BDNF Augmentation Using Riluzole Reverses Doxorubicin-Induced Decline in Cognitive Function and Neurogenesis

Abstract

Cancer-related cognitive impairment (CRCI) considerably affects the quality of life of millions of cancer survivors. Brain-derived neurotrophic factor (BDNF) has been shown to promote survival, differentiation, and maintenance of in vivo dentate neurogenesis, and chemotherapy induces a plethora of physiological and cellular alterations, including a decline in neurogenesis and increased neuroinflammation linked with cognitive impairments. In our clinical studies, breast cancer patients treated with doxorubicin (Adriamycin®, ADR) experienced a significant reduction in the blood levels of BDNF that was associated with a higher risk of CRCI. Our past rodent studies in CRCI have also shown a significant reduction in dentate neurogenesis accompanied by cognitive impairment. In this study, using a female mouse model of ADR-induced cognitive decline, we tested the impact of riluzole (RZ), an orally active BDNF-enhancing medication that is FDA-approved for amyotrophic lateral sclerosis. ADR-treated mice receiving RZ in the drinking water for 1 month showed significant improvements in hippocampal-dependent learning and memory function (spatial recognition), fear extinction memory consolidation, and reduced anxiety-like behavior. RZ prevented chemotherapy-induced reductions of BDNF levels in the hippocampus. Importantly, RZ mitigated chemotherapy-induced loss of newly born, immature neurons, dentate neurogenesis, and neuroinflammation. In conclusion, this data provides pre-clinical evidence for a translationally feasible approach to enhance the neuroprotective effects of RZ treatment to prevent CRCI.

Brain-derived neurotrophic factor as a biomarker in cancer-related cognitive impairment among adolescent and young adult cancer patients

“…These findings strengthen the current evidence 11 – 15 that circulating BDNF may predict CRCI risk to pre-emptively identify cancer patients who are at greater predisposition to develop cognitive symptoms and provide timely interventions. Our data has also provided preliminary evidence that augmentation of BDNF levels in humans may provide an avenue to manage CRCI, which echoes with a recent study showing that augmenting BDNF levels in mouse models can improve cognitive outcomes 21 . Nevertheless, we noted several research questions to be addressed in future to further establish BDNF as a clinical and translational biomarker in CRCI.…”

Senolytic treatment alleviates doxorubicin‐induced chemobrain

“…This study found only modest changes in gene expression (~100 total genes) induced by Dox treatment, including decreased expression of genes for nervous system development. We confirmed that Dox treatment decreased expression of genes for nervous system development, including genes linked to neurogenesis (Janelsins et al., 2010 ; McElroy et al., 2020 ; Park et al., 2018 ; Rendeiro et al., 2016 ; Usmani et al., 2023 ). Nevertheless, analyses of gene enrichment did not reveal large changes in other biological processes normally associated with aging (Barter et al., 2020 ; Budamagunta et al., 2023 ; Ianov, De Both, et al., 2017 ; Smith et al., 2020 ; Zeier et al., 2011 ).…”

Mitochondrial dysfunction following repeated administration of alprazolam causes attenuation of hippocampus-dependent memory consolidation in mice

“…Moreover, BDNF is essential for memory consolidation [ 44 ], and its expression was evaluated in the hippocampus. The protein expression was significantly downregulated in the hippocampus of mice in the Alp group compared to the control group, further illustrating that repeated administration of Alp impairs the memory consolidation process by reducing the expression of BDNF protein.…”