Neuroprotective effect of CPDT on THA-induced cortical motor neuron death in an organotypic culture model.
Brain stroke, trauma, and motor neuron disease each can result in cortical motoneuron (CMN) death or impairment. Glutamate excitotoxicity induces motor neuron damage in both acute motor neuron loss and chronic motor neuron degeneration. It is necessary to find effective strategies to protect CMNs from excitotoxicity in a variety of pathological conditions. 5,6-Dihydrocyclopenta-1,2-dithiole-3-thione (CPDT) is one of the phase II enzyme inducers. In our previous report, CPDT was shown to have neuroprotective effects on the spinal cord, by activating the Nrf2/ARE pathway to increase antioxidative capacity. In this study, in order to figure out whether CPDT can prevent CMN's from THA-induced death, we set up an organotypic brain slice culture system. Threo-hydroxyaspartate (THA), a glutamate transport inhibitor, was added to the culture medium to induce CMN death by glutamate excitotoxicity. Brain slices were pretreated with CPDT for 48h, then treated with CPDT and THA simultaneously for 3 weeks. We found that pretreatment with CPDT significantly increased CMN survival. Glutamate concentration in the culture medium was significantly greater following THA treatment, whereas no significant decrease was found in the CPDT pretreatment group. However, both Nrf2 and HO-1 protein expression was significantly elevated in the CPDT pretreatment group, and Nrf2 protein translocated to the nucleus after CPDT stimulation. These findings suggest that CPDT can protect CMNs from THA-induced motor neuron death by activating the Nrf2 pathway and increasing HO-1 protein expression. Therefore, increasing antioxidative defense capacity should benefit to upper motor neuron survival following a glutamate excitotoxicity insult.
Liu
Xiao-Yun
XY
Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province 05000, China.
Li
Chun-Yan
CY
Bu
Hui
H
Li
Zhe
Z
Li
Bin
B
Sun
Meng-Meng
MM
Zhang
Li
L
Tian
Miao
M
Fan
Zhi-Liang
ZL
Ren
Wen-Bo
WB
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D009044:Motor Cortex / Q000166:cytology*; D009046:Motor Neurons / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats
D001427:Bacterial Toxins; C029352:Clostridium perfringens delta-toxin; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; C011274:3-hydroxyaspartic acid; D001224:Aspartic Acid; D018698:Glutamic Acid; D051547:Heme Oxygenase-1