Neuronal metabolism role in ketogenic diet improvements in bortezomib-induced painful peripheral neuropathy mouse model.

Introduction: A ketogenic diet (KD) can benefit a range of neurological conditions, including different types of peripheral neuropathy. Bortezomib (BTZ), a first-line chemotherapy for treating multiple myeloma, has neurotoxic effects and often induces chemotherapy-induced peripheral neuropathy. Objectives: Here, we tested whether a KD could prevent the onset of small fiber neuropathy and behavioral hypersensitivity associated with bortezomib-induced peripheral neuropathy (BIPN). Methods: Male C57BL/6 mice were fed either a standard chow diet or a KD for 10 days. During the first 5 days of KD administration, mice received daily intraperitoneal injections of BTZ or vehicle. Mice entered a BTZ washout period on day 6 while remaining on their specific diets. Hindpaw responses to mechanical (von Frey) and cold (acetone) stimuli were measured to determine how KD and BTZ treatment affected behavioral sensitivity. Footpads were harvested for analysis of intraepidermal nerve fiber density (IENFD), and lumbar dorsal root ganglia were collected for in vitro analysis of neurite outgrowth and cellular bioenergetics. Results: Bortezomib-treated, KD-fed mice exhibited decreased mechanical hypersensitivity, normalized cold hypersensitivity, preserved IENFD, and decreased extracellular acidification rate compared with BTZ-treated, chow-fed mice. In vitro analysis of ketones' ability to protect against BTZ-induced reductions in neurite growth revealed that cultured neurons pretreated with ketones were protected from BTZ-induced neurite degeneration. Conclusion: Findings suggest that KD protects against reductions in IENFD, behavioral hypersensitivity, and bioenergetic shifts induced by BIPN, and provides evidence that KD provides protection against BTZ and could be a potential therapeutic for BIPN.