LCZ696 (sacubitril/valsartan) protects against cyclophosphamide-induced testicular toxicity in rats: Role of neprilysin inhibition and lncRNA TUG1 in ameliorating apoptosis

Abstract

Cyclophosphamide (CP) is widely used as chemotherapy in various cancers; however, testicular atrophy has been encountered as an associated adverse effect. Oxidative stress, enhanced endoplasmic reticulum (ER) stress, and subsequent apoptosis are involved in the molecular mechanisms of CP-induced testicular toxicity. In addition to the cardiovascular benefits of LCZ696 (sacubitril/valsartan (VAL)), neprilysin inhibition was shown to mediate Ca2+ sequestration inside the ER. Furthermore, long noncoding RNA taurine-upregulated gene 1 (lncRNA TUG1) was shown to ameliorate apoptosis in various diseases. This tempted us to investigate the possible benefit of LCZ696 against CP-induced testicular dysfunction in rats through neprilysin inhibition axis, and the downstream apoptotic cascade, with highlighting the impact of lncRNA TUG1 in regulating testicular toxicity. Sixty adult male Wistar rats were randomly allocated as control, LCZ696, VAL, CP, CP + LCZ696, and CP + VAL. Testicular atrophy was induced by single-dose injection of CP (200 mg/kg; i.p.). LCZ696 treated group received LCZ696 (30 mg/kg; p.o.) for 6 days, with CP (200 mg/kg; i.p.) single-dose on day 5. LCZ696 increased lncRNA TUG1 expression, improved sperm characteristics, hormonal profile, testicular function, antioxidant defences, and Bcl-2. The histopathological picture and reduced oxidative and ER stress markers, aligned with declined Bax, caspase-3 and the expression of CHOP, PUMA, Noxa, Bim, and p53, with a subtle superior effect over VAL-treated group. In conclusion, the current study highlights the promising impact of LCZ696 in ameliorating chemotherapy-induced testicular atrophy; yet, further investigation regarding longer duration and different doses of LCZ696 is warranted.