bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a Hoxd10‐regulated transcriptional network and combinatorial interactions with Hoxa10 during spinal cord development
Authors: Hedlund Eva , Karsten Stanislav L. , Kudo Lili , Geschwind Daniel H. , Carpenter Ellen M. 
Published: January 2004

AbstractHoxd10 is expressed in the posterior spinal cord and hindlimbs of the mouse. Hoxd10, along with other Hox transcription factors, is thought to regulate the activity of genes involved in nervous system patterning and motor neuron development, but little is known about the downstream targets regulated by this gene. cDNA microarrays were used to investigate the transcriptional network regulated by Hoxd10 in homozygous knockout animals. Sixty‐nine genes were identified with altered expression levels in mutant spinal cords. Among these were genes involved in such diverse cellular events as cellular communication, cell cycle control, development and differentiation, and neuronal survival. The expression of some of these genes was investigated using reverse transcriptase‐polymerase chain reaction (RT‐PCR) and in situ hybridization. Nine genes showed changes in expression of the same sign and similar magnitude using RT‐PCR in Hoxd10 single mutant animals, with additional changes in expression seen in Hoxa10/Hoxd10 double mutant animals. In situ hybridization studies also demonstrated changes in expression consistent with microarray results. Analysis of putative promoter regions for Hox protein binding sites suggested that some genes may be direct Hoxd10 targets, whereas others likely are regulated through intermediate steps. Using cDNA microarrays to study a single gene knockout during critical developmental stages has identified a large number of genes regulated by Hoxd10, many of which would not have been approached as candidates for Hox gene regulation based on function or expression. © 2004 Wiley‐Liss, Inc.
Protein kinase A and calcium/calmodulin‐dependent protein kinase II regulate glycine and GABA release in auditory brain stem nuclei
Authors: Zhang J. , Suneja S.K. , Potashner S.J. 
Published: January 2004

AbstractWe reported previously that unilateral cochlear ablation (UCA) in young adult guinea pigs induced protein kinase C (PKC)‐dependent plastic changes in the electrically evoked release of exogenous [14C]glycine ([14C]Gly) or [14C]‐γ‐aminobutyric acid ([14C]GABA) in several brain stem auditory nuclei. The present study assessed whether such changes depended on protein kinase A (PKA) and calcium/calmodulin‐dependent protein kinase II (CaMKII). In the major subdivisions of the cochlear nucleus (CN) and the main nuclei of the superior olivary complex (SOC) dissected from intact animals, dibutyryl‐cyclic adenosine monophosphate (DBcAMP) (0.2 mM), a PKA activator, elevated release by 1.6–2.3‐fold. The PKA inhibitor, H‐89 (2 μM), did not alter the release but blocked the stimulatory effects of DBcAMP. These findings suggested that PKA could positively regulate glycinergic and GABAergic release. After UCA, PKA regulation declined and failed in the ventral CN but persisted in the SOC nuclei. After 145 postablation days, H‐89 reversed elevations of [14C]GABA release in the medial nucleus of the trapezoid body (MNTB). A CaMKII inhibitor, KN‐93, reversed depressions of [14C]Gly release in the DCN. Thus, the postablation plasticities in these nuclei probably depended on PKA or CaMKII. Both H‐89 and KN‐93 depressed [14C]Gly release in the lateral superior olive (LSO) and ipsilateral medial superior olive (MSO), suggesting that either kinase was used by endogenous mechanisms in these nuclei to upregulate glycinergic release. In contrast, KN‐93 elevated [14C]GABA release in the contralateral MNTB, suggesting a downregulatory action of CaMKII, an action opposite to that of PKA. © 2003 Wiley‐Liss, Inc.
Kynurenic acid synthesis in cerebral cortical slices of rats with progressing symptoms of thioacetamide‐induced hepatic encephalopathy
Authors: Saran Tomasz , Hilgier Wojciech , Urbańska Ewa M. , Turski Waldemar A. , Albrecht Jan 
Published: January 2004

AbstractIncreased ammonia is a major pathogenic factor in hepatic encephalopathy (HE), a neurologic syndrome associated with glutamatergic dysfunction. Previous studies have shown that in rat cerebral cortical slices or a glia‐derived cell line, acute treatment with ammonia in vitro and in vivo inhibits the production of a broad‐spectrum antagonist of excitatory amino acid receptors, kynurenic acid (KYNA). The present study analyzed KYNA synthesis in cerebral cortical slices obtained from rats with progressing HE symptoms accompanying acute liver failure induced by one, two, or three intraperitoneal administrations of thioacetamide (TAA) at 24‐hr intervals. KYNA synthesis was found decreased to 83% of control 24 hr after one administration of TAA and unaffected after two TAA injections, when moderate hyperammonemia was associated by metabolic and bioelectric activation of the central nervous system, but was not accompanied by typical HE symptoms. KYNA synthesis was elevated to 155% of control after three TAA administrations, a period in which the rats showed advanced HE symptoms including stupor or coma. KYNA synthesis at the advanced HE stage was inhibited by glutamate in a degree comparable to that observed in control slices. The elevation of KYNA synthesis was associated with increased activity of a kynurenine aminotransferase (KAT) isomer, KAT‐II. KYNA synthesis did not differ from control 21 days after the third TAA administration when HE symptoms receded. The results suggest that alterations of KYNA synthesis may contribute to the imbalance between neural excitation and inhibition at different stages of HE. © 2003 Wiley‐Liss, Inc.
Increased transcription and activity of glutathione synthase in response to deficiencies in folate, vitamin E, and apolipoprotein E
Authors: Tchantchou Flaubert , Graves Michael , Ashline David , Morin Amy , Pimenta Aurea , Ortiz Daniela , Rogers Eugene , Shea Thomas B. 
Published: January 2004

AbstractOxidative stress is a major contributing factor in neurodegeneration and can arise from dietary, environmental, and genetic sources. Here we examine the separate and combined impact of deprivation of folate and vitamin E, coupled with dietary iron as a prooxidant, on normal mice and transgenic mice lacking apolipoprotein E (ApoE–/– mice). Both mouse strains exhibited increased levels of glutathione when deprived of folate and vitamin E, but a substantial further increase was observed in ApoE–/– mice. To determine the mechanism(s) underlying this increase, we quantified transcription and activity of glutathione synthase (GS). Both normal and ApoE–/– mice demonstrated increased GS activity when deprived of folate and vitamin E. However, transcription was increased only in ApoE–/– mice deprived of folate and vitamin E. These findings demonstrate that deficiency in one gene can result in compensatory up‐regulation in a second relevant gene and, furthermore, indicate that compensation for oxidative stress can occur in brain tissue at epigenetic and genetic levels depending on the nature and/or extent of oxidative stress. © 2004 Wiley‐Liss, Inc.
Graded reoxygenation with chemical inhibition of oxidative phosphorylation improves posthypoxic recovery in murine hippocampal slices
Authors: Huber Roman , Spiegel Tobias , Büchner Maren , Riepe Matthias W. 
Published: January 2004

AbstractRapid and complete tissue reoxygenation is a prime goal of present stroke therapy. However, reoxygenation may trigger detrimental cascades that partially antagonize beneficial effects. It was our goal to investigate selective grading of reoxygenation with targeting of single mitochondrial complexes in murine hippocampal slices. Population spike amplitude (PSAP) and NADH were measured during hypoxic hypoxia (15 min) and recovery (45 min). With onset of reoxygenation, slices were treated for different times with amobarbital (1 mM), malonate (2 mM), or cyanide (1 mM), inhibitors of mitochondrial complex I, II, or IV, respectively. Other slices were treated with nicotinamide (1 mM). Posthypoxic recovery of PSAP increased from 32% ± 43% of onset in control slices to 52% ± 59% (P < .05) upon treatment with amobarbital for 1 min and to 62% ± 37% (P < .05) upon treatment with malonate. With nicotinamide, posthypoxic recovery improved to 73% ± 25% (P < .05). Oxidation of NADH was prolonged upon treatment with amobarbital, whereas no change in NADH oxidation was observed with malonate and nicotinamide. Thus, grading of reoxygenation with selective targeting of mitochondrial complex I or II but not of complex IV improves outcome upon reoxygenation in murine hippocampal slices. © 2003 Wiley‐Liss, Inc.
Chronic exposure to aluminum in drinking water increases inflammatory parameters selectively in the brain
Authors: Campbell A. , Becaria A. , Lahiri D.K. , Sharman K. , Bondy S.C. 
Published: January 2004

AbstractA link between aluminum (Al) exposure and age‐related neurological disorders has long been proposed. Although the exact mechanism by which the metal may influence disease processes is unknown, there is evidence that exposure to Al causes an increase in both oxidative stress and inflammatory events. These processes have also been suggested to play a role in Alzheimer's disease (AD), and exposure to the metal may contribute to the disorder by potentiating these events. Al lactate (0.01, 0.1, and 1 mM) in drinking water for 10 weeks increased inflammatory processes in the brains of mice. The lowest of these levels is in the range found to increase the prevalence of AD in regions where the concentrations of the metal are elevated in residential drinking water (Flaten [2001] Brain Res. Bull. 55:187–196). Nuclear factor‐κB as well as tumor necrosis factor‐α (TNF‐α) and interleukin 1α (IL‐1α) levels were increased in the brains of treated animals. The mRNA for TNF‐α was also up‐regulated following treatment. Enhancement of glial fibrillary acidic protein levels and reactive microglia was seen in the striatum of Al‐treated animals. The level of amyloid beta (Aβ40) was not significantly altered in the brains of exposed animals. Insofar as no parallel changes were observed in the serum or liver of treated animals, the proinflammatory effects of the metal may be selective to the brain. Al exposure may not be sufficient to cause abnormal production of the principal component of senile plaques directly but does exacerbate underlying events associated with brain aging and thus could contribute to progression of neurodegeneration. © 2004 Wiley‐Liss, Inc.
Biphasic form of experimental autoimmune neuritis in dark agouti rats and its oral therapy by antigen‐specific tolerization
Authors: Jung Stefan , Gaupp Stefanie , Korn Thomas , Köllner Gabriele , Hartung Hans‐Peter , Toyka Klaus V. 
Published: January 2004

AbstractA new and biphasic form of experimental autoimmune neuritis (EAN) is described in dark agouti rats (DA rats) and is inducible by a single immunization with bovine peripheral nerve myelin (BPM) in complete Freund's adjuvant (DA‐EAN). Animals develop a mild episode of disease; after recovery, 66–100% of the rats suffer from a more severe bout of EAN with paraparesis 25–30 days after immunization. By histology, DA‐EAN is an inflammatory and demyelinating polyradiculoneuropathy virtually without axonal damage. Demyelination affects mainly spinal roots. This is also reflected by markedly increased F‐wave latencies in nerve conduction studies of sciatic nerves. In sciatic nerves, inflammation and demyelination are found only focally and may be the histopathologic basis for conduction failure in some fibers. Immunologic investigations revealed stronger proliferative responses of DA than of Lewis rat lymph node cells to BPM and various peptides derived from the P2 protein. Proliferative and Th1‐cytokine responses were particularly pronounced in spleen during the late phase of DA‐EAN as compared to the monophasic EAN of Lewis rats. The data suggest that persistent lymphocyte proliferation with secretion of interferon (IFN)‐γ may be relevant for the relapsing course of DA‐EAN whereas epitope spreading may explain the increased severity of the second bout of disease. The extended Th1 response in DA rats did not go along with a lack of downregulatory mechanisms, because the second DA‐EAN attack was self‐limited and splenocytes from DA rats produced considerable amounts of interleukin (IL)‐10 and transforming growth factor (TGF)‐β. To substantiate further a functional immunoregulation in DA rats, we modulated DA‐EAN by antigen‐specific oral tolerization, which is known to involve active suppressor mechanisms. Preventive feeding of BPM in combination with cholera toxin (CT) induced a long‐lasting resistance to DA‐EAN. Even therapeutic administration of BPM or BPM/CT after onset of signs of disease significantly mitigated the further course of disease and prevented development of paraparesis. Because DA‐EAN is easily inducible and leads consistently to relapses in most rats, it can be used for studies of immune factors that determine a relapsing course of autoimmunity. Furthermore, DA‐EAN may serve as a model for relapsing inflammatory demyelinating polyneuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) and for treatment studies. Our findings on effective prevention and therapy of DA‐EAN by oral application of myelin/CT corroborate this form of immunomodulation as a treatment strategy for cell‐mediated processes in chronic inflammatory neuropathies. © 2003 Wiley‐Liss, Inc.
Semi‐chronic increase in striatal level of 3,4‐dihydroxyphenylacetaldehyde does not result in alteration of nigrostriatal dopaminergic neurones
Authors: Legros Hélène , Janin François , Dourmap Nathalie , Bonnet Jean‐Jacques , Costentin Jean 
Published: January 2004

AbstractThis work was carried out to evaluate the potential in vivo toxicity of 3,4‐dihydroxyphenylacetaldehyde (DOPAL), an aldehyde formed from dopamine by monoamine oxidase (MAO) that is oxidised mainly to 3,4‐dihydroxyphenylacetic acid (DOPAC) by brain aldehyde dehydrogenases (ALDH). In this study, male Sprague‐Dawley rats were treated with levodopa (L‐dopa)‐benserazide, which increases DOPAL production by MAO, and disulfiram, an irreversible inhibitor of ALDH, which reduces the formation of DOPAC from DOPAL. An acute systemic intraperitoneal (i.p.) injection of 100 mg/kg disulfiram and L‐dopa‐benserazide (100 mg/kg + 25 mg/kg, 24 hr later) significantly increased DOPAL striatal level. A 30‐day treatment with disulfiram (100 mg/kg i.p., once every 2 days) and L‐dopa‐benserazide (100 mg/kg + 25 mg/kg, two times/day) did not affect either indexes used to assess integrity of the nigrostriatal dopaminergic neurones (i.e., the striatal content in dopamine and binding to the vesicular monoamine transporter on striatal membranes). These results do not evidence any deleterious effect of DOPAL and argue against toxicity of L‐dopa therapy. © 2004 Wiley‐Liss, Inc.
CRE‐mediated gene transcription in the peri‐infarct area after focal cerebral ischemia in mice
Authors: Sugiura Shiro , Kitagawa Kazuo , Omura‐Matsuoka Emi , Sasaki Tsutomu , Tanaka Shigeru , Yagita Yoshiki , Matsushita Kohji , Storm Daniel R. , Hori Masatsugu 
Published: January 2004

AbstractCyclic AMP response element binding protein (CREB) is a transcription factor expressed constitutively primarily in neurons and is activated by phosphorylation at Ser133 residue. CREB mediates expression of several neuroprotective proteins, including B‐cell CLL/lymphoma 2 (BCL‐2) and brain‐derived neurotrophic factor (BDNF). Although phosphorylation of CREB after ischemia has been investigated extensively, CRE‐mediated gene transcription after ischemia is not as well studied. We investigated temporal changes in CRE‐mediated gene transcription in the cerebral cortex after focal ischemia in transgenic mice with a CRE‐lacZ reporter gene. In the ischemic core, X‐gal‐positive cells, which reflected expression of the CRE‐lacZ reporter gene, were observed rarely at any time point, though transient phosphorylation of CREB was detected. In contrast, the peri‐infarct area showed a persistent increase in the number of X‐gal‐positive cells, of which more than half were positive for neuronal nuclei (NeuN). Our results suggest that CRE‐mediated gene transcription, the pattern of which is not always consistent with that of CREB phosphorylation, occurs primarily in neurons in the peri‐infarct area after focal cerebral ischemia and may be a neuroprotective response against ischemic insult. © 2003 Wiley‐Liss, Inc.
Apoptotic characteristics of cell death and the neuroprotective effect of homocarnosine on pheochromocytoma PC12 cells exposed to ischemia
Authors: Tabakman Rinat , Jiang Hao , Levine Robert A. , Kohen Ron , Lazarovici Philip 
Published: January 2004

AbstractWe recently improved an in vitro ischemic model, using PC12 neuronal cultures exposed to oxygen‐glucose deprivation (OGD) for 3 hr in a special device, followed by 18 hr of reoxygenation. The cell death induced in this ischemic model was evaluated by a series of markers: lactate dehydrogenase (LDH) release, caspase‐3 activation, presence of cyclin D1, cytochrome c leakage from the mitochondria, BAX cellular redistribution, cleavage of poly (ADP‐ribose) polymerase (PARP) to an 85‐kDa apoptotic fragment, and DNA fragmentation. The OGD insult, in the absence of reoxygenation, caused a strong activation of the mitogen‐activated protein kinase (MAPK) isoforms extracellular regulated kinase (ERK), c‐Jun NH2‐terminal kinase (JNK), and stress‐activated protein kinase (SAPK), also known asp‐38. The detection of apoptotic markers and activation of MAPKs during the ischemic insult strongly suggest that apoptosis plays an important role in the PC12 cell death. Homocarnosine, a neuroprotective histidine dipeptide, present in high concentrations in the brain, was found to provide neuroprotection, as expressed by a 40% reduction in LDH release and caspase‐3 activity at 1 mM. Homocarnosine reduced OGD activation of ERK 1, ERK 2, JNK 1, and JNK 2 by 40%, 46%, 55%, and 30%, respectively. These results suggest that apoptosis is an important characteristic of OGD‐induced neuronal death and that antioxidants, such as homocarnosine, may prevent OGD‐induced neuronal death by inhibiting the apoptotic process and/or in relation to the differential attenuation of activity of MAPKs. © 2004 Wiley‐Liss, Inc.
Mutational analysis of neurotensin in familial restless legs syndrome
Authors: Desautels Alex , Turecki Gustavo , Xiong Lan , Rochefort Daniel , Montplaisir Jacques , Rouleau Guy A. 
Published: January 2004

AbstractA susceptibility locus for restless legs syndrome (RLS) has been identified recently on chromosome 12q. This region contains several transcribed genes including neurotensin (NTS), which, as an important modulator of the dopaminergic transmission, represents a strong functional and positional candidate in the context of RLS. In this study, NTS was evaluated for mutational analysis. A panel of 19 individuals from 4 families supporting linkage to 12q was investigated using a combined denaturing high‐performance liquid chromatography (dHPLC) and direct sequencing method. Analysis of the NTS genomic sequence revealed 2 intronic polymorphisms and 1 variant located in the 5′ untranslated region (UTR). None of the observed variants co‐segregated with RLS and no disease‐associated polymorphisms were detected in any of the analyzed families. Based on these results, it is unlikely that NTS is the gene responsible for RLS in chromosome 12‐linked families. © 2003 Movement Disorder Society
One‐Hz repetitive transcranial magnetic stimulation of the premotor cortex alters reciprocal inhibition in DYT1 dystonia
Authors: Huang Ying‐Zu , Edwards Mark J. , Bhatia Kailash P. , Rothwell John C. 
Published: January 2004

AbstractRepetitive transcranial magnetic stimulation (rTMS) can produce long‐lasting effects not only underneath the site of stimulation, but also at distant connected sites. This study aimed to assess how low frequency rTMS over the premotor area might affect abnormalities in spinal motor function in patients with generalised dystonia associated with the DYT1 gene mutation. We assessed reciprocal inhibition (RI) in a group of 8 manifesting carriers of the DYT1 gene (DYT1) and 10 healthy controls. All subjects then received 20 minutes of 1 Hz rTMS over the premotor area, and RI was assessed again. Before rTMS, the second and third phases of RI were abnormal in DYT1 subjects compared to controls. After 20 minutes of 1 Hz rTMS over the premotor area, a significant increase in inhibition was noted in the third and possibly the first phase of RI in the DYT1 group. No changes in RI were observed in control subjects after rTMS. We have shown for the first time to date that reducing cortical excitability in patients with dystonia using rTMS can produce corresponding changes in abnormal spinal motor output. These findings make a case for further exploring rTMS as a tool to modulate abnormal cortical and spinal excitability in individuals with dystonia and even as a potential form of treatment for dystonic symptoms. © 2003 Movement Disorder Society
Effects of subthalamic nucleus stimulation on characteristics of EMG activity underlying reaction time in Parkinson's disease
Authors: Kumru Hatice , Summerfield Christopher , Valldeoriola Francesc , Valls‐Solé Josep 
Published: January 2004

AbstractWe examined the effects of high‐frequency deep brain stimulation of the subthalamic nucleus (STN‐DBS) on characteristics of electromyographic (EMG) activity of the agonist muscle in 8 patients with Parkinson's disease (PD). Patients were examined during STN‐DBS (ON), and 30 minutes after switching off both stimulators (OFF). They were asked to make a ballistic movement in paradigms of simple reaction time (SRT) and choice reaction time (CRT) tasks. Onset of movement (MOVonset) was measured as the latency of the initial displacement from baseline of the signal from an accelerometer attached to the dorsum of the hand. In the associated EMG activity, recorded from wrist extensor muscles, we measured onset latency (EMGonset), size of the first EMG burst (EMGsize), and number of EMG bursts (EMGbursts) counted between EMGonset and task execution. MOVonset and EMGonset were significantly shorter in ON than in OFF conditions in CRT. EMGsize was larger, EMGbursts were reduced, and peak of the acceleration profile was larger in ON compared with OFF conditions in both SRT and CRT. Our results indicate that STN‐DBS induces a significant improvement in motor performance of reaction time tasks in PD patients. Such improvement is associated with a change in features of the EMG activity suggesting an increase in the excitability of the motor pathways engaged in ballistic movements. © 2003 Movement Disorder Society