Aneurysmal subarachnoid hemorrhage is a medical emergency associated with high early mortality and morbidity. The mechanisms underlying early deaths are poorly understood and no specific therapy to reduce early mortality currently exists. Survival and outcome are influenced by SAH intensity;the greater the intensity the greater the chances of death and disability. Our long term goal is to identify treatments that increase survival and improve outcome after SAH. We are studying contribution of brain injury in early mortality after high intensity experimental SAH. We have found that injury in cerebral vasculature and in neurons is present within 24 hours after SAH. Vessel injury is observed as structural damage and neuronal injury as degeneration and apoptosis. In addition, we have found substantial behavioral and neurological deficits and limited survival (at most 72 hours) in SAH animals. In preliminary experiments we have found that gentamicin administered post-SAH increases survival and improves neurological outcome in SAH animals. The objective of this application is to obtain proof of principle on efficacy of gentamicin in extending survival and improving neurological outcome after SAH. The data obtained will be used as a guide to apply for funds to develop gentamicin as first-line therapy against mortality and morbidity in SAH patients. The rationale that underlies proposed research is that it will identify a therapeutic option that would reduce early mortality and morbidity after SAH. Guided by strong preliminary data this hypothesis will be tested by pursuing three specific aims: 1) establish an optimal dose range of gentamicin for reducing mortality and improving outcome after SAH;(2) examine the effectiveness of delayed gentamicin treatment on post-SAH mortality and outcome;and (3) establish safety of gentamicin after SAH. As the purpose of this application is to obtain data towards clinical translation, all studies will include both low and high intensity SAH groups. Under the first aim, three doses of gentamicin will be compared for improvement in survival and neurological outcome after SAH. Under the second aim, the duration after SAH for which gentamicin remains effective in improving survival and outcome will be determined;the first 24 hours will be studied. Under the third aim, time required for serum gentamicin clearance, serum creatinine and urea and urine protein concentration in dose and time matched SAH and sham operated animals will be compared. The approach is innovative because it focuses on gentamicin, currently not used against SAH to reduce mortality and improve neurological outcome. The proposed study is significant because it is expected to establish a therapeutic agent that could dramatically reduce early mortality and morbidity in a patient population for which currently no such therapy option exist.
Approximately 48% of patients die within 48 hours after subarachnoid hemorrhage. The proposed research is relevant to public health as it will reveal the potential of gentamicin in reducing early mortality and morbidity after experimental SAH and set the stage for the translating this therapy in SAH patients. This research is relevant to the part of NIH's mission as it will produce fundamental knowledge to enhance health, lengthen life and reduce the burdens of illness and disability.
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