title: GM1485, a nonimmunosuppressive immunophilin ligand, promotes neurofunctional improvement and neural regeneration following stroke.
abstract: Stroke is the leading cause of disability in the industrialized world, and the development of pharmacologic strategies to promote poststroke recovery is of paramount importance. GM1485, a nonimmunosuppressive immunophilin ligand, promotes regeneration of multiple cell types following injury. In the present study, we evaluated the effect of GM1485 treatment on functional recovery and neurogenesis following rat stroke. Transient cerebral ischemia was induced in rats receiving daily GM1485 (5 mg/kg) beginning 24 hr postischemia and continuing for a total of 6 weeks. Neurological function was evaluated over this period using a battery of neurobehavioral tests, and immunostaining for stem-cell markers was performed following animal sacrifice. An in vitro model of oxidative stress was also employed to evaluate the ability of GM1485 to mediate stem-cell-like induction and plasticity. GM1485-treated rats demonstrated improved neurological function as well as increased Sox2(+) cells in the ipsilateral SVZ and striatum relative to vehicle-treated rats. Additionally, GM1485-treated fibroblasts subjected to oxidative stress were reprogrammed to a stem-cell-like phenotype and were able to differentiate down a neuronal lineage. These data demonstrate that GM1485 administration improves neurological function and is consistent with an upregulation of endogenous neurogenesis following stroke in rats. Further experiments are necessary to characterize the molecular pathways involved in these processes.
authors.affiliation: Department of Neurological Surgery, Columbia University, New York, New York, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ducruet
authors.forename: Peter A
authors.initials: PA
authors.lastname: DeRosa
authors.forename: Brad E
authors.initials: BE
authors.lastname: Zacharia
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Sosunov
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
authors.forename: David E
authors.initials: DE
authors.lastname: Weinstein
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020104:Immunophilins / Q000494:pharmacology* / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007262:Infusions, Intravenous; D008024:Ligands; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C486238:GPI 1485; D008024:Ligands; D009414:Nerve Growth Factors; D020104:Immunophilins; D016559:Tacrolimus