Anti-ischemic Effects of Focal Brain Cooling are Mediated by Modulation of Transient Receptor Potential Vanilloid 4 Channels in Mice

Anti-ischemic Effects of Focal Brain Cooling are Mediated by Modulation of Transient Receptor Potential Vanilloid 4 Channels in Mice

Focal brain cooling (FBC) at 15℃ and transient receptor potential vanilloid 4 (TRPV4) deficiency relieve brain infarction. TRPV4 channels are inactivated by cooling (< 27℃), suggesting that the anti-ischemic effects of FBC include those of TRPV4 inactivation. However, the extent to which TRPV4 inactivation contributes to the anti-ischemic, anti- blood-brain barrier (BBB) disruption, and anti-apoptosis effects of FBC on cerebral infarction remains unclear. We investigated the contribution and mechanisms of RN1734, a TRPV4 antagonist, in FBC for cerebral infarction using TRPV4 knockout and wild-type mice. Focal cerebral infarction was induced by photochemically induced thrombosis. Infarct volume, BBB disruption, and number of apoptotic cells were evaluated. The TRPV4 antagonist or deficiency showed similar anti-ischemic and anti-BBB disruptive effects to those of FBC. Intracerebroventricular injection of RN1734 showed a similar reduction in the number of apoptotic cells to that of FBC. These anti-ischemic and -apoptotic effects were completely inhibited with injection of GSK1016790A, a TRPV4 agonist, immediately before FBC. Our results showed that TRPV4 modulation is the primary factor contributing to the antiischemic effects of FBC, and TRPV4 channel inactivation relieve focal ischemic infarction by relieving BBB disruption and preventing apoptosis. Therefore, FBC treatment improves ischemic stroke through the modulation of TRPV4 channels.

Creators Mori Naomasa

Creators Moriyama Hiroshi

Creators Okazaki Koki

Creators Oka Fumiaki

Creators Fujiyama Yuichi

Creators Shinoyama Mizuya

Creators Nomura Sadahiro

Creators Inoue Takao

Creators Suzuki Michiyasu

Creators Ishihara Hideyuki

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