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Title: The novel tetramethylpyrazine bis-nitrone (TN-2) protects against MPTP/MPP+-induced neurotoxicity via inhibition of mitochondrial-dependent apoptosis
Authors: Xu, D
Duan, H
Zhang, Z
Cui, W
Wang, L
Sun, Y
Lang, M
Hoi, PM
Han, Y 
Wang, Y
Lee, SMY
Keywords: Parkinson's disease
Dopaminergic neuron
Mitochondrial-dependent apoptosis
Issue Date: 2014
Publisher: Springer
Source: Journal of neuroimmune pharmacology, 2014, v. 9, no. 2, p. 245-258 How to cite?
Journal: Journal of neuroimmune pharmacology
Abstract: 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.
ISSN: 1557-1890
EISSN: 1557-1904
DOI: 10.1007/s11481-013-9514-0
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