Beneficial Effects of Delayed P7C3-A20 Treatment After Transient MCAO in Rats
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ORIGINAL ARTICLE
Beneficial Effects of Delayed P7C3-A20 Treatment After Transient MCAO in Rats Zachary B. Loris 1,2 & Justin R. Hynton 1 & Andrew A. Pieper 3,4,5 & W. Dalton Dietrich 1,2,6
Received: 13 June 2017 / Revised: 10 August 2017 / Accepted: 11 August 2017 / Published online: 25 August 2017 # Springer Science+Business Media, LLC 2017
Abstract Despite ischemic stroke being the fifth leading cause of death in the USA, there are few therapeutic options available. We recently showed that the neuroprotective compound P7C3-A20 reduced brain atrophy, increased neurogenesis, and improved functional recovery when treatment was initiated immediately post-reperfusion after a 90min middle cerebral artery occlusion (MCAO). In the present study, we investigated a more clinically relevant therapeutic window for P7C3-A20 treatment after ischemic stroke. MCAO rats were administered P7C3-A20 for 1 week, beginning immediately or at a delayed point, 6 h post-reperfusion. Delayed P7C3-A20 treatment significantly improved strokeinduced sensorimotor deficits in motor coordination and
* Andrew A. Pieper [email protected] * W. Dalton Dietrich [email protected] 1
Department of Neurological Surgery, Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
2
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA
3
Department of Psychiatry, College of Medicine, University of Iowa Carver College of Medicine, 169 Newton Road, Iowa City, IA 52242, USA
4
Department of Neurology, University of Iowa Carver College of Medicine, 169 Newton Road, Iowa City, IA 52242, USA
5
Department of Free Radical and Radiation Biology Program, Department of Radiation Oncology Comprehensive Cancer Center, Department of Veterans Affairs, University of Iowa Carver College of Medicine, 169 Newton Road, Iowa City, IA 52242, USA
6
Department of Neurological Surgery, University of Miami, Leonard M. Miller School of Medicine, 1095 NW 14th Terrace, Suite 2-30, Miami, FL 33136-1060, USA
symmetry, as well as cognitive deficits in hippocampaldependent spatial learning, memory retention, and working memory. In the cerebral cortex, delayed P7C3-A20 treatment significantly increased tissue sparing 7 weeks after stroke and reduced hemispheric infarct volumes 48 h after reperfusion. Despite no reduction in striatal infarct volumes acutely, there was a significant increase in spared tissue volume chronically. In the hippocampus, only immediately treated P7C3-A20 animals had a significant increase in tissue sparing compared to vehicle-treated stroke animals. This structural protection translated into minimal hippocampal-dependent behavioral improvements with delayed P7C3-A20 treatment. However, all rats treated with delayed P7C3-A20 demonstrated a significant improvement in both sensorimotor tasks compared to vehicle controls, suggesting a somatosensory-driven recovery. These results demonstrate that P7C3-A20 improves chronic functional and histopathological outcomes after ischemic str
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