The novel tetramethylpyrazine bis-nitrone (TN-2) protects against MPTP/MPP+-induced neurotoxicity via inhibition of mitochondrial-dependent apoptosis.
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.
Daping
D
Xu
Hongwei
H
Duan
Zaijun
Z
Zhang
Wei
W
Cui
Liang
L
Wang
Yewei
Y
Sun
Ming
M
Lang
Pui Man
PM
Hoi
Yifan
Y
Han
Yuqiang
Y
Wang
Simon MingYuen
SM
Lee
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020267:MPTP Poisoning / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D011719:Pyrazines; C017953:tetramethylpyrazine