Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation.
Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative disorders such as Parkinson's disease (PD). γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has recently been shown to play an inhibitory role in the immune system. Tiagabine, a piperidine derivative, enhances GABAergic transmission by inhibiting GABA transporter 1 (GAT 1). In the present study, we found that tiagabine pretreatment attenuated microglial activation, provided partial protection to the nigrostriatal axis and improved motor deficits in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The protective function of tiagabine was abolished in GAT 1 knockout mice that were challenged with MPTP. In an alternative PD model, induced by intranigral infusion of lipopolysaccharide (LPS), microglial suppression and subsequent neuroprotective effects of tiagabine were demonstrated. Furthermore, the LPS-induced inflammatory activation of BV-2 microglial cells and the toxicity of conditioned medium toward SH-SY5Y cells were inhibited by pretreatment with GABAergic drugs. The attenuation of the nuclear translocation of nuclear factor κB (NF-κB) and the inhibition of the generation of inflammatory mediators were the underlying mechanisms. Our results suggest that tiagabine acts as a brake for nigrostriatal microglial activation and that it might be a novel therapeutic approach for PD.
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.|Research Center for Translational Medicine and Institute of Heart Failure, East Hospital, Tongji University, Shanghai 200120, China.
Jie
J
Liu
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Dongping
D
Huang
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Jing
J
Xu
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Jiabin
J
Tong
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Zishan
Z
Wang
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Li
L
Huang
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Yufang
Y
Yang
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Xiaochen
X
Bai
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Pan
P
Wang
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Haiyun
H
Suo
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Yuanyuan
Y
Ma
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Mei
M
Yu
School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.|Shanghai Research Center for Model Organisms, Pudong, Shanghai 201203, China.
Jian
J
Fei
The State Key Laboratory of Medical Neurobiology, the Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.|Key Laboratory of Smart Drug Delivery, Fudan University, Ministry of Education, Shanghai 201203, China.
Fang
F
Huang
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D020267:MPTP Poisoning / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D009118:Muscimol / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000633:toxicity*; D009557:Nipecotic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000078308:Tiagabine
D050485:GABA Plasma Membrane Transport Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009557:Nipecotic Acids; D009118:Muscimol; D001418:Baclofen; D000078308:Tiagabine