The Novel Tetramethylpyrazine Bis-nitrone (TN-2) Protects Against MPTP/MPP+-Induced Neurotoxicity via Inhibition of Mitochondrial-Dependent Apoptosis

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• 作者：Daping Xu (1)
  Hongwei Duan (2)
  Zaijun Zhang (1) (2) (3) (5)
  Wei Cui (3)
  Liang Wang (1) (2)
  Yewei Sun (2)
  Ming Lang (2)
  Pui Man Hoi (1)
  Yifan Han (3)
  Yuqiang Wang (2)
  Simon MingYuen Lee (1) (4)
  
• 关键词：Parkinson’s disease ; MPTP ; Dopaminergic neuron ; Mitochondrial ; dependent apoptosis
• 刊名：Journal of Neuroimmune Pharmacology
• 出版年：2014
• 出版时间：March 2014
• 年：2014
• 卷：9
• 期：2
• 页码：245-258
• 全文大小：4,672 KB
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• 作者单位：Daping Xu (1)
  Hongwei Duan (2)
  Zaijun Zhang (1) (2) (3) (5)
  Wei Cui (3)
  Liang Wang (1) (2)
  Yewei Sun (2)
  Ming Lang (2)
  Pui Man Hoi (1)
  Yifan Han (3)
  Yuqiang Wang (2)
  Simon MingYuen Lee (1) (4)
  
  1. State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Tomás Pereira S.J., Macao, SAR, China
  2. Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Guangzhou, 510632, China
  3. Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, Hong Kong Polytechnic University, Hong Kong, China
  5. Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, China
  4. Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
  
• ISSN：1557-1904

文摘

Mitochondrial-dependent apoptosis plays an important role in the degeneration of dopaminergic neurons in Parkinson’s disease (PD). Methyl-4-phenyl-1,2,3,6-tetra- hydropyridine (MPTP), the most widely used neurotoxin to simulate PD, is converted to 1-methyl-4-phenylpyridinium (MPP+) in vivo. MPP+ induces excessive intracellular reactive oxygen species (ROS), leading to mitochondrial-dependent apoptosis via sequentially opening mitochondria permeability transition pore (mPTP) to release cytochrome c from mitochondria into cytoplasm and activate pro-apoptotic caspase proteins. We have previously synthesized 2,5-[[(1,1-dimethylethyl)oxidoimino]methyl]-3,6-trimethylpyrazine (TN-2), a novel derivative of the Chinese herb medicine tetramethylpyrazine (TMP). TN-2 is armed with two powerful free radical-scavenging nitrone moieties. TN-2 significantly reversed the loss of dopaminergic neurons in the substantia nigra and the decrease in dopamine level in the striatum induced by MPTP in mice. TN-2 ameliorated the MPTP-induced decrease of brain superoxide dismutase activity and glutathione concentration and increase of brain malondialdehyde. In addition, TN-2 inhibited MPP+-induced neuronal damage/apoptosis in primary cerebellum granular neurons (CGNs) and SH-SY5Y cells. TN-2 decreased excessive intracellular ROS, prevented the loss of mitochondrial membrane potential, blocked the release of mitochondrial cytochrome c and inhibited the activation of caspase-3 and caspase-9. Moreover, TN-2 treatment increased the mRNA expression of mitochondrial biogenesis factors peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1 (PGC- 1α and β) and mitochondrial transcription factor A (Tfam) in SH-SY5Y cells and CGNs. These results suggest that TN-2 protects dopaminergic neurons against MPTP/MPP+-induced neurotoxicity via the inhibition of mitochondrial-dependent apoptosis and possibly via the activation of mitochondrial biogenesis, indicating that TN-2 is a potential new treatment for PD.