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