To develop a new therapeutic option for subarachnoid hemorrhage—from clinical to bench

Abstract

Cerebrovascular accidents are the major cause of disability and considerably increase the risk of dementia which is another important cause of disability Aneurysmal subarachnoid hemorrhage (SAH) represents 5–10% of all cerebrovascular accidents and leads to the worst outcome among all strokes Of the survivors the rate of related permanent disability is estimated to be 10–20% and long-term cognitive dysfunction affects up to 50–60% of survivors The first section of my PhD research aimed to study the risk of dementia after stroke using nationwide population-based cohort study In comparison with non-stroke controls patients with stroke had increased risk of dementia Among various stroke subtypes SAH and hemorrhagic stroke had higher impact on the development of dementia than ischemic stroke Thus I intend to find a new therapeutic option to improve the outcome of SAH The underlying mechanism of brain injury after SAH is biphasic acute brain injury and delayed vasospasm Experimental and clinical studies have indicated that SAH causes cerebral ischemic injury via glutamatergic excitotoxicity at acute stage Based on the excitotoxicity theory the antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors may provide neuroprotection to limit secondary brain injury after SAH However high affinity NMDA antagonists will indiscriminately block physiologic effect of NMDA receptors and cause undesirable side effects Memantine (1-amino-3 5-dimethyladamantane hydrochloride) with its characteristic of low affinity uncompetitive NMDA antagonist has been used clinically for years as treatment of dementia and Parkinson’s disease without serious adverse effects It has also been proven to reduce brain injury in several neurological diseases For this reason using a SAH animal model I investigated the pathophysiological mechanisms of SAH and the therapeutic potential of memantine in SAH The results showed memantine suppressed SAH-induced apoptotic cascades Moreover up-regulated neuronal nitric oxide synthase activity peroxynitrite formation and subsequent oxidative/nitrosative stress after SAH were reduced by memantine treatment Memantine finally rescued SAH-induced neuronal injury and improved neurobehavioral outcome On the other hand memantine also prevented the damage of neurovascular unit after SAH It not only preserved blood-brain barrier integrity at acute stage but also attenuated delayed vasospasm via restoring endothelial functionality Taken together SAH suggests increased risk of dementia Memantine which is a clinically tolerable drug has therapeutic potential in experimental SAH and may help combat SAH-induced brain damage These findings warrant further investigation in patients with SAH Afterward I intend to conduct clinical trials targeting the treatment of SAH using NMDA receptor antagonists I expect the NMDA-based therapy is a potential therapeutic option to improve the outcome of SAH

Date of Award	2015 Apr 23
Original language	English
Supervisor	Kuen-Jer Tsai (Supervisor)