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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061808-05
Application #
8417713
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2009-02-15
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$310,308
Indirect Cost
$103,436
Name
University of Maryland Baltimore
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Stokum, Jesse A; Gerzanich, Volodymyr; Simard, J Marc (2016) Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab 36:513-38
Urday, Sebastian; Beslow, Lauren A; Dai, Feng et al. (2016) Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage. Crit Care Med 44:790-7
Kurland, David B; Gerzanich, Volodymyr; Karimy, Jason K et al. (2016) The Sur1-Trpm4 channel regulates NOS2 transcription in TLR4-activated microglia. J Neuroinflammation 13:130
Iqbal, Sana; Hayman, Erik G; Hong, Caron et al. (2016) Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications. Brain Circ 2:8-19
Urday, Sebastian; Kimberly, W Taylor; Beslow, Lauren A et al. (2015) Targeting secondary injury in intracerebral haemorrhage--perihaematomal oedema. Nat Rev Neurol 11:111-22
Mehta, Rupal I; Tosun, Cigdem; Ivanova, Svetlana et al. (2015) Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts. J Neuropathol Exp Neurol 74:835-49
Caffes, Nicholas; Kurland, David B; Gerzanich, Volodymyr et al. (2015) Glibenclamide for the treatment of ischemic and hemorrhagic stroke. Int J Mol Sci 16:4973-84
Stokum, Jesse A; Kurland, David B; Gerzanich, Volodymyr et al. (2015) Mechanisms of astrocyte-mediated cerebral edema. Neurochem Res 40:317-28
Tosun, Cigdem; Hong, Caron; Carusillo, Brianna et al. (2015) Angiogenesis induced by prenatal ischemia predisposes to periventricular hemorrhage during postnatal mechanical ventilation. Pediatr Res 77:663-73
Karimy, Jason K; Kahle, Kristopher T; Kurland, David B et al. (2015) A novel method to study cerebrospinal fluid dynamics in rats. J Neurosci Methods 241:78-84

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