The Study On The Role Of γ-aminobutyric Acid (GABA)Ergic Agents In Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. The pathologic hallmark of PD is the progressive loss of pigmented, dopaminergic neuron of the substantia nigra in the mesencephalon. Neural inflammation and over activation of microglia are closely related to the development and progression of neurodegenerative disease. Inhibition of microglia over activation has been proven to be therapeutic in PD. y-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter in the mammalian central nervous system. Neural protective effects of GABAergic enhancement have already been demonstrated, such as anti-excitotoxicity and anti-apoptosis. The therapeutic implications of GABA agonists on ischemia, epilepsy, Huntington’s disease and Alzheimer’s disease have also been reported. Recent study showed that GABAergic system also plays a major inhibitory role in the immune system. So it is reasonable to speculate that those neural protective effects of GABA will also be beneficial to the Parkinson’s disease.To know whether GABA agonists affect the neural inflammation progress in Parkinson’s disease and whether these agents are beneficial to the treatment of PD. Three representative GABAergic agents were selected:the GABAA receptor agonist muscimol, the GABB receptor agonist baclofen and the GABA transporter-1 (GAT-1) inhibitor tiagabine. Mouse microglia cell line BV-2 was used to study the effect of these GABA agents on microglial activation in vitro; LPS-induced brain inflammation model and MPTP-induced PD model were also applied to study the effects of these GABA agents on the in vivo inflammation as well as the progression of PD.Our results were demonstrated as follows:1. GAT-1 inhibitor tiagabine ameliorates MPTP induced nigrostriatal neural toxicity, reduces the degenerating neuron and improves the motor deficits in mice. GAT-1 knockout blocks these protective effects of tiagabine. Muscimol and baclofen failed to protect nigrostriatal pathway from MPTP toxicity; 2. GABA, muscimol, baclofen and tiagabine inhibit LPS induced BV-2 microglial activation in vitro. And further study elucidated that these effects were achieved by blocking the NF-kB signal pathway; 3. Muscimol, baclofen and tiagabine inhibit LPS induced microglial activation and ameliorate dopaminergic neuron loss in the substantia nigra.The neural protection and anti-inflammatory property of tiagabine demonstrated in our study indicate that it could be a potential treatment to PD. And the inhibitory role of muscimol and baclofen on microglial activation showed in our study also provide new evidence to the anti-inflammatory role of GABAergic system in the immune system.