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* Brain Disease Research Center and
Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea;
Division of Neurology, Department of Medicine, University of British Columbia Hospital, University of British Columbia, Vancouver, British Columbia, Canada; and
Sensory Research Group, Creative Research Initiatives, Seoul National University, College of Pharmacy, Seoul, Korea
The present study examined the expression of transient receptor potential vanilloid subtype 1 (TRPV1) in microglia, and its association with microglial cell death. In vitro cell cultures, RT-PCR, Western blot analysis, and immunocytochemical staining experiments revealed that rat microglia and a human microglia cell line (HMO6) showed TRPV1 expression. Furthermore, exposure of these cells to TRPV1 agonists, capsaicin (CAP) and resiniferatoxin (RTX), triggered cell death. This effect was ameliorated by the TRPV1 antagonists, capsazepine and iodo-resiniferatoxin (I-RTX), suggesting that TRPV1 is directly involved. Further examinations revealed that TRPV1-induced toxicity was accompanied by increases in intracellular Ca2+, and mitochondrial damage; these effects were inhibited by capsazepine, I-RTX, and the intracellular Ca2+ chelator BAPTA-AM. Treatment of cells with CAP or RTX led to increased mitochondrial cytochrome c release and enhanced immunoreactivity to cleaved caspase-3. In contrast, the caspase-3 inhibitor z-DEVD-fmk protected microglia from CAP- or RTX-induced toxicity. In vivo, we also found that intranigral injection of CAP or 12-hydroperoxyeicosatetraenoic acid, an endogenous agonist of TRPV1, into the rat brain produced microglial damage via TRPV1 in the substantia nigra, as visualized by immunocytochemistry. To our knowledge, this study is the first to demonstrate that microglia express TRPV1, and that activation of this receptor may contribute to microglial damage via Ca2+ signaling and mitochondrial disruption.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from the BRC of the 21st Century Frontier Research Program of the Korea Ministry of Science (to B.K.J), from the Brain Disease Research Center/Korea Science and Engineering Foundation, and Grant R01-2005-000-10179-0 from the Basic Research Program/Korea Science and Engineering Foundation.
2 Address correspondence and reprint requests to Dr. Byung K. Jin, Brain Disease Research Center, Ajou University School of Medicine, Suwon 443-479, Korea. E-mail address: bkjin{at}ajou.ac.kr
3 Abbreviations used in this paper: TRPV1, transient receptor potential vanilloid subtype 1; CAP, capsaicin; RTX, resiniferatoxin; 12-HPETE, 12-hydroperoxyeicosatetraenoic acid; [Ca2+]i, intracellular Ca2+; CZP, capsazepine; I-RTX, iodo-RTX; SN, substantia nigra; TH, tyrosine hydroxylase; Eth-1, ethidium homodimer-1; TL, tomato lectin; ip, immunopositive; GFAP, glial fibrillary acidic protein; calcein-AM, calcein-acetoxymethyl ester.
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