Repositioning of baricitinib for management of memory impairment in ovariectomized/D-galactose treated rats: A potential role of JAK2/STAT3-PI3K/AKT/mTOR signaling pathway.

Autor: Hindam MO; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. Electronic address: merhan.ossama@pharma.cu.edu.eg., Ahmed LA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., El Sayed NS; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., Khattab M; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., Sallam NA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2024 Aug 15; Vol. 351, pp. 122838. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1016/j.lfs.2024.122838
Abstrakt: Aims: Neuroinflammation plays a pivotal role in amyloid β (Aβ) plaques formation which is among the hallmarks of Alzheimer's disease (AD). The present study investigated the potential therapeutic effects of baricitinib (BAR), a selective JAK2/ STAT3 inhibitor, in ovariectomized/ D-galactose (OVX/D-gal) treated rats as a model for AD.
Main Methods: To induce AD, adult female rats (130-180 g) underwent bilateral ovariectomy and were injected daily with 150 mg/kg, i.p. D-gal for 8 consecutive weeks. BAR (10 and 50 mg/kg/day) was then given orally for 14 days.
Key Findings: BAR in a dose-dependent effect mitigated OVX/D-gal-induced aberrant activation of JAK2/STAT3 signaling pathway resulting in significant decreases in the expression of p-JAK 2, and p-STAT3 levels, along with deactivating AKT/PI3K/mTOR signaling as evidenced by deceased protein expression of p-AKT, p-PI3K, and p-mTOR. As a result, neuroinflammation was diminished as evidenced by decreased NF-κβ, TNF-α, and IL-6 levels. Moreover, oxidative stress biomarkers levels as iNOS, and MDA were reduced, whereas GSH was increased by BAR. BAR administration also succeeded in reverting histopathological alterations caused by OVX/D-gal, increased the number of intact neurons (detected by Nissl stain), and diminished astrocyte hyperactivity assessed as GFAP immunoreactivity. Finally, treatment with BAR diminished the levels of Aβ. These changes culminated in enhancing spatial learning and memory in Morris water maze, and novel object recognition test.
Significance: BAR could be an effective therapy against neuroinflammation, astrogliosis and cognitive impairment induced by OVX/ D-gal where inhibiting JAK2/STAT3- AKT/PI3K/mTOR seems to play a crucial role in its beneficial effect.
Competing Interests: Declaration of competing interest none declared.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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