London, United Kingdom 2013 Poster Session Red Cerebrovasc Dis 2013; 35 (suppl 3)1-854 297 38 Acute stroke: new treatment concepts Molecular mechanisms of Notch mediated neuronal cell death in ischaemic stroke Y.L. Cheng1, C.G. Sorbey2, D.G. Jo3, T.V. Arumugam4 School of Biomedical Sciences, the University of Queensland, Brisbane, AUSTRALIA1, De-partment of Pharmacology, Monash University, Melbourne, AUSTRALIA2, School of Pharmacy, Sungkyunkwan University, Seoul, SOUTH KOREA3, School of Biomedical Sciences, University of Queensland, Brisbane, AUSTRALIA4 Background: Notch is a cell surface receptor governing cell fate decision in development and has been shown to be detrimental in ischaemic stroke when activated through g-secretase by releasing Notch intracellular domain (NICD). Notch signalling is believed to coordinate with other pathways to fulfil its pleiotropic roles according to the cell’s context. However, little is known about the cross-talk between these pathways during stroke in neurons, thus this study aims to investigate how Notch signalling integrates with nuclear factor kappa B (NFkB), hypoxia-inducing factor (HIF-1a), and mi-togen activated protein kinase (MAPK) pathways following stroke and in which way it contributes to neuronal cell death. Methods: Neuronal oxygen and glucose deprived (OGD) and middle cerebral artery occlusion (MCAO) were used as in vitro and in vivo models of ischaemic stroke, respectively. Antagonist for g-secretase, NFkB, HIF-1a and MAPKs were used, and cell viability and the expression of key cell death proteins were measured and compared between control, individual treatment and combined treatment groups. Infarct size and neuralogical score were evaluated in vivo. Immunostaining and co-immunoprecipitation for NICD, HIF-1a and MAPKs were performed. Results: All antagonist treated groups showed lower neuronal death than controls in response to OGD. The combined treatment of antagonists further decreased cell death when compared to either treatment, and it resulted in decreased levels of cleaved caspase-3, HIF-1a and MAPK expression. NICD, HIF-1a and MAPKs were co-expressed in neurons and physical binding of NICD and HIF- 1a was revealed. Mice undergoing combined treatment also showed better outcomes after MCAO. Conclusion: To exert its detrimental role conducing to neuronal death, Notch integrates with HIF-1a, MAPK and NFkB pathways. This study provides more understanding of Notch-mediated neuronal cell death through crosstalks with other pathways and reveal a new therapeutic target against isch-aemic stroke. 39 Acute stroke: new treatment concepts Simple and easy way using time-intensity curve of perfusion-weighted images to find salvage-able penumbra in stroke patients within 12 hours of onset due to the carotid artery occlusion T. Mori1, T. Iwata2, Y. Miyazaki3, M. Nakazaki4, Y. Takahashi5 Shonan Kamakura General Hospital Stroke Center, Kamakura, JAPAN1, Shonan Kamakura General Hospital Stroke Center, Kamakura, JAPAN2, Shonan Kamakura General Hospital Stroke Center, Kamakura, JAPAN3, Shonan Kamakura General Hospital Stroke Center, Kamakura, JA-PAN4, Shonan Kamakura General Hospital Stroke Center, Kamakura, JAPAN5 Background and Purpose: It remains uncertain how to find cerebral ischemic penumbra leading to no in-hospital death but se-vere disability unless rescued. The aim of our study was to find time-intensity curve (TIC) pattern, a simple and easy way of perfusion-weighted images (PWI), indicating the salvageable penumbra in stroke patients. Methods and Materials: Included were patients 1) who were admitted within 12 hours of onset between Jan 2006 and De-cember 2012, 2) in whom emergency MRA suggested the affected carotid artery occlusion and 3) who did not undergo any reperfusion therapy. We assessed, NIHSS on admission (NIHadm), DWI-ASPECT score, TIC parameters, NIHSS on the 7th day (NIH7th), and in-hospital death (iHD). Early neurological improvement (ENI) was defined as NIHadm - NIH7th of more than 4 or NIH7th of less than 5. TICs were generated on region of interests set at symmetrical positions of the bilat-eral MCA territories. We measured the time to peak (TP) and the peak value (PV) of bilateral TICs. Comparing the affected side (a) with the contralateral side (c), we defined TPa-TPc as TP_delay and PVa/PVc x100 as PV%. Relationship between TIC parameters, ENI and iHD were assessed. Results: Sixty-nine patients were analyzed. Average age was 79 years. Median ASPECTS was 3, NIHadm 20, NIH7th 22, TP_delay 6.2 s and PV% 50%. Twenty-six patients (37.7%) died during hospital-ization. TP_delay and PV% were significantly correlated with ENI and iHD. In no-ENI and ENI groups, lower 10% point of TP_delay were 2.7 and 1.0 s. ROC curves showed that cut-off points of PV% for ENI and in-hospital death were 85 and 50%, respectively. Among 44 patients with TP_de-lay of 2 sec or more and PV% of 85% or less, 41 (93%) had no-ENI. Among the 44 patients, 21 with PV% of 50% or less died during hospitalization. Conclusion: The TIC pattern of TP_delay of 2 sec or more and PV% of 85% or less and more than 50% may in-dicate a salvageable ischemic penumbra.
Karger_ESC London_2013
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