Crosstalk between PI3K/AKT/KLF4 signaling and microglia M1/M2 polarization as a novel mechanistic approach towards flibanserin repositioning in parkinson's disease.

Autor: El-Deeb NK; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Egypt., El-Tanbouly DM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Egypt. Electronic address: dalia.eltanbouly@pharma.cu.edu.eg., Khattab MA; Department of Cytology and Histology, Faculty of Veterinary Medicine, Cairo University, 12211, Egypt., El-Yamany MF; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Egypt., Mohamed AF; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Egypt.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2022 Nov; Vol. 112, pp. 109191. Date of Electronic Publication: 2022 Aug 30.
DOI: 10.1016/j.intimp.2022.109191
Abstrakt: Balancing microglia M1/M2 polarization has been shown as a prospective therapeutic strategy for Parkinson's disease (PD). Various vital signaling pathways are likely to govern the microglial phenotype. The implication of 5HT1A receptors in neurodegenerative disorders has raised interest in exploring the repositioning of flibanserin (Flib), a 5HT1A agonist, as an effective neuroprotective agent for PD. Therefore, this study was designed to assess the ability of Flib to modulate microglia phenotype switching from M1 to M2 via PI3K/AKT downstream targets in a rotenone model of PD. Rats received rotenone (1.5 mg/kg) every other day and were concurrently treated with Flib (40 mg/kg/day) with or without wortmannin (15 μg/kg/day), a PI3K inhibitor, for 21 days. Flib improved the motor perturbations induced by rotenone, as confirmed by the reversion of histopathological damage and tyrosine hydroxylase immunohistochemical alterations in both the striata and substantia nigra. The molecular signaling of Flib was elaborated by inducing striatal AKT phosphorylation and the expression of its substantial target, KLF4. Flib induced STAT6 phosphorylation to promote M2 polarization as demonstrated by the increased CD163 ++ microglial count with striatal arginase activity. In parallel, it markedly inhibited M1 activation as evidenced by the reduction in CD86 ++ microglia count with striatal proinflammatory mediators, IL-1β and iNOS. The pre-administration of wortmannin mostly negated Flib's neuroprotective effects. In conclusion, Flib AKT/ KLF4-dependently amended M1/M2 microglial imbalance to exert a promising neuroprotective effect, highlighting its potential as a revolutionary candidate for conquering PD.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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