Halcinonide activates smoothened to ameliorate ischemic stroke injury

  • Life Sci. 2025 Jan 15:361:123324. doi: 10.1016/j.lfs.2024.123324.
Jingjing Liu  1 ,  Wenyang Zhao  2 ,  Jia Kang  2 ,  Xiangxiang Li  2 ,  Liang Han  2 ,  Zhuozhou Hu  2 ,  Jing Zhou  2 ,  Xinrui Meng  2 ,  Xiaoshan Gao  2 ,  Yixuan Zhang  2 ,  Youquan Gu  3 ,  Xiaohua Liu  4 ,  Xinping Chen  5
Affiliations
  • 1. School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; School of Basic Medical Sciences, University of South China, Hengyang, Hunan 421001, PR China. Electronic address: [email protected].
  • 2. School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
  • 3. Department of Neurology, First Hospital of Lanzhou University, Lanzhou 730000, PR China. Electronic address: [email protected].
  • 4. School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China. Electronic address: [email protected].
  • 5. School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou 730000, PR China; Southeast Research Institute, Lanzhou University, Lanzhou 730000, PR China. Electronic address: [email protected].
PMID: 39710062 DOI: 10.1016/j.lfs.2024.123324
Abstract

Objectives: The Shh pathway may shed new light on developing new cell death inhibitors for the therapy of ischemic stroke. We aimed to examine whether the Shh co-reporter Smo or its agonist halcinonide can upregulate Bcl-2 to suppress neuronal cell death, ultimately improving behavioral deficits and reducing cerebral infarction in an ischemic stroke model.

Methods: Halcinonide or genetic manipulation of Smo was conducted in PC12 cells to examine their impacts on oxidative or OGD/R stress, and the chemical, along with AAV-SMO or AAV-EGFP were tested in MCAO rats to investigate their potential protective effects against neuronal damages due to cerebral I/R injury. The amounts or activities of L-LA, LDH, ROS, MDA, SOD, MPO, GSSG, and GSH were detected using the corresponding biochemical kits. The levels of TNF-α and IL-6 were analyzed by ELISA.

Results: The results show that halcinonide alleviated neurological score and cerebral infarction, and the abnormal changes in L-LA, LDH, MDA, SOD, MPO, GSH, GSSG, TNF-α, and IL-6 were also reversed in MCAO rats. Through expression or knockout of Smo, we discovered that Smo worked similarly to halcinonide, protecting neuronal cells from oxidative or OGD/R stress, and AAV-SMO prevented cerebral damages of MCAO rats caused by ischemia and reperfusion. Halcinonide inhibited Bcl-2/Bax-mediated Apoptosis, at least partially by promoting the Shh signaling pathway through enhancing Smo expression in vivo and in vitro.

Conclusion: This study identified a new target and a candidate chemical for therapy of ischemic stroke, hopefully reducing its morbidity and mortality.

Keywords
Adeno-associated virus; Halcinonide; Ischemic stroke; Smoothened; Sonic hedgehog pathway.
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