Leucine metabolite β -hydroxy- β -methyl-butyrate alleviates cisplatin-induced peripheral neuropathy by destabilizing CTR1 in dorsal root ganglia

Abstract Peripheral neuropathy is a common side effect of cisplatin; however, there is no definitive treatment for this condition. In humans, β-hydroxy-β-methyl-butyrate (HMB) is an endogenous metabolite of leucine. To date, none data is available about the effects of HMB on cisplatin-induced peripheral neuropathy (CIPN). Herein, oral administration of HMB considerably alleviated cisplatin-induced hyperalgesia in Wistar rats, a symptom of peripheral neuropathy affecting the extremities of the limbs. The primary mechanism of CIPN is apoptosis in the sensory neurons of the dorsal root ganglion (DRG) arising from the accumulation of platinum (Pt). HMB mitigated CDDP-induced neurotoxicity in DRG neurons through reducing Pt accumulation within these cells, as evidenced by the recovery of cell viability and reduced apoptosis. In addition, HMB treatment down-regulated the levels of copper transporter 1 (CTR1), a key molecule mediates the influx of cisplatin. And artificial recovery of CTR1 expression by CTR1-overexpression plasmids transfection abrogated the inhibition of HMB on Pt accumulation in DRG neurons. Moreover, enhanced ubiquitylation, arising from increased NEDD4L expression, mediated the down-regulation of CTR1 by HMB. Finally, as evidenced by the data from lung cancer model in vivo and in vitro, HMB did not interfere with cisplatin’s ability to induce tumor cell death. These findings suggest that HMB can alleviate CIPN by destabilizing CTR1 in DRG neurons without affecting cisplatin’s chemotherapeutic effects. Therefore, HMB could be developed as an adjuvant therapy to relieve neurotoxicity in cisplatin-based treatment protocols.