Lurasidone ameliorates doxorubicin-induced chemobrain in male Wistar rats: involvement of the hippocampal and prefrontal cortex CREB/BDNF/Glt-1 axis and glutamate homeostasis.

INTRODUCTION: Chemotherapy-induced cognitive impairment, commonly referred to as "chemobrain", represents a frequent and distressing complication of cancer therapy. Doxorubicin (DOX), a widely used chemotherapeutic agent, contributes to these deficits partly through mechanisms involving oxidative stress, inflammatory cascades, and disruption of glutamate homeostasis, but unfortunately, the precise role of altered glutamate transport and neurotrophic signaling remains poorly addressed. Lurasidone (LURA), an atypical antipsychotic, exhibits potent 5-HT7 receptor antagonism and pro-cognitive properties, making it a strong candidate to counteract these deficits. However, its potential to rescue glutamate homeostasis and neuroplasticity pathways in chemobrain has not been explored. This study investigated whether LURA could counteract DOX-induced chemobrain by restoring CREB/BDNF/Glt-1 signaling and re-establishing glutamate homeostasis in the hippocampus and prefrontal cortex. METHODS: Forty-eight male Wistar rats were assigned to control, LURA, DOX, or DOX/LURA groups. Behavioral performance was assessed using the open field, novel object recognition, and Morris water maze tests. Hippocampal and prefrontal tissues were evaluated for protein expression of the CREB/BDNF/Glt-1 pathway, glutamate and GABA levels, oxidative stress indices, and histopathological and immunohistochemical markers of neurodegeneration, apoptosis, and astrocytic activation. RESULTS: DOX administration resulted in pronounced cognitive decline, oxidative stress, neuroinflammation, neuronal loss, and substantial downregulation of CREB/BDNF/Glt-1 signaling, accompanied by elevated glutamate and reduced GABA levels. LURA co-treatment markedly improved behavioral outcomes, reinstated CREB/BDNF/Glt-1 expression, ameliorated glutamate/GABA balance, and reduced neurodegeneration, caspase-3 activation, and astrocytic reactivity. DISCUSSION: This study provides the first evidence that lurasidone mitigates doxorubicin-induced chemobrain. This neuroprotective effect is associated with the restoration of glutamate homeostasis and the upregulation of hippocampal and prefrontal CREB/BDNF/Glt-1 signaling, highlighting lurasidone as a promising therapeutic option for chemotherapy-induced cognitive impairment.