No abstract

The mitochondrial benzodiazepine receptor (mBzR)

The decrement in dopamine levels exceeds the loss of dopaminergic neurons in Parkinson's disease (PD) patients and experimental models of PD. This discrepancy is poorly understood and may represent an important event in the pathogenesis of PD. Herein, we report that the ratelimiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), is a selective target for nitration following exposure of PC12 cells to either peroxynitrite or 1-methyl-4-phenylpyridiniun ion (MPP ؉ ). Nitration of TH also occurs in mouse striatum after MPTP administration. Nitration of tyrosine residues in TH results in loss of enzymatic activity. In the mouse striatum, tyrosine nitration-mediated loss in TH activity parallels the decline in dopamine levels whereas the levels of TH protein remain unchanged for the first 6 hr post MPTP injection. Striatal TH was not nitrated in mice overexpressing copper͞zinc superoxide dismutase after MPTP administration, supporting a critical role for superoxide in TH tyrosine nitration. These results indicate that tyrosine nitration-induced TH inactivation and consequently dopamine synthesis failure, represents an early and thus far unidentified biochemical event in MPTP neurotoxic process. The resemblance of the MPTP model with PD suggests that a similar phenomenon may occur in PD, inf luencing the severity of parkisonian symptoms.Parkinson's disease (PD) is a common neurodegenerative disorder characterized by disabling motor abnormalities attributed to a profound deficit in dopamine (1). The decline in dopamine level has been thought to arise solely from the severe loss of dopaminergic neurons in the nigrostriatal pathway. However, the dopamine deficit in the affected regions of the brain significantly exceed the loss of dopaminergic neurons (2, 3), suggesting that dopamine synthesis is impaired before cellular demise. Support for this hypothesis comes from studies of experimental models of PD demonstrating that the reduction in dopamine metabolism-related markers such as tyrosine hydroxylase (TH) and dopamine transporter is far greater than the loss of neuronal cell bodies (4-6). Because the severity of PD symptoms correlates with the magnitude of dopamine deficit, elucidating mechanisms that impair dopamine synthesis and metabolism in neurons that undergo selective degeneration in PD may have important therapeutic implications.There is experimental evidence from studies of humans and animals in support of the hypothesis that oxidative stress contributes to the pathogenesis of PD (7). Studies performed in the MPTP model of PD suggest that peroxynitrite, a reactive species formed by the nearly diffusion-limited reaction of nitric oxide with superoxide, may be a mediator of nigrostriatal damage in PD (8-10). The potential role of peroxynitrite in the pathogenesis of PD is further supported by demonstrating that exposure of the monoamine-producing PC12 cells to peroxynitrite induced a dose-dependent alteration in dopamine synthesis that was not due to cell death or the oxidation of dopamine (11)....

Background and Purpose: Nitric oxide has been implicated as a mediator of glutamate excitotoxicity in primary neuronal cultures.Methods: A number of indicators of brain nitric oxide production (nitrite and cyclic guanosine monophosphate [cGMP] concentrations and nitric oxide synthase activity) were examined after bilateral carotid ligation and right middle cerebral artery occlusion in adult rats.Results: Brain nitrite was significantly increased in the right versus left cortex 5, 10, and 20 minutes after middle cerebral artery occlusion (P<.05), with a return to baseline at 60 minutes. There were no significant changes in cerebellar concentrations. Cortical levels of cGMP were increased at 10, 20, and 60 minutes after occlusion, with significant right-to-left differences (P<.05). Cerebellar concentrations of cGMP were also increased but without significant side-to-side differences. Nitric oxide synthase activity increased approximately 10-fold from baseline 10 minutes after occlusion in the right cortex but decreased markedly by 60 minutes from its peak at 10 minutes. The right-to-left difference in nitric oxide synthase activity was significant at 20 minutes (P<.05). Pretreatment of rats with NG-nitro-L-arginine, a nitric oxide synthase inhibitor, abolished the rise in nitrite and cGMP.Conclusions: These results suggest that a sharp transient increase in the activity of nitric oxide synthase occurs during the first hour of cerebral ischemia, which leads to a burst in nitric oxide production and activation of guanylate cyclase. (Stroke. 1993;24:1709-1716 KEY WORDs * cerebral arteries * cerebral ischemia * nitric oxide

The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.

The objective of this study was to assess brain involvement through the presence of antineuronal antibodies in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) and in uncomplicated active Group A streptococcal infection. We compared serum antibrain antibody to human basal ganglia sections assessed by indirect tissue immunofluorescence in two groups: a PANDAS group, comprised of 22 patients (mean age 10.1 years; 20 male, 2 female) who met strict National Institutes of Mental Health diagnostic criteria for PANDAS and had clinically active tics or obsessive-compulsive disorder, or both; and a GABHS control group consisting of 22 patients (mean age 9.1 years; 15 mol/L, 7 female) with clinical evidence of active Group A beta-hemolytic streptococcal (GABHS) infection confirmed by throat culture and elevated antistreptolysin O titers but without history or clinical evidence of tics or obsessive-compulsive disorder. We observed positive anti-basal ganglia staining (defined as detectable staining at 1:10 serum dilution) in 14/22 patients in the PANDAS group (64%) but only 2/22 (9%) in the GABHS control group (P < 0.001, Fisher's exact test). These results suggest that antibrain antibodies are present in children with PANDAS that cannot be explained merely by a history of GABHS infection.

The highly potent bell pepper odorant 2-isobutyl-3-[3H]methoxypyrazine ([3HJIBMP) binds specifically and saturably to bovine and rat nasal epithelium. Specific binding is not detected in 11 other tissues assayed, and in the rat binding is 9 times higher in olfactory than in respiratory epithelium. We have purified to apparent homogeneity a soluble pyrazine odorant binding protein that constitutes ;1% of the total soluble protein in bovine nasal epithelium. Preparation of Bovine Tissue. Cow nasal epithelia were obtained from a local slaughterhouse within 2 hr of killing. Nasal tissue was dissected from the cribriform plate to a point three-fourths of the distance to the external nares. This dissection included primary olfactory sensory neurons and respiratory tissues. Typically, dissection of a single cow nose yielded 50 g of tissue (wet weight, excluding cartilage and bone) containing 1.2 g of protein.The tissue was suspended in 2 vol of ice-cold 50 mM Tris buffer (pH 7.7 at 250C), minced finely with scissors, homogenized in a Waring blender for 30 sec, and homogenized in a Brinkmann Polytron for 30 sec. For studies on crude preparations, the suspension was centrifuged at 40,000 x g for 20 min at 4TC, and the supernatant was assayed directly. For purification studies, the suspension was centrifuged at 20,000 x g for 10 min at 4TC. The pellet was resuspended in Tris buffer, recentrifuged, and the supernatant fractions were pooled.Binding 3050The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Streptococcal infection in children is usually benign and self-limited. In a small percentage of children, prominent neurologic and/or psychiatric sequelae can occur. Sydenham chorea is the best defined and best recognized. PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) is a well-defined syndrome in which tics (motor and/or vocal) and/or obsessive-compulsive disorder consistently exacerbate in temporal correlation to a group A beta-hemolytic streptococcal infection. PANDAS constitutes a subset of children with tics, Tourette syndrome, and obsessive-compulsive disorder. In addition to strictly defined PANDAS, we and others have recognized several PANDAS variants, including adult-onset variant, a dystonic variant, a myoclonic variant, and a "chronic" PANDAS variant. The nosology and classification of these entities are rapidly evolving. The recognition that some pediatric neurobehavioral syndromes have infectious and/or immunologic triggers points to important new avenues of disease treatment. In this review, we summarize this complex and rapidly evolving area of clinical research.