Ketogenic diet prevents paclitaxel‐induced neuropathic nociception through activation of PPARγ signalling pathway and inhibition of neuroinflammation in rat dorsal root ganglion

Abstract

Chemotherapy‐induced peripheral neuropathy (CIPN) is a common side effect during the course of cancer treatment, which is mainly manifested as a series of sensory abnormalities. At present, there are no recommended prevention or treatment strategies, and the underlying mechanisms are unclear. The ketogenic diet (KD), a special diet that is high in fat and low in carbohydrate intake, shows good therapeutic potential in children with epilepsy. In this study, it was found that KD significantly prevented paclitaxel‐induced neuropathic nociception. Using the GSE113941 database, 281 differentially expressed genes (DEGs) were found in an animal model of CIPN and controls. The DEGs were mainly enriched in peroxisome proliferator activated receptor (PPAR) and oxidative phosphorylation signalling pathways. As a main regulatory pathway of lipid metabolism, the PPARγ signalling pathway was significantly upregulated in the KD model. In addition, KD also inhibited the expression of pro‐inflammatory cytokines and the TLR4/NF‐κB signalling pathway in the dorsal root ganglion (DRG) in paclitaxel‐treated rats. In vitro, rat primary DRG neurons were used to investigate the role of PPARγ in paclitaxel‐induced neurotoxicity. It was found that PPARγ agonist rosiglitazone significantly protected DRG neurons against cell apoptosis and reactive oxygen species generation induced by paclitaxel administration. Therefore, KD is a prospective treatment option when applied as a dietary intervention in the prevention and treatment of paclitaxel‐induced neuropathic nociception, possibly through the activation of PPARγ and its neuroprotective functions.

Ketogenic diet prevents methylglyoxal-evoked nociception by scavenging methylglyoxal

“…Overall, these findings are consistent with emerging evidence that suggest a ketogenic diet may benefit MGO-driven painful pathologies. 13,17,31,32,44 These results suggest a broader application of ketogenic diets as therapeutic interventions in other MGO-related pathologies and chronic pain conditions.…”

“…[12][13][14]17,31,32 We and others have demonstrated success in using a ketogenic diet in reversing small-fiber neuropathies where MGO accumulation has been implicated, including DPN 12,13,17 and chemotherapy-induced neuropathy. 44 Moreover, Salom ón et al 33 demonstrated that MGO can be scavenged in blood by the ketone body acetoacetate.…”

Ketolysis is Required for the Proper Development and Function of the Somatosensory Nervous System

“…Deficiencies in ketolysis have been recently revealed in neurodegenerative diseases, including Friedreich’s ataxia and amyotrophic lateral sclerosis [14, 15]. Meanwhile, ketogenic diets are being studied in various neuropathies [17-19, 24, 25, 47, 48]. Our findings on the loss of Oxct1 and SCOT in peripheral neurons provide new information towards our understanding of ketone oxidation for developing and maintaining the peripheral sensory nervous system.…”

“…There is mounting evidence that ketone utilization is protective [17, 24, 25] and, in some cases, promotes regeneration [19] in the somatosensory nervous system of rodent models of chronic pain and neuropathy. SCOT is a mitochondrial enzyme expressed in peripheral tissues and required for ketolysis, catalyzing the conversion of acetoacetate and succinyl-CoA to acetoacetyl-CoA and succinate.…”

Upregulation of the oxytocin receptor in dorsal root ganglion mediated peripheral analgesia of oxytocin in chemotherapy-induced peripheral neuropathic pain

“…The mechanism underlying PTX-induced neuropathic pain is complicated andrecent ndings suggested thatPTX-induced peripheral neuropathy is often associated with neuroin ammation in the peripheral nervous system [9][10][11]. For example, compared with control rats, it is found that plasma levels of IL-1α, IL-1β, IL-6, TNF-α, INF-γ and MCP-1 were signi cantly upregulated in PTX-treated rats [12].…”