bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroprotective effects of non‐steroidal anti‐inflammatory drugs by direct scavenging of nitric oxide radicals
Authors: Asanuma Masato , Nishibayashi‐Asanuma Sakiko , Miyazaki Ikuko , Kohno Masahiro , Ogawa Norio 
Published: March 2003

Recently, it has been reported that inflammatory processes are associated with the pathophysiology of Alzheimer's disease and that treatment of non‐steroidal anti‐inflammatory drugs reduce the risk for Alzheimer's disease. In the present study, we examined nitric oxide radical quenching activity of non‐steroidal anti‐inflammatory drugs and steroidal drugs using our established direct in vitro nitric oxide radical detecting system by electron spin resonance spectrometry. The non‐steroidal anti‐inflammatory drugs, aspirin, mefenamic acid, indomethacin and ketoprofen directly and dose‐dependently scavenged generated nitric oxide radicals. In experiments of nitric oxide radical donor, NOC18‐induced neuronal damage, these four non‐steroidal drugs significantly prevented the NOC18‐induced reduction of cell viability and apoptotic nuclear changes in neuronal cells without affecting the induction of inducible nitric oxide synthase‐like immunoreactivity. However, ibuprofen, naproxen or steroidal drugs, which had less or no scavenging effects in vitro, showed almost no protective effects against NOC18‐induced cell toxicity. These results suggest that the protective effects of the former four non‐steroidal anti‐inflammatory drugs against apoptosis might be mainly due to their direct nitric oxide radical scavenging activities in neuronal cells. These direct NO· quenching activities represent novel effects of non‐steroidal anti‐inflammatory drugs. Our findings identified novel pharmacological mechanisms of these drugs to exert not only their anti‐inflammatory, analgesic, antipyretic activities but also neuroprotective activities against neurodegeneration.
A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid β‐peptide
Authors: Culmsee Carsten , Zhu Xiaoxiang , Yu Qian‐Sheng , Chan Sic L. , Camandola Simonetta , Guo Zhihong , Greig Nigel H. , Mattson Mark P. 
Published: March 2003

The tumor suppressor protein p53 is essential for neuronal death in several experimental settings and may participate in human neurodegenerative disorders. Based upon recent studies characterizing chemical inhibitors of p53 in preclinical studies in the cancer therapy field, we synthesized the compound pifithrin‐α and evaluated its potential neuroprotective properties in experimental models relevant to the pathogenesis of stroke and neurodegenerative disorders. Pifithrin‐α protected neurons against apoptosis induced by DNA‐damaging agents, amyloid β‐peptide and glutamate. Protection by pifithrin‐α was correlated with decreased p53 DNA‐binding activity, decreased expression of the p53 target gene Bax and suppression of mitochondrial dysfunction and caspase activation. Mice given pifithrin‐α exhibited increased resistance of cortical and striatal neurons to focal ischemic injury and of hippocampal neurons to excitotoxic damage. These preclinical studies demonstrate the efficacy of a p53 inhibitor in models of stroke and neurodegenerative disorders, and suggest that drugs that inhibit p53 may reduce the extent of brain damage in related human neurodegenerative conditions.
Aging alters the multichemical networking profile of the human brain: an in vivo1H‐MRS study of young versus middle‐aged subjects
Authors: Grachev Igor D. , Swarnkar Amar , Szeverenyi Nikolaus M. , Ramachandran Tarakad S. , Apkarian A. Vania 
Published: March 2003

In our most recent study of normal aging, we found decreased concentration of multiple chemicals in the brain of middle‐aged subjects, as compared with younger subjects using in vivo proton magnetic resonance spectroscopy (1H‐MRS). We hypothesized that these age‐dependent differences in brain chemistry changes might be a reflection of the multichemical‐networking‐profile (MCNP) changes during aging. Using 1H‐MRS and correlation analysis, we examined the patterns of regional chemical levels and MCNP within and across multiple brain regions for all nine chemicals of 1H‐MR spectra. The brain chemistry changes and MCNP patterns were compared between 21 young (19–31‐year‐old) and 31 middle‐aged (40–52‐year‐old) normal volunteers. Middle‐aged subjects demonstrated a significant decrease of chemical levels in the prefrontal cortex and sensorimotor cortex (SMC), as compared with the young age group. Of these, neurotransmitters GABA and glutamate in the dorsolateral prefrontal cortex (DLPFC) were altered the most. We also found a significant increase of overall chemical correlation strength in MCNP within and across all studied brain regions with increased age. These changes were caused by alterations in the pattern of negative chemical connectivity across brain regions, which become weaker (less negative) in middle‐aged subjects. The interregional chemical connectivity for the cingulate cortex, SMC and the thalamus was changed the most with increased age. Increased levels of chemical correlation strength across brain regions in aging were found for most chemicals studied (including neurotransmitters GABA and glutamate), and not for N‐acetyl aspartate. These age‐related differences in the connectivity of neurotransmitters were not region dependent. The results suggest that aging is associated with changes of the regional brain chemistry and the brain MCNP. The latter process may reflect an adaptive or compensatory response (possibly related to the elongation of dendrites with aging) to reduced levels of regional brain chemicals. The 1H‐MRS approach proposed here can be used as a valuable tool in the study of the brain chemistry, MCNP and their relationships in normal and abnormal aging.
G protein‐coupled receptor kinase 2 mediates µ‐opioid receptor desensitization in GABAergic neurons of the nucleus raphe magnus
Authors: Li Allen H. , Wang Hung‐Li 
Published: March 2003

Nucleus raphe magnus (NRM) sends the projection to spinal dorsal horn and inhibits nociceptive transmission. Analgesic effect produced by µ‐opioid receptor agonists including morphine partially results from activating the NRM‐spinal cord pathway. It is generally believed that µ‐opioid receptor agonists disinhibit spinally projecting neurons of the NRM and produce analgesia by hyperpolarizing GABAergic interneurons. In the present study, whole‐cell patch‐clamp recordings combined with single‐cell RT‐PCR analysis were used to test the hypothesis that DAMGO ([D‐Ala2,N‐methyl‐Phe4,Gly‐ol5]enkephalin), a specific µ‐opioid receptor agonist, selectively hyperpolarizes NRM neurons expressing mRNA of glutamate decarboxylase (GAD67). Homologous desensitization of µ‐opioid receptors in NRM neurons could result in the development of morphine‐induced tolerance. G protein‐coupled receptor kinase (GRK) is believed to mediate µ‐opioid receptor desensitization in vivo. Therefore, we also investigated the involvement of GRK in mediating homologous desensitization of DAMΑΜGO‐induced electrophysiological effects on NRM neurons by using two experimental strategies. First, single‐cell RT‐PCR assay was used to study the expression of GRK2 and GRK3 mRNAs in individual DAMGO‐responsive NRM neurons. Whole‐cell recording was also performed with an internal solution containing the synthetic peptide, which corresponds to Gβγ‐binding domain of GRK and inhibits Gβγ activation of GRK. Our results suggest that DAMGO selectively hyperpolarizes NRM GABAergic neurons by opening inwardly rectifying K+ channels and that GRK2 mediates short‐term homologous desensitization of µ‐opioid receptors in NRM GABAergic neurons.
Reduced activation and expression of ERK1/2 MAP kinase in the post‐mortem brain of depressed suicide subjects
Authors: Dwivedi Y. , Rizavi H. S. , Roberts R. C. , Conley R. C. , Tamminga C. A. , Pandey G. N. 
Published: March 2003

The extracellular regulated kinases (ERK) 1 and ERK2 are members of mitogen‐activated protein (MAP) kinase family that play an important role in transducing extracellular signals to the nucleus and have been implicated in a broad spectrum of biological responses. To test the hypothesis that MAP kinases may be involved in depression, we examined the activation of p44/42 MAP kinase and expression of ERK1 and ERK2 in the post‐mortem brain tissue obtained from non‐psychiatric control subjects (n = 11) and age‐ and the post‐mortem interval‐matched depressed suicide subjects (n = 11). We observed that p44/42 MAP kinase activity was significantly decreased in the prefrontal cortical areas (Brodmann's areas 8, 9 and 10) and the hippocampus of depressed suicide subjects without any change in the cerebellum. This decrease was associated with a decrease in mRNA and protein levels of ERK1 and ERK2. In addition, the expression of MAP kinase phosphatase (MKP)2, a ‘dual function’ ERK1/2 phosphatase, was increased in the prefrontal cortex and hippocampus. These studies suggest that p44/42 MAP kinases are less activated in the post‐mortem brain of depressed suicide subjects and this may be because of reduced expression of ERK1/2 and increased expression of MKP2. Given the role of MAP kinases in various physiological functions and gene expression, alterations in p44/42 MAP kinase activation and expression of ERK1/2 may contribute significantly to the pathophysiology of depressive disorders.
Cytokine‐induced cell death in immortalized Schwann cells: roles of nitric oxide and cyclic AMP
Authors: Nagano Sukehisa , Takeda Margaret , Ma Lan , Soliven Betty 
Published: March 2003

Tumor necrosis factor‐α and interferon‐γ are pleiotropic cytokines that regulate Schwann cell responses during injury and inflammatory demyelination. We have previously shown that cyclic AMP (cAMP)‐elevating agents decrease the demyelination and Wallerian degeneration in experimental allergic neuritis. In this study, we examined the role of cAMP in cytokine‐mediated signaling in a spontaneously immortal Schwann cell clone (iSC). We found that tumor necrosis factor‐α and interferon‐γ exert synergistic inhibitory action on Schwann cell viability via the production of nitric oxide (NO) and ceramide (cer). Furthermore, we found that: (i) NO synthase inhibitors attenuate the cytokine‐induced cer accumulation and cell death indicating that NO acts upstream of cer; and (ii) cytokine‐induced cell death is decreased in iSCs pretreated continuously for 48–72 h with forskolin, an activator of adenylate cyclase. Although forskolin modulates the phosphorylation of ERKs and Akt, it decreases the susceptibility of iSC to cytokines via a separate mechanism operating after NO induction and before cer accumulation. We propose that the protective effect of cAMP‐elevating agents in experimental allergic neuritis may be mediated in part via modulation of Schwann cell responses to cytokines.
Dependence of excitotoxic neurodegeneration on mitochondrial aconitase inactivation
Authors: Li Qing‐You , Pedersen Cynthia , Day Brian J. , Patel Manisha 
Published: March 2003

Using the inactivation of mitochondrial and cytosolic aconitases as markers of compartment‐specific superoxide (O2−) production, we show that oxygen‐glucose deprivation (OGD) or excitotoxin exposure produce a time‐dependent inactivation of mitochondrial, but not cytosolic, aconitase in cortical cultures. To determine if mitochondrial O2− production was an important determinant in neuronal death resulting from OGD, metalloporphyrins with varying superoxide dismutase (SOD) activity were tested for their ability to protect against mitochondrial aconitase inactivation and cell death. OGD‐induced mitochondrial aconitase inactivation and cell death was inhibited by manganese tetrakis (4‐benzoic acid) porphyrin (MnTBAP), manganese tetrakis (N‐ethylpyridinium‐2‐yl) porphyrin (MnTE‐2‐PyP) and NMDA receptor antagonists. By contrast, NMDA‐ or kainate (KA)‐induced mitochondrial aconitase inactivation and cell death was inhibited by MnTBAP, but not MnTE‐2‐PyP. Moreover, both MnTBAP and MnTE‐2‐PyP penetrated mitochondrial fractions of cortical cells. These data suggest that mitochondrial aconitase inactivation closely correlates with subsequent neuronal death following excitotoxicity produced by OGD or NMDA/KA exposure. Assessment of biological rather biochemical antioxidant activities better predicted neuroprotection by metalloporphyrins. Moreover, antioxidants that protect oxidant‐sensitive mitochondrial targets such as aconitase may be useful as therapies for disease states involving excitotoxicity.
Evaluation of neurotoxicity of TIQ and MPTP and of parkinsonism‐preventing effect of 1‐MeTIQ by in vivo measurement of pre‐synaptic dopamine transporters and post‐synaptic dopamine D2 receptors in the mouse striatum
Authors: Ishiwata Kiichi , Koyanagi Yasuhiro , Abe Kenji , Kawamura Kazunori , Taguchi Kyoji , Saitoh Toshiaki , Toda Jun , Senda Michio , Sano Takehiro 
Published: March 2003

Parkinsonism‐inducing neurotoxicity of 1,2,3,4‐tetrahydroisoquinoline (TIQ), as contrasted to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), and parkinsonism‐preventing effect of 1‐methyl‐1,2,3,4‐tetrahydroisoquinoline (1‐MeTIQ) have been investigated in mice by measuring their effects on the in vivo binding of radioligand to pre‐synaptic dopamine transporters (DATs) or to dopamine D2 receptors (D2R) in the striatum. A significant reduction of the ligand‐DATs binding was found in the mice treated with MPTP, but not with TIQ, under the dosage inducing behavioral abnormality and loss of tyrosine hydroxylase‐positive cells in the substantia nigra. A slight decrease in the ligand‐DATs binding was observed in the mice given a larger dose of TIQ. Compensatory up‐regulation in the post‐synaptic D2Rs was found in the MPTP‐treated mice. Pre‐treatment with (S)‐enantiomer, but not (R)‐enantiomer, of 1‐MeTIQ prevented the degeneration of DATs to some extent. We concluded that the TIQ‐induced parkinsonism model is different from the MPTP‐induced model as evaluated by the radioligand‐DATs binding and that (S)‐1‐MeTIQ has a preventing effect for the degeneration of the DATs to a certain extent.
Long‐term behavioral and neurochemical effects of chronic stress exposure in rats
Authors: Mangiavacchi Simona , Masi Flavio , Scheggi Simona , Leggio Benedetta , De Montis M. Graziella , Gambarana Carla 
Published: March 2003

Rats exposed to acute unavoidable stress develop a deficit in escaping avoidable aversive stimuli that lasts as long as unavoidable stress exposure is repeated. A 3‐week exposure to unavoidable stress also reduces dopamine (DA) output in the nucleus accumbens shell (NAcS). This study showed that a 7‐day exposure to unavoidable stress induced in rats an escape deficit and a decrease in extraneuronal DA basal concentration in the NAcS. Moreover, animals had reduced DA and serotonin (5‐HT) accumulation after cocaine administration in the medial pre‐frontal cortex (mPFC) and NAcS, compared with control animals. After a 3‐week exposure to unavoidable stress, escape deficit and reduced DA output in the NAcS were still significant at day 14 after the last stress administration. In the mPFC we observed: (i) a short‐term reduction in DA basal levels that was back to control values at day 14; (ii) a decrease in DA accumulation at day 3 followed by a significant increase beyond control values at day 14; (iii) a significant reduction in 5‐HT extraneuronal basal levels at day 3, but not at day 14. Finally, a significant decrease in 5‐HT accumulation following cocaine administration was present in the NAcS and mPFC at day 3, but not at day 14. In conclusion, a long‐term stress exposure induced long‐lasting behavioral sequelae associated with reproducible neurochemical modifications.
Co‐administration of IGF‐I and glycosaminoglycans greatly delays motor neurone disease and affects IGF‐I expression in the wobbler mouse: a long‐term study
Authors: Gorio Alfredo , Lesma Elena , Madaschi Laura , Di Giulio Anna Maria 
Published: March 2003

AbstractThe study on wobbler mouse has shown that the combined treatment with low doses of glycosaminoglycans (GAGs) and insulin‐like growth factor‐I (IGF‐I) fully prevented motor neurone death and forelimb impairment up to 9–12 weeks of a mouse's life. The effect was accompanied by the prevention of the early hypertrophy of wobbler neurones, an effect likely due to the promotion of neuronal survival. At the 18th week, wobbler mice treated with IGF‐I + GAGs still showed significantly improved forelimb function, reduced muscle atrophy and a higher number of cervical motor neurones. IGF‐I alone and GAGs alone were active up to the 3rd week of treatment; thereafter the beneficial effects of single treatments decreased drastically. GAGs and IGF‐I treatments also affected IGF‐I plasma and muscle levels. In wobbler mice there was a progressive reduction in IGF‐I plasma levels that was prevented by IGF‐I or GAGs alone and greatly increased, even above heterozygote levels, by the combination treatment. Such a powerful increase was correlated by a small enhancement in insulin‐like growth factor binding protein‐3 (IGFBP‐3) plasma levels, while treatment with IGF‐I alone affected very significantly both IGFBP‐1 and IGFBP‐3. Co‐treatment also prevented the decrease in IGF‐I content observed in vehicle‐treated wobbler mice forelimb muscles.
Expression of the neonatal Fc receptor (FcRn) at the blood–brain barrier
Authors: Schlachetzki Felix , Zhu Chunni , Pardridge William M. 
Published: March 2003

AbstractThe blood–brain barrier (BBB) restricts transport of immunoglobulin G (IgG) in the blood to brain direction. However, IgG undergoes rapid efflux in the brain to blood direction via reverse transcytosis across the BBB after direct intracerebral injection. This BBB IgG transport system has the characteristics of an Fc receptor (FcR), but there is no molecular information on the putative BBB FcR. The present study uses confocal microscopy and an antibody to the rat neonatal FcR (FcRn), and demonstrates the expression of the FcRn at the brain microvasculature and choroid plexus epithelium. Co‐localization with the Glut1 glucose transporter indicates the brain microvascular FcRn is expressed in the capillary endothelium. The capillary endothelial FcRn may mediate the ‘reverse transcytosis’ of IgG in the brain to blood direction.
Mass‐spectrometric analysis of myelin proteolipids reveals new features of this family of palmitoylated membrane proteins
Authors: Bizzozero Oscar A. , Malkoski Steve P. , Mobarak Charlotte , Bixler Heather A. , Evans James E. 
Published: March 2003

AbstractIn this study, we have investigated the structure of the native myelin proteolipid protein (PLP), DM‐20 protein and several low molecular mass proteolipids by mass spectrometry. The various proteolipid species were isolated from bovine spinal cord by size‐exclusion and ion‐exchange chromatography in organic solvents. Matrix‐assisted laser desorption ionization‐time of flight‐mass spectrometry (MALDI–TOF–MS) of PLP and DM‐20 revealed molecular masses of 31.6 and 27.2 kDa, respectively, which is consistent with the presence of six and four molecules of thioester‐bound fatty acids. Electrospray ionization‐MS analysis of the deacylated proteins in organic solvents produced the predicted molecular masses of the apoproteins (29.9 and 26.1 kDa), demonstrating that palmitoylation is the major post‐translational modification of PLP, and that the majority of PLP and DM‐20 molecules in the CNS are fully acylated. A series of myelin‐associated, palmitoylated proteolipids with molecular masses raging between 12 kDa and 18 kDa were also isolated and subjected to amino acid analysis, fatty acid analysis, N‐ and C‐terminal sequencing, tryptic digestion and peptide mapping by MALDI–TOF–MS. The results clearly showed that these polypeptides correspond to the N‐terminal region (residues 1–105/112) and C‐terminal region (residues 113/131–276) of the major PLP, and they appear to be produced by natural proteolytic cleavage within the 60 amino acid‐long cytoplasmic domain. These proteolipids are not postmortem artifacts of PLP and DM‐20, and are differentially distributed across the CNS.
Inhibitors of nitric oxide synthase attenuate nerve growth factor‐mediated increases in choline acetyltransferase expression in PC12 cells
Authors: Kalisch Bettina E. , Bock Nicholas A. , Davis Wanda L. , Rylett R. Jane 
Published: March 2003

AbstractNGF can regulate nitric oxide synthase (NOS) expression and nitric oxide (NO) can modulate NGF‐mediated neurotrophic responses. To investigate the role of NO in NGF‐activated expression of cholinergic phenotype, PC12 cells were treated with either the nonselective NOS inhibitor l‐NAME (N ω‐nitro‐l‐arginine methylester) or the inducible NOS selective inhibitor MIU (s‐methylisothiourea), and the effect on NGF‐stimulated ChAT mRNA levels and ChAT specific activity was determined. NGF increased steady‐state levels of mRNA and protein for both inducible and constitutive isozymes of NOS in PC12 cells, and led to enhanced NOS activity and NO production. MIU and, to a lesser extent, l‐NAME blocked neurite outgrowth in nerve growth factor (NGF)‐treated PC12 cells. Both l‐NAME and MIU attenuated NGF‐mediated increases in choline transferase (ChAT)‐specific activity and prevented the increase in expression of ChAT mRNA normally produced by NGF treatment of PC12 cells. The present study indicates that NO may be involved in the modulation of signal transduction pathways by which NGF leads to increased ChAT gene expression in PC12 cells.
Protein synthesis in synaptosomes: a proteomics analysis
Authors: Jiménez C. R. , Eyman M. , Lavina Z. Scotto , Gioio A. , Li K. W. , Van Der Schors R. C. , Geraerts W. P. M. , Giuditta A. , Kaplan B. B. , Van Minnen J. 
Published: March 2003

AbstractA proteomics approach was used to identify the translation products of a unique synaptic model system, squid optic lobe synaptosomes. Unlike its vertebrate counterparts, this preparation is largely free of perikaryal cell fragments and consists predominantly of pre‐synaptic terminals derived from retinal photoreceptor neurones. We metabolically labelled synaptosomes with [35S]methionine and applied two‐dimensional gel electrophoresis to resolve newly synthesized proteins at high resolution. Autoradiographs of blotted two‐dimensional gels revealed de novo synthesis of about 80 different proteins, 18 of which could be matched to silver‐stained gels that were run in parallel. In‐gel digestion of the matched spots and mass spectrometric analyses revealed the identities of various cytosolic enzymes, cytoskeletal proteins, molecular chaperones and nuclear‐encoded mitochondrial proteins. A number of novel proteins (i.e. not matching with database sequences) were also detected. In situ hybridization was employed to confirm the presence of mRNA and rRNA in synaptosomes. Together, our data show that pre‐synaptic endings of squid photoreceptor neurones actively synthesize a wide variety of proteins involved in synaptic functioning, such as transmitter recycling, energy supply and synaptic architecture.