Abstract
Hypothermia shows promise for stroke neuroprotection, but current cooling strategies cause undesirable side effects that limit their clinical applications. Increasing efforts have focused on pharmacological hypothermia as a treatment option for stroke. Previously, we showed that activation of a thermoregulatory ion channel, transient receptor potential vanilloid 1 (TRPV1), by dihydrocapsaicin (DHC) produces reliable hypothermia. In this study, we investigate the effects of TRPV1-mediated hypothermia by DHC on long-term ischemic stroke injury and functional outcome. Hypothermia initiated at 3.5 hours after stroke significantly reduced primary cortical injury. Interestingly, hypothermia by DHC also significantly reduced secondary thalamic injury, as DHC-treated stroke mice exhibited 53% smaller thalamic lesion size. DHC-treated stroke mice further demonstrated decreased neuronal loss and astrogliosis in the thalamus and less thalamic fiber loss by diffusion tensor imaging (DTI). Importantly, a single 8 hour treatment of hypothermia by DHC after stroke provided long-term improvement in functional outcome, as DHC-treated mice exhibited improved behavioral recovery at one month post-stroke. These findings indicate that TRPV1-mediated hypothermia is effective in reducing both primary cortical injury and remote secondary thalamic injury, and a single treatment can produce persistent effects on functional recovery. These data highlight the therapeutic potential for TRPV1 agonism for stroke treatment.
Highlights
Rapid and sustained hypothermia in rodents, cynomologus monkeys and young cattle[8,12]
We demonstrate that transient receptor potential vanilloid 1 (TRPV1)-mediated pharmacological hypothermia reduces both primary cortical infarct area and secondary thalamic injury area following cerebral ischemia/reperfusion
A single eight-hour treatment of TRPV1-mediated hypothermia provides persistent behavioral recovery through one month post-stroke. This is the first study to demonstrate that application of pharmacological hypothermia can protect against remote secondary injury and provide lasting recovery of function following ischemic stroke
Summary
Rapid and sustained hypothermia in rodents, cynomologus monkeys and young cattle[8,12]. Our group[9] and Muzzi et al.[13] have reported that TRPV1 agonist induced hypothermia provides significant neuroprotection within the first few days following ischemic stroke in mice. Despite its neuroprotective effects in the acute phase after stroke, it is unclear whether TRPV1-mediated hypothermia has long-term benefit on ischemic injury and functional recovery. Secondary degenerative injury has been reported in the thalamus after the distal middle cerebral artery occlusion (dMCAO). This progressive secondary thalamic injury contributes to somatosensory dysfunction and can affect the final neurological behavioral outcome[14]. The current study investigates the long-term effects of TRPV1-mediated pharmacological hypothermia on both primary and secondary post-stroke injury and functional outcome during one month after stroke
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