Galantamine Ameliorates Doxorubicin-Induced Cognitive Impairment in Female Rats via Modulation of Neuroinflammation, BDNF/TrkB Pathway and Synaptic Plasticity

Background: Chemotherapy-related cognitive impairment is a debilitating neurocognitive syndrome with no approved treatment. Doxorubicin induces neuroinflammation, disrupts neurotrophic signaling, and impairs synaptic plasticity. Galantamine, an acetylcholinesterase inhibitor, has anti-inflammatory and neuroprotective properties. This study investigated the dose-dependent effects of galantamine (2.5 and 5 mg/kg) on cognitive behavior, neuroinflammation, the BDNF/TrkB pathway, and synaptic plasticity in a rat model of doxorubicin-induced cognitive impairment. Methods: Female Sprague Dawley rats were divided into control, doxorubicin (4 mg/kg/week, i.p.), doxorubicin + galantamine (2.5 mg/kg/day, oral), and doxorubicin + galantamine (5 mg/kg/day, oral) groups. After four weeks, spatial learning and memory were assessed using the Morris water maze, and recognition memory using the novel object recognition test. Hippocampal IL-1β, IL-10, BDNF, and AChE levels were measured by ELISA. Histopathology was assessed by H&E staining. TrkB expression was evaluated by immunohistochemistry, and PSD-95 and synaptophysin by Western blot. Results: Doxorubicin impaired spatial learning and memory and reduced discrimination index in the NOR test. Galantamine, especially at 5 mg/kg, attenuated these deficits. Doxorubicin increased IL-1β and AChE, while decreasing IL-10 and BDNF. Galantamine at both doses reversed IL-1β and AChE increases and increased BDNF; only the 2.5 mg/kg dose increased IL-10. Doxorubicin-induced neuronal shrinkage and apoptosis were ameliorated by galantamine. Doxorubicin upregulated TrkB, which was normalized by high-dose galantamine. Western blot showed that doxorubicin increased PSD-95 and decreased synaptophysin; galantamine did not alter PSD-95 but reversed the synaptophysin decrease at low dose. Conclusions: Galantamine exerts dose-dependent neuroprotective effects against doxorubicin-induced cognitive impairment by reducing neuroinflammation, modulating BDNF and TrkB levels, and preserving presynaptic plasticity. These findings suggest galantamine as a potential option for preventing chemotherapy-related cognitive impairment.