One of the major consequences of diabetes mellitus that has gained attention due to its rising incidence is cognitive impairment. Recent research suggested that sodium-glucose cotransporter-2 (SGLT-2) inhibitors can mitigate memory impairment linked to Alzheimer’s disease and are now being explored for their cognitive benefits. However, their mechanisms were not thoroughly studied. This research investigates the hypothesis of the neuroprotective effect of empagliflozin administration against scopolamine-heavy metal mixture (SCO + HMM)-treated Alzheimer’s rat models in comparison with memantine as a reference drug and the impact of their combination. Yet, the neuroprotective effects of memantine and empagliflozin combination against cognitive impairment have not been previously explored. This study employed adult male albino rats categorized into five groups. The impact of empagliflozin, memantine, and their concomitant administration on cognitive performance was assessed in a scopolamine and heavy metal mixture-treated Alzheimer’s disease model in rats. The assessment of rats’ cognitive behavior, memory, and spatial learning was conducted, followed by an evaluation of hippocampal brain-derived neurotrophic factor (BDNF), beta-secretase (BACE-1), oxidative stress (OS), and inflammatory marker activity. And, a western blot analysis was conducted to detect phosphorylated 5’ AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of rapamycin (p-mTOR), and heme oxygenase-1 (HO-1). Hippocampal and cerebellar histopathology were thoroughly examined, in addition to the expressions of amyloid β (Aβ). The current data demonstrate the involvement of the pAMPK/mTOR/HO-1 signaling pathway in empagliflozin neuroprotection against SCO + HMM-induced AD. In addition, it reduces AD hallmarks (Aβ and BACE1), neuro-inflammation, and oxidative stress sequelae, and enhances neurogenesis and synaptic density via BDNF. This study proposes that EMPA, especially when co-administered with other conventional anti-Alzheimer therapy, may be formulated into an innovative therapeutic strategy for the enhancement of cognitive impairments associated with neurodegenerative disorders.

Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterized by ovarian dysfunction, hormonal imbalance, and emerging ferroptosis-related abnormalities. This study investigated the effects of alpha-lipoic acid (ALA), saxagliptin (Saxa), and their combination in a letrozole-induced PCOS model, with focus on the ovarian FGF21/NOX4–NRF2/HO-1 and ferroptosis-related pathways. PCOS was induced in female rats by oral letrozole administration for 21 days. Rats were allocated into control, PCOS, ALA, Saxa, and ALA/Saxa groups, followed by 14 days of treatment. Body weight, ovarian index, ovarian histopathology, reproductive hormones, oxidative stress markers, ovarian FGF21 and NOX4 expression, NRF2/HO-1 signaling, and ferroptosis-related markers, including Fe²⁺, GPX4, and SLC7A11, were assessed. Letrozole induced weight gain, ovarian hypertrophy, follicular disruption, endocrine imbalance, and ferroptosis-related alterations, marked by increased ROS, MDA, Fe²⁺, and NOX4, alongside reduced FGF21, NRF2/HO-1, GPX4, and SLC7A11. ALA or Saxa attenuated these alterations, whereas ALA/Saxa produced greater improvements in ovarian morphology, hormonal status, redox homeostasis, and ferroptosis-related markers. These effects were associated with FGF21 upregulation, NOX4 suppression, enhanced NRF2/HO-1 signaling, and preservation of GPX4 and SLC7A11. In conclusion, ALA/Saxa therapy markedly ameliorated letrozole-induced PCOS in rats, accompanied by restoration of ovarian FGF21/NOX4 homeostasis, associated with enhancement of NRF2/HO-1 antioxidant responses, and attenuation of ferroptosis-related alterations.