Abstract
Background and PurposeIn the acute phase of ischemia-reperfusion, hypoperfusion associated with ischemia and reperfusion in microvascular regions and disruption of the blood–brain barrier (BBB) contribute to post-ischemic brain injury. We aimed to clarify whether brain injury following transient middle cerebral artery occlusion (tMCAO) is ameliorated in Transient receptor potential vanilloid 4 knockout (Trpv4–/–) mice.MethodstMCAO was induced in wild-type (WT) and Trpv4–/– mice aged 8–10 weeks. Ischemia-induced lesion volume was evaluated by 2,3,5-triphenyltetrazolium chloride staining at 24 h post-tMCAO. Tissue water content and Evans blue leakage in the ipsilateral hemisphere and a neurological score were evaluated at 48 h post-tMCAO. Transmission electron microscopy (TEM) was performed to assess the morphological changes in microvasculature in the ischemic lesions at 6 h post-tMCAO.ResultsCompared with WT mice, Trpv4–/– mice showed reduced ischemia-induced lesion volume and reduced water content and Evans blue leakage in the ipsilateral hemisphere alongside milder neurological symptoms. The loss of zonula occludens-1 and occludin proteins in the ipsilateral hemisphere was attenuated in Trpv4–/– mice. TEM revealed that parenchymal microvessels in the ischemic lesion were compressed and narrowed by the swollen endfeet of astrocytes in WT mice, but these effects were markedly ameliorated in Trpv4–/– mice.ConclusionThe present results demonstrate that TRPV4 contributes to post-ischemic brain injury. The preserved microcirculation and BBB function shortly after reperfusion are the key neuroprotective roles of TRPV4 inhibition, which represents a promising target for the treatment of acute ischemic stroke.
Highlights
MATERIALS AND METHODSAcute ischemic stroke secondary to large artery occlusion is a common and devastating condition that results in death or long-term disability in a high proportion of patients
These findings indicate that Transient receptor potential vanilloid 4 (TRPV4) has a large influence on ischemia-induced brain injury and indicate that inhibition of TRPV4 has a neuroprotective role in acute ischemic stroke
Because brain edema progressed to the maximum level on the second and third days, the tissue water content in the ipsilateral hemisphere was measured at 48 h post-transient MCAO (tMCAO)
Summary
MATERIALS AND METHODSAcute ischemic stroke secondary to large artery occlusion is a common and devastating condition that results in death or long-term disability in a high proportion of patients. Despite the high rates of early recanalization, some patients still experience poor outcomes In these cases, lack of reperfusion due to blockade of the microcirculation leading to hypoperfusion associated with ischemia and reperfusion and disruption of the blood–brain barrier (BBB) may contribute to post-ischemic brain injury (Molina and Alvarez-Sabín, 2009). TRPV4 contributes to Ca2+ influx in both astrocytes and neurons and to extracellular glutamate accumulation during peri-infarct depolarizations (Rakers et al, 2017) These findings indicate that TRPV4 has a large influence on ischemia-induced brain injury and indicate that inhibition of TRPV4 has a neuroprotective role in acute ischemic stroke. The mechanism for the neuroprotective effects of TRPV4 in acute ischemic stroke remains inconclusive Given this context, we aimed to investigate the differences in post-ischemic brain injury between Trpv4−/− and WT mice, and to clarify the mechanism for any identified differences using a transient MCAO (tMCAO) model in the C57BL/6N mouse strain. We aimed to clarify whether brain injury following transient middle cerebral artery occlusion (tMCAO) is ameliorated in Transient receptor potential vanilloid 4 knockout (Trpv4−/−) mice
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