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.
| Hayman, Erik G; Wessell, Aaron; Gerzanich, Volodymyr et al. (2017) Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 26:301-310 |
| Grunwald, Zachary; Beslow, Lauren A; Urday, Sebastian et al. (2017) Perihematomal Edema Expansion Rates and Patient Outcomes in Deep and Lobar Intracerebral Hemorrhage. Neurocrit Care 26:205-212 |
| Hayman, Erik G; Patel, Akil P; James, Robert F et al. (2017) Heparin and Heparin-Derivatives in Post-Subarachnoid Hemorrhage Brain Injury: A Multimodal Therapy for a Multimodal Disease. Molecules 22: |
| 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; 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 |
| Stokum, Jesse A; Gerzanich, Volodymyr; Simard, J Marc (2016) Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab 36:513-38 |
| 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 |
| 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 |
| 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 |
Showing the most recent 10 out of 46 publications
