Comparative Evaluation of Imatinib and Nilotinib in a Streptozotocin-Induced Rat Model of Alzheimer's Disease : Neuroprotective, Anti-inflammatory, and Cognitive Outcomes.

OBJECTIVE: Alzheimer's disease is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) peptide aggregation, representing a major therapeutic target. Emerging evidence suggests certain chemotherapeutic agents may attenuate Aβ pathology. METHODS: This study investigated the effects of imatinib, a tyrosine kinase inhibitor with limited blood-brain barrier (BBB) penetration, and nilotinib, with enhanced BBB permeability, in an intracerebroventricular streptozotocin (ICV-STZ) rat model of Alzheimer's disease. Outcomes included behavioral assessments (learning latency), hippocampal CA1 and CA3 neuronal counts, and brain concentrations of tumor necrosis factor (TNF)-α, nuclear factor kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), and neuregulin-1 (NRG-1). RESULTS: ICV-STZ administration significantly elevated TNF-α and NF-κB levels and reduced BDNF and NRG-1 expression. Both imatinib and nilotinib mitigated these alterations, with imatinib demonstrating greater efficacy despite its limited BBB permeability. Imatinib and nilotinib reduced TNF-α and NF-κB levels, increased BDNF and NRG-1 expression, and significantly improved cognitive performance, with latency periods extending from 69.8 seconds in the disease model to 193.5 and 183.1 seconds, respectively. CONCLUSION: Imatinib and nilotinib ameliorated neuroinflammation, restored neurotrophic support, and improved cognitive deficits in a preclinical Alzheimer's disease model. These findings highlight the therapeutic potential of tyrosine kinase inhibitors, warranting further translational research in human studies.