Beneficial Effects of Delayed P7C3-A20 Treatment After Transient MCAO in Rats
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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 90-min 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 stroke-induced sensorimotor deficits in motor coordination and symmetry, as well as cognitive deficits in hippocampal-dependent 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 stroke with an extended therapeutic window.
KeywordsAminopropyl carbazole Ischemic stroke Neuroprotection P7C3-A20 Therapeutic window
The authors would like to thank Dr. Melissa Carballosa-Gautam, Ofelia Furones-Alonso, Ryan Treu, and William Javier Moreno for their technical contributions to this study. This work was funded with the support of the American Heart Association Grant No. 16PRE27050003 and the Florida Department of Health #7JK03 Miami Project to Cure Paralysis. A.A.P. was supported for this work by funds from an anonymous donor to the Mary Alice Smith Fund for Neuropsychiatry Research, the Titan Neurology Research Fund, and a Department of Veterans Affairs Merit Award 1I01BX00244.
Compliance with Ethical Standards
Conflict of Interest
Andrew A. Pieper owns patents related to the P7C3 series of neuroprotective compounds.
Research Involving Animals
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Informed consent was obtained from all individual participants included in the study.
- 3.Saver JL. Time is brain—quantified. Stroke. 2006;37(1):263–6. https://doi.org/10.1161/01.STR.0000196957.55928.ab.CrossRefPubMedGoogle Scholar
- 7.Fonarow GC, Smith EE, Saver JL, Reeves MJ, Hernandez AF, Peterson ED, et al. Improving door-to-needle times in acute ischemic stroke: the design and rationale for the American Heart Association/American Stroke Association’s Target: Stroke initiative. Stroke. 2011;42(10):2983–9. https://doi.org/10.1161/strokeaha.111.621342.CrossRefPubMedGoogle Scholar
- 8.Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723–31. https://doi.org/10.1016/s0140-6736(16)00163-x.CrossRefPubMedGoogle Scholar
- 18.Dutca LM, Stasheff SF, Hedberg-Buenz A, Rudd DS, Batra N, Blodi FR, et al. Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243. Invest Ophthalmol Vis Sci. 2014;55(12):8330–41. https://doi.org/10.1167/iovs.14-15468.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Kemp SW, Szynkaruk M, Stanoulis KN, Wood MD, Liu EH, Willand MP, et al. Pharmacologic rescue of motor and sensory function by the neuroprotective compound P7C3 following neonatal nerve injury. Neuroscience. 2015;284:202–16. https://doi.org/10.1016/j.neuroscience.2014.10.005.CrossRefPubMedGoogle Scholar
- 20.Tesla R, Wolf HP, Xu P, Drawbridge J, Estill SJ, Huntington P, et al. Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2012;109(42):17016–21. https://doi.org/10.1073/pnas.1213960109.CrossRefPubMedPubMedCentralGoogle Scholar
- 24.DeMars KM, Yang C, Hawkins KE, McCrea AO, Siwarski DM, Candelario-Jalil E. Spatiotemporal changes in P-glycoprotein levels in brain and peripheral tissues following ischemic stroke in rats. J Exp Neurosci. 2017;11:1179069517701741. https://doi.org/10.1177/1179069517701741.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Bi J, Li H, Ye SQ, Ding S. Pre-B-cell colony-enhancing factor exerts a neuronal protection through its enzymatic activity and the reduction of mitochondrial dysfunction in in vitro ischemic models. J Neurochem. 2012;120(2):334–46. https://doi.org/10.1111/j.1471-4159.2011.07566.x.CrossRefPubMedGoogle Scholar
- 38.Wang SN, Xu TY, Wang X, Guan YF, Zhang SL, Wang P, et al. Neuroprotective efficacy of an aminopropyl carbazole derivative P7C3-A20 in ischemic stroke. CNS Neurosci Ther. 2016; https://doi.org/10.1111/cns.12576.