Multi-pathway neuroprotective effects of a novel salidroside derivative SHPL-49 against acute cerebral ischemic injury

Pei Zhang; Jiazhen Xu; Qianfei Cui; Guoqiang Lin; Feiyun Wang; Xinyue Ding; Suxin You; Nina Sang; Junchao Tan; Wenwen Xu; Changsen Zhan; Yuying Zhu; Jiange Zhang

doi:10.1016/j.ejphar.2023.175716

Multi-pathway neuroprotective effects of a novel salidroside derivative SHPL-49 against acute cerebral ischemic injury

Eur J Pharmacol. 2023 Jun 15:949:175716. doi: 10.1016/j.ejphar.2023.175716. Epub 2023 Apr 13.

Authors

Affiliations

¹ The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
² Shanghai Hutchison Pharmaceuticals Limited, Shanghai Engineering Research Center for Innovation of Solid Preparation of TCM, Shanghai, China.
³ The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: jgzhang@shutcm.edu.cn.

PMID: 37059375
DOI: 10.1016/j.ejphar.2023.175716

Abstract

SHPL-49 ((2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-(4-methoxyphenyl) butoxy) tetrahydro-2H-pyran-3,4,5-triol) is a novel glycoside derivative obtained from structural modification of salidroside, which is isolated from the medicinal plant Rhodiola rosea L. SHPL-49 was administered to rats with permanent middle cerebral artery occlusion (pMCAO) for 5 days, and it was found that SHPL-49 could alleviate the cerebral infarct volume and reduce the neurological deficit score. Moreover, the effective time window of SHPL-49 in the pMCAO model was from 0.5 to 8 h after embolization. In addition, the result of immunohistochemistry showed that SHPL-49 could increase the number of neurons in the brain tissue and reduce the occurrence of apoptosis. Morris water maze and Rota-rod experiments showed that SHPL-49 could improve neurological deficits, repair neurocognitive and motor dysfunction, and enhance learning and memory ability in the pMCAO model after 14 days of SHPL-49 treatment. Further in vitro experiments showed that SHPL-49 significantly reduced the calcium overload of PC-12 cells and the production of reactive oxygen species (ROS) induced by oxygen and glucose deprivation (OGD), and increased the levels of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased the production of malondialdehyde (MDA). Furthermore, SHPL-49 could reduce cell apoptosis by increasing protein expression ratio of anti-apoptotic factor Bcl-2 to pro-apoptotic factor Bax in vitro. SHPL-49 also regulated the expression of Bcl-2 and Bax in ischemic brain tissue, and even inhibited the caspase cascade of pro-apoptotic proteins Cleaved-caspase 9 and Cleaved-caspase 3. Taken together, SHPL-49 exhibited neuroprotective effects against cerebral ischemic injury through multiple pathways, such as alleviating calcium overload, reducing oxidative stress damage, and inhibiting apoptosis.

Keywords: Apoptosis; Ischemic stroke; Neuroprotective; Oxidative stress; Salidroside derivative.

MeSH terms

Animals
Apoptosis
Brain Injuries*
Brain Ischemia* / drug therapy
Brain Ischemia* / metabolism
Calcium / metabolism
Infarction, Middle Cerebral Artery / drug therapy
Infarction, Middle Cerebral Artery / metabolism
Ischemia
Neuroprotective Agents* / pharmacology
Neuroprotective Agents* / therapeutic use
Oxidative Stress
Proto-Oncogene Proteins c-bcl-2 / metabolism
Rats
Reperfusion Injury* / drug therapy
Reperfusion Injury* / metabolism
bcl-2-Associated X Protein / metabolism

Substances

rhodioloside
Neuroprotective Agents
bcl-2-Associated X Protein
Calcium
Proto-Oncogene Proteins c-bcl-2