title: The neuroprotective compound P7C3-A20 promotes neurogenesis and improves cognitive function after ischemic stroke.
abstract: Ischemic stroke is a devastating condition with few therapeutic interventions available. The neuroprotective compound P7C3-A20 inhibits mature neuronal cell death while also increasing the net magnitude of postnatal neurogenesis in models of neurodegeneration and acute injury. P7C3 compounds enhance flux of nicotinamide adenine dinucleotide (NAD) in mammalian cells, a proposed therapeutic approach to treating cerebral ischemia. The effectiveness of P7C3-A20 treatment on chronic histopathological and behavioral outcomes and neurogenesis after ischemic stroke has not previously been established. Here, a transient middle cerebral artery occlusion in rats was followed by twice daily injection of P7C3-A20 or vehicle for 7days. P7C3-A20-treated rats performed significantly better than vehicle-treated controls in sensorimotor cylinder and grid-walk tasks, and in a chronic test of spatial learning and memory. These behavioral improvements with P7C3-A20 treatment were correlated with significantly decreased cortical and hippocampal atrophy, and associated with increased neurogenesis in the subventricular zone and hippocampal dentate gyrus subgranular zone. Furthermore, cerebral ischemia significantly reduced NAD in the cortex but P7C3-A20 treatment restored NAD to sham levels. Thus, P7C3-A20 treatment mitigates neurodegeneration and augments repair in the brain after focal ischemia, which translates into chronic behavioral improvement. This suggests a new therapeutic approach of using P7C3 compounds to safely augment NAD and thereby promote two independent processes critical to protecting the brain from ischemic stroke: mature neuron survival and postnatal neurogenesis throughout the post-ischemic brain.
authors.affiliation: Department of Neurological Surgery, Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, United States; The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, United States.
authors.forename: Zachary B
authors.initials: ZB
authors.lastname: Loris
authors.affiliation: Departments of Psychiatry, Neurology, and Free Radical and Radiation Biology Program, Department of Radiation Oncology Comprehensive Cancer Center, Department of Veterans Affairs, University of Iowa Carver College of Medicine, Iowa City, IA, United States; Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, United States. Electronic address: andrew-pieper@uiowa.edu.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
authors.affiliation: Department of Neurological Surgery, Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, United States; The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, United States. Electronic address: ddietrich@miami.edu.
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
mesh_terms: D000818:Animals; D001284:Atrophy; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000523:psychology*; D002227:Carbazoles / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000523:psychology; D008297:Male; D008568:Memory / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects; D065853:Spatial Learning / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000523:psychology*; D016138:Walking
chemical_list: D002227:Carbazoles; D018696:Neuroprotective Agents; C552520:P7C3 compound; D009243:NAD
keywords: Aminopropyl carbazole; Ischemic stroke; NAD; Neurogenesis; Neuroprotection; P7C3-A20