the selected phospholipase. The buffer solution may contain up to 10mM Ca ++ if it is a requirement for enzyme activation, or it may contain up to 10mM ethyienediaminetetraacetic acid (EDTA) to chelate all traces of Ca ++ if the enzyme is not Ca ++ -dependent. Additional co-factors such as adenosine triphosphate (ATP) may also be added if required. To this is added an aqueous solution of DTNB. Test 'activator' compound may then be added, and the solution placed in a 1.0ml cuvette. After monitoring the absorbance at 405nm to set a stable baseline, a sample of the phospholipase is added, and the rate of change in absorbance measured, from which the rate of substrate hydrolysis by the enzyme can be calculated. Enhancement of the rate of substrate hydrolysis in the presence of 'activator compound', compared with the rate of hydrolysis in the presence of enzyme alone, is indicative of an activation effect. This assay can be readily reduced to a volume of 225μl, to enable it to be carried out with a degree of automation using 96 well plate technologies. This assay is not as sensitive as the radiometric assay described below. Radiolabelled fatty acid hydrolysis. This assay measures release of 1 C or 3 H radiolabelled fatty acid from a phospholipid substrate by phospholipase enzymes. It is the most widely used and most sensitive phospholipase assay. However, it has the disadvantage that the radiolabelled free fatty acid end product must be separated away from the radiolabelled substrate before quantification of the extent of reaction. A suitable phospholipase substrate, such as sn-1-stearoyl, sn-2- 14 C- docosahexaenoyl-phosphatidylethanolamine. This may be prepared as a custom synthesis by Amersham Life Sciences, or NEN Life Sciences. The [ 3 H]-labelled substrate is easier to form from purified, unlabelled phospholipid, by non-specific substitution of any hydrogen by [ 3 H]. However, the reaction is likely to saturate the carbon double bonds in the DHA. The [ 14 C] isotope labelled form of fatty acids may be synthesised eg using a biological fermentation system, and then isolate the [ 14 C]- DHA containing phospholipids subsequently; alternatively sn-1-stearoyl, sn-2- 14 C- arachidonyi-phosphatidylcholine or sn-2- 14 C-arachidonyl-phosphatidylethanolamine may be used, all of which are available from Amersham Life Sciences, UK at approximately 40-60 mCi/mmol (1.48-2.22 GBq/mmol) is prepared at 450 pmols in 20 μl of a suitable Tris-based buffer at the pH optimal for the selected phospholipase enzyme. To this is added 180 μl of the same buffer, containing 'activator compound', Ca ++ , or EDTA or ATP as required (see above). The reaction is started by adding a sample of phospholipase and incubating at 37°C for 1 hour. The reaction is stopped by adding 1 ml isohexane with 0.1% acetic acid to extract the free fatty acids. Following centrifugation to separate the organic and aqueous phases, 100 μl of the organic phase is added to sufficient scintillant and counted. Significantly enhanced liberation of free 14 C-labelled fatty acid in the presence of "activator compound", compared with release in the presence of phospholipase enzyme alone, is taken to indicate an "activator" effect. Example 3: DHA treatment mimics the effect of ECS in mice With reference to Figure 1 , C57/BL6 mice in groups of 10 were given either a single or repeated ECS (5 times over 10 days) via earclip electrodes using a Hugo Basille ECS unit, at 200V, 99mA, 250Hz, 0.9msec pulse width for 1 second. Control groups had earclip electrodes attached, but no current was passed (sham ECS). Brains were then fixed at increasing times post-ECS using head-focussed microwave radiation, and dissected free. These were then homogenised in 1 M HCI, free fatty acids extracted in 40% hexane/ 60% isopropanol, methylated overnight using Methoprep II, then analysed by gas chromatography against an internal C17:0 standard. Results are expressed as percentage change from control group whole brain free fatty acid level at each time point for docosahexaenoic acid and arachidonic acid (A and B respectively). With reference to Figure 2, C57/BL6 mice in groups of 14 were halothane anaesthetised then injected i.c.v. with 200 pmole DHA in 4 ml 0.5% digol in saline vehicle 3 times over 5 days (DHA x 3), or 5 times over 10 days (DHA x 5). Control groups received vehicle i.c.v only, using the two treatment regimens. Brains were then removed, cortical hemispheres dissected free, homogenised and membranes prepared essentially as described in Cheetham et al, (1988). 5-HT^ receptor binding was characterised with [ 3 H]-ketanserin, using 5mM methysergide to define non-specific binding. Significance from control was tested using a 2-tailed t-test; * = significant increase in 5-HT ∑A Bmax with 5 x DHA treatment (P ≤ 0.05). With reference to Figure 3, C57/BL6 mice in groups of up to 15 were halothane anaesthetised then injected i.c.v. with fatty acid in 0.5% digol in saline vehicle, or in groups of up to 25 given ECS via earclip electrodes (as described in Figure 1). Controls received either 0.5% digol in saline vehicle alone, or sham ECS treatment (as described in Figure 1). Treatment was given either on one occasion only (treatments denoted 'x 1 ') or on 5 occasions over 10 days (denoted 'x 5'). A: ECS or varying doses of docosahexaenoic acid were given, as denoted on the abscissa. B: ECS or 200 pmole doses of arachidonic acid (AA), oleic acid (OA) or docosahexaenoic acid (DHA) were given. Animals were then given 5-methyoxy-N,N, dimethyltryptamine, 2mg/kg s.c, left for 10 minutes, then the number of head twitches counted during a 30 second interval. Results are expressed as percentage difference in the number of headtwitches compared with the appropriate control group (ECS vs Sham ECS; fatty acid vs digol). Differences were analysed using Bonferroni's multiple comparison test and significances have been indicated. * p ≤ 0.05; ** p < 0.01. With reference to Figure 4, C57/BL6 mice in groups of 10 were anaethetised with brietal and given ECS 5 times over 10 days, or anaesthetised with halothane and given docosahexaenoic acid (DHA) 400 pmole, in 4 ml 0.5% digol in saline vehicle i.c.v., 5 times over 10 days, or anaesthetised with halothane and given a mixture of 200 pmoie each of docosahexaenoic acid (DHA), arachidonic acid (AA) and oleic acid (OA) in 12 ml digol vehicle, i.c.v. 5 times over 10 days. Controls received brietal and sham ECS, halothane and 4 ml digol vehicle, or halothane and 12 ml digol vehicle. 24 hours after the last treatment, animals were placed individually in circular tanks of warm water and the animal's movement estimated over a 1 minute interval using the Doppler effect of the moving water surface, measured with an overhead emitter and sensor (Buckett et al, 1982). Results are expressed as percentage difference compared with the relevant control group. Significant differences were analysed by two-way ANOVA with treatment and Doppler recorder channel as factors, followed by Wlliam's test (DHA to digol) or multiple t-test (ECS to Sham ECS and DHA/A/OA to 3x digol). * p ≤ 0.05. ECS and DHA treatment produced a significant increase in the animals' movement, which is taken to indicate an antidepressant effect. In conclusion these data demonstrate that many of the beneficial effects of ECT can be mimicked by treatment with DHA. The proposed mechanism by which we believe DHA activates SHT^ gene expression is shown in Figure 5. All components have been identified at the molecular level, and interactions of fatty acids in this system are described in the literature. 1. Extracellular DHA (released by actions of ECT or phospholipase A 2 activator) is transported to the cytosol by a fatty acid transporter. Alternatively, intracellularly released DHA remains cytosolic. 2. in the cytosol, fatty acid binding proteins (FABP) transport fatty acids between subcellular compartments (eg PS in endopiasmic reticulum is transferred to mitochondria for conversion to PE). Such a fatty acid binding protein transfers DHA to the nucleus. 3. In the nucleus, a steroid hormone nuclear receptor binds DHA. This may be a DHA specific receptor (eg orphan nuclear receptor) or the type II glucocorticoid receptor. (Glucocorticoid receptors can also bind their ligands in the cytosol then translocate to the nucleus). 4. The DHA-bound, activated nuclear receptor binds to a specific DNA recognition sequence (response element) in the promoter region of the 5-HT 2A 9 ene - 5. Nuclear receptor-DNA binding near the promoter enhances RNA polymerase (RNA poly) binding to the promoter to increase gene transcription. (Nuclear receptor-DNA binding too close to the promoter can also block RNA polymerase binding to reduce gene transcription, as for the 5-HT 1A gene). 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Claims: Claims 1. A method of identifying a compound which increases the activity of a phospholipase A 2 towards a given phospholipid substrate the method comprising determining whether the activity of phospholipase A 2 towards the given substrate is increased in the presence of a compound compared to its activity in the absence of the same compound. 2. A method of identifying a compound which increases the production or expression of phospholipase A 2 in a cell the method comprising determining directly or indirectly whether the production or expression of phospholipase A 2 in a cell is increased in the presence of a compound compared to its production or expression in the absence of the same compound. 3. A method according to Claim I or 2 wherein the phospholipase A 2 is one which is capable of releasing docosahexaenoic acid from a human brain membrane phospholipid. 4. A method according to Claim 1 or 2 wherein the phospholipase A 2 has selectively for docosahexaenoic acid at the sn-2 position of the phospholipid substrate. 5. A method according to Claim 1 or 2 wherein the phospholipase A 2 has selectively for phosphoserine or phosphoethanolamine at the sn-3 position of the phospholipid substrate. 6. A method according to Claim 1 or 2 wherein the phospholipase A 2 is any one of a calcium-independent (type VI) cytosolic phospholipase A 2 or a cytosolic phospholipase A 2 with phosphatidylserine or phosphatidylethanoiamine selectivity. 7. A method according to Claim 2 wherein the expression of phospholipase A 2 is measured indirectly using a promoter from the gene encoding the phospholipase A 2 operably linked to a reporter molecule. 8. A method according to Claim 7 wherein the phospholipase is as defined in any one of Claims 3 to 6. 9. A method of selecting a drug, or lead compound for producing a drug, useful in treating a psychiatric or neurological disorder the method comprising selecting a compound which increases the activity of phospholipase A 2 as defined in Claim 1 or which increases the production or expression of phospholipase A 2 as defined in Claim 2. 10. A method according to Claim 9 further comprising the step of determining whether the compound is capable of activating docosahexaenoic acid release in a brain homogenate which homogenate comprises phospholipase A 2 enzymes and brain membrane phospholipids and selecting a compound which substantially activates release of docosahexaenoic acid. 11. A method according to Claim 9 or 10 further comprising the step of determining whether the compound is capable of activating arachidonic acid release in a brain homogenate which homogenate comprises phospholipase A 2 enzymes and brain membrane phospholipids and selecting a compound which does not substantially activate release of arachidonic acid. 12. A method according to any one of Claims 9 to 11 further comprising the step of determining whether the compound is capable of mimicking the antidepressant effect of electroconvulsive shock in an animal. 13. Use of a compound which increases the release of docosahexaenoic acid from brain membrane phospholipids in the manufacture of a medicament for treating a psychiatric or neurological disorder. 14. Use as defined in Claim 13 wherein the compound activates phospholipase A 2 . 15. Use as defined in Claim 13 or 14 wherein the compound does not substantially increase the release of arachidonic acid from brain membrane phospholipids. 16. Use as defined in any one of Claims 13 to 15 wherein the compound is obtainable by the method of any one of Claims 1 to 12. 17. A method of treating a psychiatric or neurological disorder in a patient the method comprising administering an effective dose of a compound which increase the release of docosahexaenoic acid from brain membrane phospholipids. 18. A method of treating a psychiatric or neurological disorder in a patient the method comprising administering an effective amount of docosahexaenoic acid or a compound that mimics the anti-pyschiatric or neurological disorder effect of docosahexaenoic acid, provided that if the method is for treating schizophrenia docosahexaenoic acid is not used in combination with arachidonic acid. 19. Use of docosahexaenoic acid or a compound that mimics the anti-psychiatric or neurological disorder effect of docosahexaenoic acid in the manufacture of a medicament for treating a psychiatric or neurological disorder provided that if the medicament is for treating schizophrenia docosahexaenoic acid is not used in combination with arachidonic acid. 20. A method of identifying a compound which mimics the effect of docosahexaenoic acid on the glucocorticoid receptor the method comprising contacting the glucocorticoid receptor with a compound and determining whether the compound has substantially the same effect as docosahexaenoic acid on the glucocorticoid receptor. 21. A method according to Claim 20 wherein the glucocorticoid receptor is comprised within a cell and the cell is contacted with the compound. 22. A method according to Claim 21 wherein the cell comprises a nucleic acid construct comprising a glucocorticoid response element operatively linked to a promoter which is operatively linked to a reporter gene. 23. A method according to Claim 22 wherein the glucocorticoid response element and promoter are from the 5-HT^ receptor gene. 24. A method according to Claim 22 or 23 wherein the reporter gene is luciferase. 25. Any novel screening assay for compounds usefui in treating a psychiatric or neurological disorder as herein described. 26. Any novel method of treating a psychiatric or neurological disorder as herein described.

Inventors: HEAL DAVID JOHN, MARTIN KEITH FRANK, THOMPSON KEVIN STUART JOHN, HEAL, DAVID, JOHN, MARTIN, KEITH, FRANK, THOMPSON, KEVIN, STUART, JOHN
Applicants: HEAL DAVID JOHN, KNOLL AG, MARTIN KEITH FRANK, THOMPSON KEVIN STUART JOHN, HEAL, DAVID, JOHN, KNOLL AKTIENGESELLSCHAFT, MARTIN, KEITH, FRANK, THOMPSON, KEVIN, STUART, JOHN
Application year: 1999
Main classification: G01N33
IPC codes: A61K31, A61K45, A61P25, C12N9, C12N15, C12Q1, G01N33