Buspirone ameliorates premature ovarian insufficiency evoked by cyclophosphamide in female rats; attention to AMPK/Nrf2/HO-1, α-Klotho/NLRP3/Caspase-1, and Caspase-3-mediated apoptosis interplay

Waleed A.I. Khallaf, Ehab E Sharata, Mina Ezzat Attya, Remon Roshdy Rofaeil, Marwa M. Khalaf, Ramadan A.M. Hemeida, Amira M. Abo‐Youssef
In: Toxicology and Applied Pharmacology · 2025 · vol. 500 , pp. 117373 · doi:10.1016/j.taap.2025.117373 · PMID:40345558 · W4410176735
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Buspirone treatment reversed cyclophosphamide-induced premature ovarian insufficiency in rats by modulating AMPK/Nrf2/HO-1, α-Klotho/NLRP3/Caspase-1 pathways and reducing apoptosis.

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Abstract

This study aims to investigate the protective impact of buspirone (BUS) against cyclophosphamide (CPA)-induced premature ovarian insufficiency (POI) by focusing on pyroptosis, apoptosis, and the AMPK/Nrf2/HO-1 signaling pathway. POI was achieved by i.p. injection of CPA in female Wistar albino rats. CPA toxicity was evaluated using biochemical analysis of the serum hormones (AMH, FSH, inhibin B, and estrogen) and histopathological examination. Oxidative stress markers (MDA, SOD) were also evaluated. Levels of inflammatory indicators (TNF-α, IL-1β, and IL-18), apoptotic marker (caspase-3), ovarian p-AMPK, ovarian NF-κB, Nrf2, and HO-1 were evaluated. RT-qPCR was used to measure Bax and Bcl-2 mRNA expression. A western blot assay was used to determine the expression of α-Klotho, NLRP3, and caspase 1. The estrous cycle and the weights of the body and ovaries were also observed. BUS, in a dose-dependent manner, attenuated CPA-induced ovarian toxicity by regulating hormonal and estrous cycle irregularities and alleviating the histopathological aberrations. It also lowered MDA levels and increased SOD activity. Furthermore, it reduced NF-κB, TNF-α, IL-1β, and IL-18 levels, as well as BAX and caspase-3 expression, while raising Bcl-2 levels. Additionally, BUS enhanced Nrf2 and HO-1 expression and boosted the protein levels of p-AMPK and α-Klotho. As well, it diminished pyroptosis by decreasing NLRP3 and caspase-1 expression. BUS attenuated POI induced by CPA, showing potential for effective protection via increasing the activity of Nrf2/HO-1 and reducing the activity of NLRP3/Caspase-1 through the participation of α-Klotho and p-AMPK, as well as inhibiting caspase-3-driven apoptosis.

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