The Effect of Histone Deacetylase Inhibitors Panobinostat or Entinostat on Motor Recovery in Mice After Ischemic Stroke

Abstract

Using rigorous and clinically relevant experimental design and analysis standards, in this study, we investigated the potential of histone deacetylase (HDAC) inhibitors panobinostat and entinostat to enhance recovery of motor function after photothrombotic stroke in male mice. Panobinostat, a pan-HDAC inhibitor, is a FDA-approved drug for certain cancers, whereas entinostat is a class-I HDAC inhibitor in late stage of clinical investigation. The drugs were administered every other day (panobinostat—3 or 10 mg/kg; entinostat—1.7 or 5 mg/kg) starting from day 5 to 15 after stroke. To imitate the current standard of care in stroke survivors, i.e., physical rehabilitation, the animals run on wheels (2 h daily) from post-stroke day 9 to 41. The predetermined primary end point was motor recovery measured in two tasks of spontaneous motor behaviors in grid-walking and cylinder tests. In addition, we evaluated the running distance and speed throughout the study, and the number of parvalbumin-positive neurons in medial agranular cortex (AGm) and infarct volumes at the end of the study. Both sensorimotor tests revealed that combination of physical exercise with either drug did not substantially affect motor recovery in mice after stroke. This was accompanied by negligible changes of parvalbumin-positive neurons recorded in AGm and comparable infarct volumes among experimental groups, while dose-dependent increase in acetylated histone 3 was observed in peri-infarct cortex of drug-treated animals. Our observations suggest that add-on panobinostat or entinostat therapy coupled with limited physical rehabilitation is unlikely to offer therapeutic modality for stroke survivors who have motor dysfunction.

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References

  1. Al Shoyaib, A., Archie, S. R., & Karamyan, V. T. (2019). Intraperitoneal route of drug administration: Should it be used in experimental animal studies? Pharmaceutical Research, 37(1), 12. https://doi.org/10.1007/s11095-019-2745-x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Alamri, F. F., Shoyaib, A. A., Biggers, A., Jayaraman, S., Guindon, J., & Karamyan, V. T. (2018). Applicability of the grip strength and automated von Frey tactile sensitivity tests in the mouse photothrombotic model of stroke. Behavioural Brain Research, 336, 250–255. https://doi.org/10.1016/j.bbr.2017.09.008.

    Article  PubMed  Google Scholar 

  3. Alamri, F. F., Al Shoyaib, A., Syeara, N., Paul, A., Jayaraman, S., Karamyan, S. T., et al. (2021). Delayed atomoxetine or fluoxetine treatment coupled with limited voluntary running promotes motor recovery in mice after ischemic stroke. Neural Regeneration Research, 16(7), 1244–1251.

    Article  Google Scholar 

  4. Atadja, P. (2009). Development of the pan-DAC inhibitor panobinostat (LBH589): Successes and challenges. Cancer Letters, 280(2), 233–241. https://doi.org/10.1016/j.canlet.2009.02.019.

    CAS  Article  PubMed  Google Scholar 

  5. Banerjee, A., Chokkalla, A. K., Shi, J. J., Lee, J., Venna, V. R., Vemuganti, R., et al. (2020). Microarray profiling reveals distinct circulating miRNAs in aged male and female mice subjected to post-stroke social isolation. Neuromolecular Medicine. https://doi.org/10.1007/s12017-020-08622-2.

    Article  PubMed  Google Scholar 

  6. Berretta, A., Tzeng, Y. C., & Clarkson, A. N. (2014). Post-stroke recovery: The role of activity-dependent release of brain-derived neurotrophic factor. Expert Review of Neurotherapeutics, 14(11), 1335–1344. https://doi.org/10.1586/14737175.2014.969242.

    CAS  Article  PubMed  Google Scholar 

  7. Carmichael, S. T. (2016). Emergent properties of neural repair: Elemental biology to therapeutic concepts. Annals of Neurology, 79(6), 895–906. https://doi.org/10.1002/ana.24653.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chen, Y. T., Zang, X. F., Pan, J., Zhu, X. L., Chen, F., Chen, Z. B., et al. (2012). Expression patterns of histone deacetylases in experimental stroke and potential targets for neuroprotection. Clinical and Experimental Pharmacology and Physiology, 39(9), 751–758. https://doi.org/10.1111/j.1440-1681.2012.05729.x.

    CAS  Article  PubMed  Google Scholar 

  9. Choi, S. A., Lee, C., Kwak, P. A., Park, C. K., Wang, K. C., Phi, J. H., et al. (2019). Histone deacetylase inhibitor panobinostat potentiates the anti-cancer effects of mesenchymal stem cell-based sTRAIL gene therapy against malignant glioma. Cancer Letters, 442, 161–169. https://doi.org/10.1016/j.canlet.2018.10.012.

    CAS  Article  PubMed  Google Scholar 

  10. Chopra, V., Quinti, L., Khanna, P., Paganetti, P., Kuhn, R., Young, A. B., et al. (2016). LBH589, a hydroxamic acid-derived HDAC inhibitor, is neuroprotective in mouse models of Huntington’s disease. Journal of Huntington’s Disease, 5(4), 347–355. https://doi.org/10.3233/jhd-160226.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Christie, B. R., Eadie, B. D., Kannangara, T. S., Robillard, J. M., Shin, J., & Titterness, A. K. (2008). Exercising our brains: How physical activity impacts synaptic plasticity in the dentate gyrus. Neuromolecular Medicine, 10(2), 47–58. https://doi.org/10.1007/s12017-008-8033-2.

    CAS  Article  PubMed  Google Scholar 

  12. Clarkson, A. N., Huang, B. S., Macisaac, S. E., Mody, I., & Carmichael, S. T. (2010). Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Nature, 468(7321), 305–309. https://doi.org/10.1038/nature09511.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Connolly, R. M., Rudek, M. A., & Piekarz, R. (2017). Entinostat: A promising treatment option for patients with advanced breast cancer. Future Oncology, 13(13), 1137–1148. https://doi.org/10.2217/fon-2016-0526.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Corbett, D., Carmichael, S. T., Murphy, T. H., Jones, T. A., Schwab, M. E., Jolkkonen, J., et al. (2017). Enhancing the alignment of the preclinical and clinical stroke recovery research pipeline: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable translational working group. International Journal of Stroke: Official Journal of the International Stroke Society, 12(5), 462–471. https://doi.org/10.1177/1747493017711814.

    Article  Google Scholar 

  15. Cramer, S. C. (2020). Issues important to the design of stroke recovery trials. The Lancet Neurology, 19(3), 197–198. https://doi.org/10.1016/s1474-4422(20)30030-2.

    Article  PubMed  Google Scholar 

  16. Dietz, K. C., & Casaccia, P. (2010). HDAC inhibitors and neurodegeneration: At the edge between protection and damage. Pharmacological Research, 62(1), 11–17. https://doi.org/10.1016/j.phrs.2010.01.011.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Elsner, V. R., Lovatel, G. A., Bertoldi, K., Vanzella, C., Santos, F. M., Spindler, C., et al. (2011). Effect of different exercise protocols on histone acetyltransferases and histone deacetylases activities in rat hippocampus. Neuroscience, 192, 580–587. https://doi.org/10.1016/j.neuroscience.2011.06.066.

    CAS  Article  PubMed  Google Scholar 

  18. Fessler, E. B., Chibane, F. L., Wang, Z., & Chuang, D. M. (2013). Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery. Current Pharmaceutical Design, 19(28), 5105–5120. https://doi.org/10.2174/1381612811319280009.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Fini, N. A., Holland, A. E., Keating, J., Simek, J., & Bernhardt, J. (2017). How physically active are people following stroke? Systematic review and quantitative synthesis. Physical Therapy, 97(7), 707–717. https://doi.org/10.1093/ptj/pzx038.

    Article  PubMed  Google Scholar 

  20. Fluri, F., Schuhmann, M. K., & Kleinschnitz, C. (2015). Animal models of ischemic stroke and their application in clinical research. Drug Design, Development and Therapy, 9, 3445–3454. https://doi.org/10.2147/DDDT.S56071.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Hakon, J., Quattromani, M. J., Sjolund, C., Tomasevic, G., Carey, L., Lee, J. M., et al. (2018). Multisensory stimulation improves functional recovery and resting-state functional connectivity in the mouse brain after stroke. Neuroimage Clinical, 17, 717–730. https://doi.org/10.1016/j.nicl.2017.11.022.

    Article  PubMed  Google Scholar 

  22. Hennika, T., Hu, G., Olaciregui, N. G., Barton, K. L., Ehteda, A., Chitranjan, A., et al. (2017). Pre-clinical study of panobinostat in xenograft and genetically engineered murine diffuse intrinsic pontine glioma models. PLoS One, 12(1), e0169485. https://doi.org/10.1371/journal.pone.0169485.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Iadecola, C., & Anrather, J. (2011). Stroke research at a crossroad: Asking the brain for directions [Research Support, N.I.H., Extramural]. Nature Neuroscience, 14(11), 1363–1368. https://doi.org/10.1038/nn.2953.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Jackson, L., Li, W., Abdul, Y., Dong, G., Baban, B., & Ergul, A. (2019). Diabetic stroke promotes a sexually dimorphic expansion of T cells. Neuromolecular Medicine, 21(4), 445–453. https://doi.org/10.1007/s12017-019-08554-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Jayaraman, S., Al Shoyaib, A., Kocot, J., Villalba, H., Alamri, F. F., Rashid, M., et al. (2020). Peptidase neurolysin functions to preserve the brain after ischemic stroke in male mice. Journal of Neurochemistry, 153(1), 120–137. https://doi.org/10.1111/jnc.14864.

    CAS  Article  PubMed  Google Scholar 

  26. Karamyan, V. T. (2021). The role of peptidase neurolysin in neuroprotection and neural repair after stroke. Neural Regeneration Research, 16(1), 21–25. https://doi.org/10.4103/1673-5374.284904.

    Article  PubMed  Google Scholar 

  27. Kassis, H., Shehadah, A., Chopp, M., & Zhang, Z. G. (2017). Epigenetics in stroke recovery. Genes (Basel), 8(3), 89. https://doi.org/10.3390/genes8030089.

    CAS  Article  Google Scholar 

  28. Kassis, H., Shehadah, A., Li, C., Zhang, Y., Cui, Y., Roberts, C., et al. (2016). Class IIa histone deacetylases affect neuronal remodeling and functional outcome after stroke. Neurochemistry International, 96, 24–31. https://doi.org/10.1016/j.neuint.2016.04.006.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Kim, H. J., Rowe, M., Ren, M., Hong, J.-S., Chen, P.-S., & Chuang, D.-M. (2007). Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: Multiple mechanisms of action. Journal of Pharmacology and Experimental Therapeutics, 321(3), 892–901. https://doi.org/10.1124/jpet.107.120188.

    CAS  Article  Google Scholar 

  30. Krakauer, J. W., Carmichael, S. T., Corbett, D., & Wittenberg, G. F. (2012). Getting neurorehabilitation right: What can be learned from animal models? Neurorehabilitation and Neural Repair, 26(8), 923–931. https://doi.org/10.1177/1545968312440745.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kwakkel, G., Meskers, C., & Ward, N. S. (2020). Time for the next stage of stroke recovery trials. The Lancet Neurology, 19(8), 636–637. https://doi.org/10.1016/S1474-4422(20)30218-0.

    Article  PubMed  Google Scholar 

  32. Langley, B., Brochier, C., & Rivieccio, M. A. (2009). Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. Stroke, 40(8), 2899–2905. https://doi.org/10.1161/strokeaha.108.540229.

    CAS  Article  PubMed  Google Scholar 

  33. Lay, S., Bernhardt, J., West, T., Churilov, L., Dart, A., Hayes, K., et al. (2016). Is early rehabilitation a myth? Physical inactivity in the first week after myocardial infarction and stroke. Disability and Rehabilitation, 38(15), 1493–1499. https://doi.org/10.3109/09638288.2015.1106598.

    Article  PubMed  Google Scholar 

  34. Leng, T., & Xiong, Z. G. (2019). Treatment for ischemic stroke: From thrombolysis to thrombectomy and remaining challenges. Brain Circulation, 5(1), 8–11. https://doi.org/10.4103/bc.bc_36_18.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lin, Y. H., Dong, J., Tang, Y., Ni, H. Y., Zhang, Y., Su, P., et al. (2017). Opening a new time window for treatment of stroke by targeting HDAC2. Journal of Neuroscience, 37(28), 6712–6728. https://doi.org/10.1523/JNEUROSCI.0341-17.2017.

    CAS  Article  PubMed  Google Scholar 

  36. Llorens-Martin, M., Torres-Aleman, I., & Trejo, J. L. (2008). Growth factors as mediators of exercise actions on the brain. Neuromolecular Medicine, 10(2), 99–107. https://doi.org/10.1007/s12017-008-8026-1.

    CAS  Article  PubMed  Google Scholar 

  37. Ma, K., Qin, L., Matas, E., Duffney, L. J., Liu, A., & Yan, Z. (2018). Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism. Neuropsychopharmacology, 43(8), 1779–1788. https://doi.org/10.1038/s41386-018-0073-1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Mattson, M. P. (2003). Excitotoxic and excitoprotective mechanisms: Abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Medicine, 3(2), 65–94. https://doi.org/10.1385/NMM:3:2:65.

    CAS  Article  PubMed  Google Scholar 

  39. Meel, M. H., de Gooijer, M. C., Metselaar, D. S., Sewing, A. C. P., Zwaan, K., Waranecki, P., et al. (2020). Combined therapy of AXL and HDAC inhibition reverses mesenchymal transition in diffuse intrinsic pontine glioma. Clinical Cancer Research, 26(13), 3319–3332. https://doi.org/10.1158/1078-0432.Ccr-19-3538.

    CAS  Article  PubMed  Google Scholar 

  40. Ng, K. L., Gibson, E. M., Hubbard, R., Yang, J., Caffo, B., O’Brien, R. J., et al. (2015). Fluoxetine maintains a state of heightened responsiveness to motor training early after stroke in a mouse model. Stroke, 46(10), 2951–2960. https://doi.org/10.1161/STROKEAHA.115.010471.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Nicholson, S., Sniehotta, F. F., van Wijck, F., Greig, C. A., Johnston, M., McMurdo, M. E., et al. (2013). A systematic review of perceived barriers and motivators to physical activity after stroke. International Journal of Stroke, 8(5), 357–364. https://doi.org/10.1111/j.1747-4949.2012.00880.x.

    Article  PubMed  Google Scholar 

  42. Price, A. R., Xu, G., Siemienski, Z. B., Smithson, L. A., Borchelt, D. R., Golde, T. E., et al. (2013). Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.” Science, 340(6135), 924. https://doi.org/10.1126/science.1234089.

    CAS  Article  PubMed  Google Scholar 

  43. Qian, Y. R., Lee, M.-J., Hwang, S., Kook, J. H., Kim, J.-K., & Bae, C. S. (2010). Neuroprotection by valproic acid in mouse models of permanent and transient focal cerebral ischemia. The Korean Journal of Physiology and Pharmacology, 14(6), 435–440. https://doi.org/10.4196/kjpp.2010.14.6.435.

    CAS  Article  PubMed  Google Scholar 

  44. Rashid, M., Wangler, N. J., Yang, L., Shah, K., Arumugam, T. V., Abbruscato, T. J., et al. (2014). Functional up-regulation of endopeptidase neurolysin during post-acute and early recovery phases of experimental stroke in mouse brain. Journal of Neurochemistry, 129(1), 179–189. https://doi.org/10.1111/jnc.12513.

    CAS  Article  PubMed  Google Scholar 

  45. Ren, M., Leng, Y., Jeong, M., Leeds, P. R., & Chuang, D. M. (2004). Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: Potential roles of histone deacetylase inhibition and heat shock protein induction. Journal of Neurochemistry, 89(6), 1358–1367. https://doi.org/10.1111/j.1471-4159.2004.02406.x.

    CAS  Article  PubMed  Google Scholar 

  46. Schaffer, D. V., & Gage, F. H. (2004). Neurogenesis and neuroadaptation. Neuromolecular Medicine, 5(1), 1–9. https://doi.org/10.1385/NMM:5:1:001.

    CAS  Article  PubMed  Google Scholar 

  47. Selvaraj, U. M., Poinsatte, K., Torres, V., Ortega, S. B., & Stowe, A. M. (2016). Heterogeneity of B cell functions in stroke-related risk, prevention, injury, and repair. Neurotherapeutics, 13(4), 729–747. https://doi.org/10.1007/s13311-016-0460-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Sen, N. (2015). Epigenetic regulation of memory by acetylation and methylation of chromatin: Implications in neurological disorders, aging, and addiction. Neuromolecular Medicine, 17(2), 97–110. https://doi.org/10.1007/s12017-014-8306-x.

    CAS  Article  PubMed  Google Scholar 

  49. Skolarus, L. E., Freedman, V. A., Feng, C., Wing, J. J., & Burke, J. F. (2016). Care received by elderly US stroke survivors may be underestimated. Stroke, 47(8), 2090–2095. https://doi.org/10.1161/STROKEAHA.116.012704.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Syeara, N., Alamri, F. F., Jayaraman, S., Lee, P., Karamyan, S. T., Arumugam, T. V., et al. (2020). Motor deficit in the mouse ferric chloride-induced distal middle cerebral artery occlusion model of stroke. Behavioural Brain Research, 380, 112418. https://doi.org/10.1016/j.bbr.2019.112418.

    CAS  Article  PubMed  Google Scholar 

  51. Tang, Y., Lin, Y. H., Ni, H. Y., Dong, J., Yuan, H. J., Zhang, Y., et al. (2017). Inhibiting histone deacetylase 2 (HDAC2) promotes functional recovery from stroke. Journal of the American Heart Association, 6(10), e007236. https://doi.org/10.1161/JAHA.117.007236.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Vijayan, M., Alamri, F. F., Al Shoyaib, A., Karamyan, V. T., & Reddy, P. H. (2019). Novel miRNA PC-5P-12969 in ischemic stroke. Molecular Neurobiology, 56(10), 6976–6985. https://doi.org/10.1007/s12035-019-1562-x.

    CAS  Article  PubMed  Google Scholar 

  53. Virani, S. S., Alonso, A., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., et al. (2020). Heart disease and stroke statistics-2020 update: A report from the American Heart Association. Circulation, 141(9), e139–e596. https://doi.org/10.1161/CIR.0000000000000757.

    Article  PubMed  Google Scholar 

  54. Wafa, H. A., Wolfe, C. D. A., Emmett, E., Roth, G. A., Johnson, C. O., & Wang, Y. (2020). Burden of stroke in Europe: Thirty-year projections of incidence, prevalence, deaths, and disability-adjusted life years. Stroke, 51(8), 2418–2427. https://doi.org/10.1161/STROKEAHA.120.029606.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Wang, Z., Tsai, L. K., Munasinghe, J., Leng, Y., Fessler, E. B., Chibane, F., et al. (2012). Chronic valproate treatment enhances postischemic angiogenesis and promotes functional recovery in a rat model of ischemic stroke. Stroke, 43(9), 2430–2436. https://doi.org/10.1161/strokeaha.112.652545.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Wangler, N. J., Santos, K. L., Schadock, I., Hagen, F. K., Escher, E., Bader, M., et al. (2012). Identification of membrane-bound variant of metalloendopeptidase neurolysin (EC 3.4.24.16) as the non-angiotensin type 1 (Non-AT1), non-AT2 angiotensin binding site. Journal of Biological Chemistry, 287(1), 114–122. https://doi.org/10.1074/jbc.M111.273052.

    CAS  Article  Google Scholar 

  57. Winstein, C. J., Stein, J., Arena, R., Bates, B., Cherney, L. R., Cramer, S. C., et al. (2016). Guidelines for adult stroke rehabilitation and recovery: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 47(6), e98–e169. https://doi.org/10.1161/STR.0000000000000098.

    Article  PubMed  Google Scholar 

  58. Xuan, A., Long, D., Li, J., Ji, W., Hong, L., Zhang, M., et al. (2012). Neuroprotective effects of valproic acid following transient global ischemia in rats. Life Sciences, 90(11–12), 463–468. https://doi.org/10.1016/j.lfs.2012.01.001.

    CAS  Article  PubMed  Google Scholar 

  59. Zeiler, S. R., Gibson, E. M., Hoesch, R. E., Li, M. Y., Worley, P. F., O’Brien, R. J., et al. (2013). Medial premotor cortex shows a reduction in inhibitory markers and mediates recovery in a mouse model of focal stroke. Stroke, 44(2), 483–489. https://doi.org/10.1161/STROKEAHA.112.676940.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Zhang, Z. Y., & Schluesener, H. J. (2013). Oral administration of histone deacetylase inhibitor MS-275 ameliorates neuroinflammation and cerebral amyloidosis and improves behavior in a mouse model. Journal of Neuropathology and Experimental Neurology, 72(3), 178–185. https://doi.org/10.1097/NEN.0b013e318283114a.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

This work was partly supported by a NIH research Grant (1R01NS106879).

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AAS, FFA, NS, JS, and VTK performed research. AAS, FFA, NS, and VTK analyzed data. STK and TVA helped with concept and methodology development and interpretation of data. VTK conceived the study. AAS and VTK wrote the paper. All authors revised and approved the manuscript.

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Correspondence to Vardan T. Karamyan.

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The research conducted in this study has been approved by the Texas Tech University Health Sciences Center Institutional Animal Care and Use Committee (Protocol # 16019).

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Al Shoyaib, A., Alamri, F.F., Syeara, N. et al. The Effect of Histone Deacetylase Inhibitors Panobinostat or Entinostat on Motor Recovery in Mice After Ischemic Stroke. Neuromol Med (2021). https://doi.org/10.1007/s12017-021-08647-1

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Keywords

  • Post-stroke recovery
  • Drug repurposing
  • Stroke pharmacotherapy
  • Pre-clinical trial
  • Neural repair
  • HDAC inhibitor