Cognitive Protective Mechanism of Crocin Pretreatment in Rat Submitted to Acute High-Altitude Hypoxia Exposure

Abstract

Inadequate oxygen availability at high altitude leads to oxidative stress, resulting in hippocampal neurodegeneration and memory impairment. In our previous study, we found that the cognitive dysfunction occurred when male SD rat was rapidly exposed to 4200 m of high altitude for 3 days. And we also found that crocin showed a cognitive protective effect under hypoxia by regulating SIRT1/PGC-1α pathways in rat’s hippocampus. In this article, focused on factors related to SIRT1/PGC-1α pathways, we proposed to further elucidate crocin’s pharmacological mechanism. Adult male Sprague-Dawley rats were randomly divided into five groups: control group, hypoxia group (rats were rapidly transported to high altitude of 4200 m for 72 h), and crocins+hypoxia groups (pretreatment with crocin of 25, 50, and 100 mg/kg/d for 3 days). The learning and memory ability was tested by Morris water maze analysis. Hippocampal histopathological changes were observed by HE staining and Nissl staining. The expression of NRF1, TFAM, Bcl-2, Bax, and caspase-3 was detected by immunohistochemistry, RT-PCR, and western blotting test. The contents of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSHPx) were detected by the TBA, WST, and colorimetry method. Neuronal apoptosis was observed by TUNEL staining. After crocin pretreatment, the traveled distance was significantly reduced and the percentage of time in the target quadrant was significantly increased tested by Morris water maze. And neuronal damage in the hippocampus was also significantly ameliorated based on HE staining and Nissl staining. Furthermore, in hippocampus tissue, mitochondrial biosynthesis-related factors of NRF1, TFAM expression was increased; oxidative stress factors of SOD, GSH, and GSHPx expression level were increased, and MDA and glutathione disulfide (GSSG) level were decreased; antiapoptotic protein Bcl-2 expression was increased, and proapoptotic proteins Bax and caspase-3 expression were decreased, with a manner of crocin dose dependent. Therefore, the cognitive protective mechanism of crocin in rat under acute hypoxia was related to promoting mitochondrial biosynthesis, ameliorating oxidative stress injury, and decreasing neuronal apoptosis.

Crocin molecular signaling pathways at a glance: A comprehensive review

“…SIRT1 expression was decreased in the hypobaric hypoxia‐induced cognitive model and crocin administration improved the SIRT1 and PGC‐1α levels. Therefore, the cognitive protective effect of crocin is related to SIRT1/PGC‐1 α pathway regulation (Zhang, Zhang, et al, 2018; Zhang, Zhang, et al, 2020). Furthermore, the antidepressant effect of crocin can be dependent on SIRT3 activation stimulation (Xiao et al, 2019).…”

A Famous Chinese Medicine Formula: Yinhuo Decoction Antagonizes the Damage of Corticosterone to PC12 Cells and Improves Depression by Regulating the SIRT1/PGC-1α Pathway

“…According to report, SIRTI can activate transcription factors and metabolic coactivators, such as PGC-1α, by targeting selected genomic sites [45]. PGC-1α is a powerful transcriptional coregulator of mitochondrial genes, which can enhance the oxidative stress and mitochondrial respiration, and effectively improving the cognitive ability of rats [46]. Yang et al found that exogenous IGF-1 alleviated depression-like behavior and hippocampal mitochondrial dysfunction via promoting the expression of PGC-1α [47].…”

Preparation, Characterization, Evaluation of Neuroprotective Effect, and Related Mechanisms of Phosphatidylserine Emulsion in 5- and 12-Week Old Mice

“…Briefly, total RNA was isolated from the hippocampus of mice using TriZol reagent. 29 Total RNA was reverse transcribed into cDNA using a cDNA reverse transcription kit (TransScript All-in-one First-Strand cDNA Synthesis SuperMix for qPCR, Beijing Transgen Biotech Co., Ltd.) to amplify the cDNA. RT-PCR amplification was performed using QuantStudio1 (Thermo Fisher Applied Biosystems).…”