Agonistic analog of growth hormone-releasing hormone promotes neurofunctional recovery and neural regeneration in ischemic stroke

  • Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2109600118. doi: 10.1073/pnas.2109600118.
Yueyang Liu  1  2 ,  Jingyu Yang  2 ,  Xiaohang Che  2 ,  Jianhua Huang  3 ,  Xianyang Zhang  4  5 ,  Xiaoxiao Fu  2 ,  Jialing Cai  2 ,  Yang Yao  1 ,  Haotian Zhang  2 ,  Ruiping Cai  1 ,  Xiaomin Su  1 ,  Qian Xu  1 ,  Fu Ren  6 ,  Renzhi Cai  4  7 ,  Andrew V Schally  8  7  9  10  11  12 ,  Ming-Sheng Zhou  13
Affiliations
  • 1. Department of Physiology, Shenyang Medical College, Shenyang 110034, China.
  • 2. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3. The First Affiliated Hospital, Jinzhou Medical University, Jinzhou 121000, China.
  • 4. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125.
  • 5. Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136.
  • 6. Department of Anatomy, Shenyang Medical College, Shenyang 110034, China.
  • 7. South Florida VA Foundation for Research and Education, Veterans Affairs Medical Center, Miami, FL 33125.
  • 8. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125; [email protected] [email protected].
  • 9. Division of Medical Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.
  • 10. Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.
  • 11. Department of Pathology & Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.
  • 12. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.
  • 13. Department of Physiology, Shenyang Medical College, Shenyang 110034, China; [email protected] [email protected].
PMID: 34782465 DOI: 10.1073/pnas.2109600118
Abstract

Ischemic stroke can induce neurogenesis. However, most stroke-generated newborn neurons cannot survive. It has been shown that MR-409, a potent synthetic agonistic analog of growth hormone-releasing hormone (GHRH), can protect against some life-threatening pathological conditions by promoting cell proliferation and survival. The present study shows that long-term treatment with MR-409 (5 or 10 μg/mouse/d) by subcutaneous (s.c.) injection significantly reduces the mortality, ischemic insult, and hippocampal atrophy, and improves neurological functional recovery in mice operated on for transient middle cerebral artery occlusion (tMCAO). Besides, MR-409 can stimulate endogenous neurogenesis and improve the tMCAO-induced loss of neuroplasticity. MR-409 also enhances the proliferation and inhibits Apoptosis of neural stem cells treated with oxygen and glucose deprivation-reperfusion. The neuroprotective effects of MR-409 are closely related to the activation of Akt/CREB and BDNF/TrkB pathways. In conclusion, the present study demonstrates that GHRH agonist MR-409 has remarkable neuroprotective effects through enhancing endogenous neurogenesis in cerebral ischemic mice.

Keywords
GHRH agonists; ischemic stroke; neural stem cells; neurogenesis; neuroplasticity.
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