title: Ethyl pyruvate ameliorates 3-nitropropionic acid-induced striatal toxicity through anti-neuronal cell death and anti-inflammatory mechanisms.
abstract: The potential neuroprotective value of ethyl pyruvate (EP) for the treatment of the striatal toxicity is largely unknown. We investigated whether EP promotes the survival of striatal neurons in a 3-nitropropionic acid (3-NP)-induced mouse model of Huntington's disease (HD). EP (5, 10, 20, and 40mg/kg/day, i.p.) was daily injected from 30min before 3-NP intoxication (pretreatment) and from onset/progression/peak point of neurological impairment by 3-NP intoxication. EP produced a neuroprotective effect in dose- and time-dependant manners. EP pretreatment of 40mg/kg/day produced the best neuroprotective effect among other conditions. Pretreatment of EP significantly attenuated neurological impairment and lethality and prevented formation of lesion area and neuronal loss in the striatum after 3-NP intoxication. This neuroprotection afforded by EP was associated with the suppression of succinate dehydrogenase activity, apoptosis, and microglial activation. The suppressive effect of EP corresponded to the down-regulation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) signal pathways, and mRNA expression of inflammatory mediators including tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, and cyclooxygenase-2 in the striatum after 3-NP intoxication. Interestingly, the intrathecal introduction of inhibitors MAPKs and NF-κB into control mice decreased the lethality after 3-NP intoxication. Our findings indicate that EP may effectively alleviate 3-NP-induced striatal toxicity by inhibition of the MAPKs and NF-κB pathways in the striatum, and that EP has a wide therapeutic window, suggesting that EP may have therapeutic value in the treatment of aspects of HD's disease related to inflammation.
authors.affiliation: Department of Convergence Medical Science, College of Oriental Medicine, and Institute of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Cancer Preventive Material Development, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Minhee
authors.initials: M
authors.lastname: Jang
authors.affiliation: Department of Convergence Medical Science, College of Oriental Medicine, and Institute of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Cancer Preventive Material Development, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Convergence Medical Science, College of Oriental Medicine, and Institute of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: ihcho@khu.ac.kr.
authors.forename: Ik-Hyun
authors.initials: IH
authors.lastname: Cho
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009574:Nitro Compounds / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D011773:Pyruvates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D011773:Pyruvates; C046522:ethyl pyruvate; C015392:3-nitropropionic acid
keywords: 3-Nitropropionic acid; Ethyl pyruvate; Huntington’s disease; Microglia; Mitogen-activated protein kinases; Nuclear factor-kappa B