دانلود رایگان مقاله تغییر انتشار گلوتامات در جسم مخطط پشتی بیماری پارکینسون

Abstract

Mitochondrial dysfunction has been implicated in the degeneration of dopamine (DA) neurons in Parkinson's disease (PD). In addition, animal models of PD utilizing neurotoxins, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have shown that these toxins disrupt mitochondrial respiration by targeting complex I of the electron transport chain, thereby impairing DA neurons in these models. A MitoPark mouse model was created to mimic the mitochondrial dysfunction observed in the DA system of PD patients. These mice display the same phenotypic characteristics as PD, including accelerated decline in motor function and DAergic systems with age. Previously, these mice have responded to L-Dopa treatment and develop L-Dopa induced dyskinesia (LID) as they age. A potential mechanism involved in the formation of LID is greater glutamate release into the dorsal striatum as a result of altered basal ganglia neurocircuitry due to reduced nigrostriatal DA neurotransmission. Therefore, the focus of this study was to assess various indicators of glutamate neurotransmission in the dorsal striatum of MitoPark mice at an age in which nigrostriatal DA has degenerated. At 28 weeks of age, MitoPark mice had, upon KCl stimulation, greater glutamate release in the dorsal striatum compared to control mice. In addition, uptake kinetics were slower in MitoPark mice. These findings were coupled with reduced expression of the glutamate re-uptake transporter, GLT-1, thus providing an environment suitable for glutamate excitotoxic events, leading to altered physiological function in these mice.

4. Conclusions

Taken together, these data demonstrate that MitoPark mice have greater glutamate release, reduced glutamate uptake, and increased mGluR5 expression, all of which may lead to excitotoxicity. Future studies will be conducted to determine at what age glutamate release and uptake are altered in MitoPark mice and if the co-administration of a glutamate receptor antagonist in combination with L-Dopa will inhibit or reduce the formation of dyskinetic behavior.