Abdel-Aal_2025_Brain.Res__149573

BACKGROUND AND AIM: Alzheimer's disease (AD) is the most progressive form of neurodegenerative disease, which severely impairs cognitive function. The leading class of drugs used to treat AD is acetylcholinesterase inhibitors (AChE-Is) as Rivastigmine (RIVA), partially ameliorate its cognitive symptoms. Since epilepsy is a common comorbidity with AD, we explored the potential that new the antiepileptic drugs; Levetiracetam (LEV) and Zonisamide (ZNS) may possess an additional therapeutic benefit to RIVA in AlCl(3)-induced AD rat model. MATERIALS AND METHODS: AlCl(3) was used to provoke AD in rats which were then supplemented with treatment drugs for 2 weeks. Treated groups were: Control, AlCl(3), RIVA, LEV, RIVA + LEV, ZNS and RIVA + ZNS. Then, the behavioral tests; passive avoidance (PA), Morris water maze (MWM) and novel object recognition (NOR) were conducted to assess cognitive behavior and memory. The Hippocampal Abeta assembly was thoroughly examined by histopathology and ELISA. alpha7 Nicotinic ACh receptors' (alpha7nAChRs) expression was assessed immunohistochemically and by real-time quantitative polymerase chain reaction (qPCR). Caspase 3 expression was also assessed by real-time qPCR in hippocampal tissues. RESULTS: AlCl(3) administration impaired memory and cognitive functions in rats, augmented hippocampal Abeta deposition, with subsequent neurodegeneration and alpha7nAChRs down-regulation. LEV, but not ZNS, administration significantly mitigated AlCl(3)-induced cognitive impairment probably through suppression of amyloid beta (Abeta) deposition, enhancement of neurogenesis and alpha7nAChRs expression. When combined to RIVA, ZNS treatment negatively affected cognition possibly through its impact on hippocampal Abeta and subsequent neuronal damage. CONCLUSION: Although our results indicated that neither LEV nor ZNS provided any extra benefit to cognitive enhancements in AD rats receiving rivastigmine, LEV demonstrated positive effects individually while ZNS had negative effects when combined with RIVA. As a result, this study suggests the use of LEV rather than ZNS for managing epilepsy in patients with AD given that Alzheimer's and epilepsy can coexist.