title: Capsazepine protects against neuronal injury caused by oxygen glucose deprivation by inhibiting I(h).
abstract: Cell death mechanisms frequently involve the influx of extracellular calcium through voltage- and ligand-gated ion channels, e.g., the NMDA receptor (Greene, 1999). The vanilloid receptor (VR1) is present in regions of the brain (Mezey et al., 2000) that are highly susceptible to neurodegenerative insults, suggesting that this ion channel might contribute to the cellular processes involved in neuronal death. We tested the effects of VR1 ligands in the oxygen glucose deprivation (OGD) model of cell death in organotypic hippocampal slice cultures. The VR1 agonist capsaicin at concentrations that are selective for VR1 did not affect cell viability per se or the extent of neurodegeneration induced by the OGD insult. In contrast, the VR1 antagonist capsazepine (0.1-10 microm) significantly reduced the amount of OGD-induced cell death. However, capsazepine was still neuroprotective in slices prepared from VR1 knock-out mice, which exhibited the same degree of neurodegeneration to that observed in slices prepared from wild-type mice, excluding the possibility that it afforded neuroprotection through inhibition of VR1. Instead, capsazepine inhibited the hyperpolarization-activated nonspecific cation channel generated current I(h) in a concentration range similar to that which was neuroprotective. Furthermore, the specific I(h) blocker ZD-7288 was also neuroprotective, mirroring the effects of capsazepine, in that it was effective at preventing cell death when applied either during or after the OGD insult. These results demonstrate that capsazepine affords neuroprotection through inhibition of I(h) rather than inhibition of VR1.
authors: Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, CM19 5AW, United Kingdom. alison_m_ray@gsk.com
authors: Alison M
authors: AM
authors: Ray
authors: Ceri D
authors: CD
authors: Benham
authors: Jenny C
authors: JC
authors: Roberts
authors: Catherine H
authors: CH
authors: Gill
authors: Christophe
authors: C
authors: Lanneau
authors: Danniel P
authors: DP
authors: Gitterman
authors: Mark
authors: M
authors: Harries
authors: John B
authors: JB
authors: Davis
authors: Christopher H
authors: CH
authors: Davies
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016923:Cell Death; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D054815:Cyclic Nucleotide-Gated Cation Channels; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000172:deficiency / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000172:deficiency / Q000235:genetics
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D015221:Potassium Channels; D011955:Receptors, Drug; D005947:Glucose; C071423:capsazepine; D002211:Capsaicin