The Cerebroprotein Hydrolysate-I Plays a Neuroprotective Effect on Cerebral Ischemic Stroke by Inhibiting MEK/ERK1/2 Signaling Pathway in Rats

Abstract

Objective: To investigate the neuroprotective effect and mechanism of cerebroprotein hydrolysate-I (CH-I) on cerebral ischemia/reperfusion injury in rats. Methods: A total of 100 adult healthy male SD rats were randomly divided into a sham group, model group, CH-I treated group, and cerebrolysin (CBL) positive group, consisting of 20 rats in each group. The middle cerebral artery occlusion/reperfusion (MCAO/R) model of rats was built by inserting a suture into the left external carotid artery (ECA) through the internal carotid artery (ICA). Treatment was performed by intraperitoneal injection of CH-I (20 mg/kg). The neurobehavioral function of rats was evaluated by modified neurological severity scores (mNSS). TTC staining was used to detect the cerebral infarction volume (CIV) of rats. The morphological and structural changes of nerve cells were observed by HE staining and the neuronal apoptosis was counted by TUNEL assay. Immunohistochemical (IHC) analysis was used to detect BDNF and pMEK1/2 expressions. The expressions of BDNF, pMEK1/2, pERK1/2, and pCREB were determined with Western blotting. Results: After treatment with CH-I, the mNSS and CIV of rats were improved (P<0.05). And the CH-I can reduce the degeneration and apoptosis of nerve cells in rats (P<0.01). Western blotting showed that the expressions of pMEK1/2, pERK1/2, and pCREB in rats were increased, while the expression of BDNF was decreased after modeling (P<0.05). After treatment, the expressions of pMEK1/2, pERK1/2, and pCREB in the CH-I group were decreased (P<0.05), while the expression of BDNF was significantly increased (P<0.05) compared with the model group. IHC showed that the expression of BDNF and pMEK1/2 was consistent with Western blotting. Conclusion:It is suggested that the CH-I might play a neuroprotective role by inhibiting the expression of MEK-ERK-CREB and enhancing the expression of BDNF after cerebral ischemia/reperfusion injury, thus improving the neurobehavioral function of MCAO/R rats.

Exploring the Neuroprotective Effects of Lithium in Ischemic Stroke: A literature review

“…The stimulation of the MEK/ERK1/2 signaling proved detrimental to the functional outcome of ischemic stroke 72 . Inhibiting the MEK/ERK1/2/CREB signaling pathway may enhance BDNF expression and exert neuroprotective effects, thereby improving neurobehavioral function in rats after middle cerebral artery occlusion/reperfusion (MCAO/R) 73 . This result contradicts previous studies that suggested a neuroprotective effect of activating this pathway in ischemic stroke 69 - 71 .…”

“…Neurotrophic factors exert their effects by binding to two types of transmembrane receptors: tropomyosin-related kinase (Trk) family and p75 neurotrophin receptor (p75NTR) 80 . Specifically, phosphorylated TrkB activates three major intracellular signaling pathways: the MAPK/ERK pathway, which influences cell growth and differentiation; the PI3K/AKT pathway, associated with cell survival; and the phospholipase C-γ (PLCγ)/Ca2+ pathway, which modulates synaptic plasticity 73 , 81 , 82 . Elevated BDNF levels regulate the PI3K/AKT pathway through TrkB, contributing to a neuroprotective role in cerebral ischemia-reperfusion injury 83 .…”

“…This activation inhibits oxidative stress, inflammation, and apoptosis, achieving neuroprotective effects 97 . Additionally, the inhibition of GSK-3β/CREB/BDNF 98 and MAPK/ERK/CREB/BDNF 73 signaling pathways can upregulate BDNF expression, thereby alleviating cerebral ischemia-reperfusion injury.…”

Identification and Validation of Active Ingredient in Cerebrotein Hydrolysate-I Based on Pharmacokinetic and Pharmacodynamic Studies

“…These technologies and strategies provided noteworthy references for the pharmacokinetic and metabolic studies of protein extracts. Cerebroprotein hydrolysate-1 (CH-1), one kind of CH developed by Hebei Zhitong Biopharmaceutical Co., Ltd (Shijiazhuang, Hebei, China), was prepared from denatured proteins and had been proved to exert a neuroprotective role by MEK/ERK1/2 and JAK2/STAT3 pathways (Ren et al, 2021;Zhu et al, 2021). The present study aims to reveal the active peptides in CH-1, and then explore the pharmacological properties of the active peptides by examining their pharmacokinetic characteristics.…”