Protective Effects of ACY-1215 Against Chemotherapy-Related Cognitive Impairment and Brain Damage in Mice.

Chemotherapy-related cognitive impairment (CRCI) is a potential long-term side effect during cancer treatment. There are currently no effective treatments for CRCI. Reduction or inhibition of histone deacetylase 6 (HDAC6) has been considered a possible therapeutic strategy for cognitive deficits. HDAC6 inhibition recently has been shown to reverse chemotherapy-induced peripheral neuropathy effectively. In the present study, we examined the effect of HDAC6 inhibitor ACY-1215 (Ricolinostat) on cisplatin-induced brain damage and cognitive deficits in mice. Our results showed that ACY-1215 ameliorated behavioral deficits and dendritic spine loss and increased synaptic density in cisplatin-treated mice. Mechanistically, HDAC6 inhibitor ACY-1215 enhanced α-tubulin acetylation in the hippocampus of cisplatin-treated mice. Furthermore, ACY-1215 recovered cisplatin-induced impaired mitochondrial transport and mitochondrial dysfunction in the hippocampus. Our results suggest that inhibition of HDAC6 improves established cisplatin-induced cognitive deficits by the restoration of mitochondrial and synaptic impairments. These results offer prospective approaches for CRCI, especially because ACY1215 currently serves as an add-on cancer therapy during clinical trials.