GJ-4 ameliorates memory impairment in focal cerebral ischemia/reperfusion of rats via inhibiting JAK2/STAT1-mediated neuroinflammation.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Gardenia jasminoides J. Ellis (Fructus Gardenia) is a traditional Chinese medicine with diverse pharmacological functions, such as anti-inflammation, anti-depression, as well as improvement of cognition and ischemia brain injury. GJ-4 is a natural extract from Gardenia jasminoides J. Ellis (Fructus Gardenia) and has been proved to improve memory impairment in Alzheimer's disease (AD) mouse model in our previous studies.

AIM OF THE STUDY:

This study aimed to evaluate the therapeutic effects of GJ-4 on vascular dementia (VD) and explore the potential mechanisms.

MATERIAL AND METHODS:

In our experiment, a focal cerebral ischemia and reperfusion rat model was successfully developed by the middle cerebral artery occlusion and reperfusion (MCAO/R). GJ-4 (10 mg/kg, 25 mg/kg, 50 mg/kg) and nimodipine (10 mg/kg) were orally administered to rats once a day for consecutive 12 days. Learning and memory behavioral performance was assayed by step-down test and Morris water maze test. The neurological scoring test was performed to evaluate the neurological function of rats. 2,3,5-Triphenyltetrazolium chloride (TTC) staining and Nissl staining were respectively employed to determine the infarct condition and neuronal injury of the brain. Iba1 immunohistochemistry was used to show the activation of microglia. Moreover, the synaptic damage and inflammatory level were detected by Western blot.

RESULTS:

GJ-4 could significantly improve memory impairment, cerebral infraction, as well as neurological deficits of VD rats induced by MCAO/R. Further research indicated VD-induced neuronal injury was alleviated by GJ-4. In addition, GJ-4 could protect synapse of VD rats by upregulating synaptophysin (SYP) expression, post synaptic density 95 protein (PSD95) expression, and downregulating N-Methyl-D-Aspartate receptor 1 (NMDAR1) expression. Subsequent investigation of the underlying mechanisms identified that GJ-4 could suppress neuroinflammatory responses, supported by inhibited activation of microglia and reduced expression of inflammatory proteins, which ultimately exerted neuroprotective effects on VD. Further mechanistic study indicated that janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) pathway was inhibited by GJ-4 treatment.

CONCLUSION:

These results suggested that GJ-4 might serve as a potential drug to improve VD. In addition, our study indicated that inhibition of neuroinflammation might be a promising target to treat VD.

• Authors: Hui Liu, Zihong Zhang, Caixia Zang, Lu Wang, Hanyu Yang, Chanjuan Sheng, Junmei Shang, Zhe Zhao, Fangyu Yuan, Yang Yu, Xinsheng Yao, Xiuqi Bao, Dan Zhang
• Journal: Journal of ethnopharmacology (J Ethnopharmacol) Vol. 267 Pg. 113491 (Mar 01 2021) ISSN: 1872-7573 [Electronic] Ireland
• PMID: 33091490 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• Drugs, Chinese Herbal
• Inflammation Mediators
• Neuroprotective Agents
• Nootropic Agents
• Plant Extracts
• STAT1 Transcription Factor
• Stat1 protein, rat
• Jak2 protein, rat
• Janus Kinase 2

Topics

• Animals
• Behavior, Animal (drug effects)
• Brain (drug effects, enzymology, pathology, physiopathology)
• Dementia, Vascular (enzymology, etiology, prevention & control, psychology)
• Disease Models, Animal
• Drugs, Chinese Herbal (pharmacology)
• Gardenia
• Infarction, Middle Cerebral Artery (complications, drug therapy, enzymology, physiopathology)
• Inflammation Mediators (metabolism)
• Janus Kinase 2 (metabolism)
• Male
• Memory (drug effects)
• Memory Disorders (enzymology, etiology, prevention & control, psychology)
• Microglia (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Nootropic Agents (pharmacology)
• Plant Extracts (pharmacology)
• Rats, Sprague-Dawley
• Reperfusion Injury (enzymology, etiology, physiopathology, prevention & control)
• STAT1 Transcription Factor (metabolism)
• Signal Transduction
• Synapses (drug effects, metabolism, pathology)
• Rats