Repurposing of cabergoline to improve cognitive decline in D-galactose-injected ovariectomized rats: Modulation of AKT/mTOR, GLT-1/P38-MAPK, and ERK1/2 signaling pathways.

Dopamine is involved in many physiological functions including reward phenomenon, motor, learning, and memory functions. Dopamine receptor agonists have been shown to reduce amyloid (Aβ) deposition, enhance memory, and improve cortical plasticity in experimental studies and Alzheimer's disease (AD) patients; however, the molecular mechanisms involved haven't been investigated yet. The target of this investigation was to elucidate the modulatory effects of cabergoline (CAB), a dopamine receptor agonist, against AD. Ovariectomized rats were injected with D-galactose (150 mg/kg/day, i.p) for ten weeks to exacerbate AD. CAB administration (1 mg/kg/day, i.p) for 28 days, beginning from the 7th week of D-galactose administration, attenuated the associated histopathological alterations and enhanced the spatial and recognition memory in Morris water maze and Novel object recognition tests, respectively. CAB decreased the hippocampal concentrations of Aβ42, p-tau, and β-secretase, while upregulating α-secretase. Moreover, CAB diminished nuclear factor-kappa β (NF-κβ), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and myeloperoxidase, while elevating brain-derived neurotrophic factor and phospho-cAMP response element binding protein. Further, CAB reduced the hippocampal phosphorylated forms of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) contrary to elevating Beclin-1, resulting in autophagy induction, which participates in accelerating Aβ42 and p-tau aggregates clearance. Moreover, CAB increased the hippocampal glutamate transporter-1 (GLT-1) protein expression, promoting glutamate uptake that possibly reduced Ca overload and consequently decreased the phosphorylated forms of P38-MAPK and ERK1/2. In conclusion, CAB improved cognitive decline of D-gal/OVX animals, restored hippocampal architecture, exerted neuroprotection, and enhanced autophagic machinery via modulating AKT/mTOR, GLT-1/P38-MAPK, and ERK1/2 pathways.