Ischemic cerebral stroke attacks approximately three quarters of a million Americans each year at a staggering cost. Only one treatment has been approved and the requirement that it be administered within a narrow time frame (currently within 3 hrs in the USA) drastically limits its applicability in the majority of cases (~90%). By focusing on medicines for improved stroke outcomes at delayed time points (? 24 hours), we will be addressing an unmet medical need that has the potential to impact the health of large numbers of stroke victims. Brain- derived Neurotropic Factor (BDNF) promotes the resilience of ischemic neurons in vitro, promotes functional recovery in animal models of stroke when administered at delayed time points after the insult (?24 hrs), and its levels positively correlate with functional recovery in stroke patients. Since the processing and secretion of BDNF can be enhanced by activating the Sigma-1 receptor (S1R) chaperone in glial and neuronal cells in vitro and in the brain in vivo, we seek to discover existing medications, which by virtue of their interactions with the S1R, might be repurposed for the functional recovery from ischemic stroke at delayed time points.
Our aims i nclude developing an in vitro and in vivo assay platform to rationally guide the selection of candidates for in vivo evaluation in a rodent model of focal cerebral ischemia. The findings from this exploratory application will set the stage for a focused translational drug repurposing effort supported by a future funding mechanism.
Stroke is the a leading cause of death and the leading cause of disability in the United States, yet over 90% of Americans who experience a stroke will not arrive to the hospital in time to benefit from the only available treatment. While a prolonged rehabilitation program can be beneficial to some stroke patients, no effective treatment is available for chronic stroke, highlighting the need for therapies capable of enhancing functional recovery. To address this unmet medical need, we are seeking to discover existing medications which could be repurposed on the basis of their actions on specific receptor targets to aid in the functional recovery from stroke even when be administered one or more days after stroke has occurred.
| Dalwadi, Dhwanil A; Kim, Seongcheol; Schetz, John A (2017) Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia. Neurochem Int 105:21-31 |
