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Protecting Cerebral Blood Flow Autoregulation: A Frontier Study on Aripiprazoles Inhibition of the MAPK Signaling Pathway after Cerebral Ischemia
Vol 38, Issue 5, 2024
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Abstract
Background: Cerebral ischemia-reperfusion injury (CIRI) is a common severe complication following cerebrovascular diseases and poses significant challenges to human health and life. Aripiprazole, due to its unique pharmacological effects, is recognized to exert a protective effect against Ischemia/Reperfusion (I/R) injury. Therefore, this study aimed to explore the protective effect of Aripiprazole on CIRI by inhibiting the p38 mitogen-activated protein kinase (MAPK) signaling pathway and its impact on the function of cerebral blood flow autoregulation. Methods: We successfully developed the CIRI rat model and divided rats into different groups: the Sham group, the I/R+DMSO group, the I/R+Aripiprazole low-dose group (1 mg/kg), and the high-dose group (3 mg/kg). The neuroprotective effect of Aripiprazole, its impact on the p38 MAPK signaling pathway, cell apoptosis, inflammatory response, oxidative stress response, and improvement of cerebral blood flow autoregulation function were evaluated using Triphenyltetrazolium Chloride (TTC) staining, western blot, terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) staining, and Enzyme-Linked Immunosorbent Assay (ELISA). Results: Compared to the I/R+DMSO group, the I/R+Aripiprazole group exhibited a significant reduction in the volume of cerebral infarction, brain edema, neurological function injury scores, and the number of TUNEL-positive cells in brain tissue (p < 0.05, p < 0.01, and p < 0.001), indicating a significant neuroprotective effect of Aripiprazole. Western blot results revealed that Aripiprazole significantly inhibited the activation of the p38 MAPK signaling pathway induced by I/R (p < 0.05, p < 0.01, and p < 0.001). Additionally, Aripiprazole significantly reduced the expressions of pro-inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), IL-6), decreased malondialdehyde (MDA) levels, and elevated the levels of superoxide dismutase (SOD) and glutathione (GSH) (p < 0.05, p < 0.01, and p < 0.001). Conclusion: Aripiprazole effectively protects rats from CIRI by inhibiting the p38 MAPK signaling pathway, reducing cell apoptosis, suppressing inflammation and oxidative stress response, and improving cerebral blood flow autoregulation function. These findings provide an experimental basis for applying Aripiprazole in treating CIRI and lay the foundation for future clinical research.
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Copyright (c) 2024 Jianghua Xu, Jie Zhu, Pengcheng Liu, Bin Ma, Tingyi Zhang
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy