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Intensive Care Unit Cognitive Disorders / Cancer Related Cognitive Impairment Studies / Advanced Breast Cancer Therapies · Journal article
Frontiers in Pharmacology · September 9, 2026
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This is the first preclinical study demonstrating that lurasidone ameliorates doxorubicin-induced cognitive deficits in rats through restoration of glutamate homeostasis and CREB/BDNF/Glt-1 signaling in the hippocampus and prefrontal cortex. While mechanistically coherent and internally consistent, the findings are confined to a rodent model and do not yet establish clinical utility or safety in humans with chemotherapy-induced cognitive impairment.
Preclinical controlled animal experiment. Male Wistar rats. Intervention: Lurasidone co-treatment in doxorubicin-exposed rats. Compared with: Doxorubicin alone and untreated control. n = 48.
DOX administration caused pronounced cognitive decline across open field, novel object recognition, and Morris water maze tests, with substantial downregulation of CREB/BDNF/Glt-1 signaling LURA co-treatment markedly improved behavioral outcomes and reinstated CREB/BDNF/Glt-1 expression LURA ameliorated glutamate/GABA imbalance, reduced neurodegeneration, caspase-3 activation, and astrocytic reactivity in DOX-treated rats
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Findings suggest a potential neuroprotective mechanism for lurasidone in chemotherapy-induced cognitive impairment, but preclinical data alone cannot guide clinical use. Translation to human trials would be required before considering lurasidone as a therapeutic intervention for chemobrain.
First-in-vivo evidence from a single small animal study without clinical validation, demonstrating mechanism but requiring confirmation in larger preclinical and human studies before clinical application.
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Findings suggest a potential neuroprotective mechanism for lurasidone in chemotherapy-induced cognitive impairment, but preclinical data alone cannot guide clinical use. Translation to human trials would be required before considering lurasidone as a therapeutic intervention for chemobrain.
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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.
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