During the last 5 decades, cerebral vasospasm has been thought to be the principal cause of poor outcome following subarachnoid hemorrhage (SAH). Recently, this idea has been challenged by the observation that successful reversal of vasoconstriction often does not result in concomitant improvement in patient outcome. Without denying the enduring significance of vasospasm, there is an emerging concept that factors other than vasoconstriction are important in the pathophysiology and prognosis post-SAH, including disruption of the blood-brain barrier, and activation of inflammatory and cell death pathways. Inflammation due to the toxic nature of blood is likely to be a very significant cause of edema formation and neuronal loss post-SAH, resulting in short-term and long-term cortical dysfunction and delayed cognitive impairment. We recently discovered a new ion channel, the sulfonylurea receptor-1 (SUR1)-regulated NC(Ca- ATP) channel, whose activation is associated with formation of cerebral edema and neuronal cell death. Our previous work demonstrated that this channel is upregulated in the context of ischemia/hypoxia. Recently, we discovered that this channel is also prominently upregulated in the context of neuroinflammation. Using a rat model of moderate SAH, in which delayed vasospasm is negligible but neuroinflammation is reliably produced, we found that: (i) the regulatory and the pore-forming subunits of the NC(Ca-ATP) channel, SUR1 and TRPM4, are prominently up-regulated in neurons, capillaries and venules in cortical regions with overlying SAH;(ii) cortical regions that show up-regulation of SUR1 and TRPM4 also show strong TNF1 upregulation, vasogenic edema and caspase-3 activation;(iii) post-SAH treatment with glibenclamide or with anti-sense oligodeoxynucleotide directed against SUR1 significantly reduces TNF1 upregulation, vasogenic edema and caspase-3 activation. In this grant, we plan 3 specific aims (SA) to: (SA1) demonstrate that glibenclamide ameliorates post-SAH inflammation and edema, that it preserves neuronal integrity and improves neurobehavioral outcome in a rat model of SAH;(SA2) demonstrate that the beneficial effects of glibenclamide are replicated by gene suppression of either of the two subunits of the channel, SUR1 and TRPM4;(SA3) demonstrate that up-regulation of SUR1 and TRPM4 protein and mRNA post-SAH is associated with functional NC(Ca-ATP) channels. We anticipate that successful completion of the proposed experiments will yield novel molecular insights into SAH-induced cortical dysfunction, and will lead to new therapeutic approaches to prevent the devastating cognitive impairments that so often afflict SAH patients.
Subarachnoid hemorrhage (SAH) results in edema, neuronal loss and cognitive dysfunction attributable in part to post-SAH hemotoxicity-induced inflammation independent of vasospasm. Using a rodent model of SAH, we discovered that SUR1 and TRPM4, the molecular subunits of the NC(Ca-ATP) channel, are prominently up-regulated post-SAH. In this proposal, we will use a rat model of SAH to establish the essential role of the NC(Ca-ATP) channel in pathophysiology post-SAH.
|Stokum, Jesse A; Kurland, David B; Gerzanich, Volodymyr et al. (2015) Mechanisms of astrocyte-mediated cerebral edema. Neurochem Res 40:317-28|
|Simard, J Marc; Sheth, Kevin N; Kimberly, W Taylor et al. (2014) Glibenclamide in cerebral ischemia and stroke. Neurocrit Care 20:319-33|
|Walcott, Brian P; Miller, Jennifer C; Kwon, Churl-Su et al. (2014) Outcomes in severe middle cerebral artery ischemic stroke. Neurocrit Care 21:20-6|
|Khanna, Arjun; Walcott, Brian P; Kahle, Kristopher T et al. (2014) Effect of glibenclamide on the prevention of secondary brain injury following ischemic stroke in humans. Neurosurg Focus 36:E11|
|Hong, Caron M; Tosun, Cigdem; Kurland, David B et al. (2014) Biomarkers as outcome predictors in subarachnoid hemorrhage--a systematic review. Biomarkers 19:95-108|
|Khanna, Arjun; Kahle, Kristopher T; Walcott, Brian P et al. (2014) Disruption of ion homeostasis in the neurogliovascular unit underlies the pathogenesis of ischemic cerebral edema. Transl Stroke Res 5:3-16|
|Kahle, Kristopher T; Walcott, Brian P; Simard, J Marc (2013) Continuous hyperosmolar therapy for traumatic brain injury-associated cerebral edema: as good as it gets, or an iatrogenic secondary insult? J Clin Neurosci 20:30-1|
|Mehta, Rupal I; Ivanova, Svetlana; Tosun, Cigdem et al. (2013) Sulfonylurea receptor 1 expression in human cerebral infarcts. J Neuropathol Exp Neurol 72:871-83|
|Ryu, Justine H; Walcott, Brian P; Kahle, Kristopher T et al. (2013) Induced and sustained hypernatremia for the prevention and treatment of cerebral edema following brain injury. Neurocrit Care 19:222-31|
|Woo, Seung Kyoon; Kwon, Min Seong; Ivanov, Alexander et al. (2013) The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel. J Biol Chem 288:3655-67|
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