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The Journal of Neuroscience, November 5, 2003, 23(31):10146-10153

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Cellular/Molecular
Capsazepine Protects against Neuronal Injury Caused by Oxygen Glucose Deprivation by Inhibiting I_h

Alison M. Ray, Ceri D. Benham, Jenny C. Roberts, Catherine H. Gill, Christophe Lanneau, Danniel P. Gitterman, Mark Harries, John B. Davis, and Christopher H. Davies

Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, CM19 5AW, United Kingdom

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 µM) 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.

Key words: capsazepine; vanilloid; organotypic slice; neuroprotection; oxygen/glucose deprivation; HCN channels; I_h

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Received July 2, 2003; revised July 2, 2003; accepted September 10, 2003.

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