Flavonoids regulating NLRP3 inflammasome: a promising approach in alleviating diabetic peripheral neuropathy

Abstract

A common and serious side effect of diabetes is diabetic peripheral neuropathy (DPN), which is characterised by gradual nerve damage brought on by oxidative stress, chronic inflammation, and prolonged hyperglycemia. Studies identify NLRP3 inflammasome as a key mediator in the pathogenesis of DPN, connecting neuroinflammation and neuronal damage to metabolic failure. Because of their strong anti-inflammatory and antioxidant qualities, flavonoids, a broad class of naturally occurring polyphenols, have drawn interest as potential treatments for DPN. The various ways that flavonoids affect the NLRP3 inflammasome and their potential as a treatment for DPN are examined in this review. It has been demonstrated that flavonoids prevent NLRP3 activation, which lowers the release of pro-inflammatory cytokines including IL-1β and IL-18 and causes neuroinflammation. Flavonoids work mechanistically by reducing oxidative stress, altering important signalling pathways, and blocking the activities of NF-κB and caspase-1, which are both essential for the activation of the NLRP3 inflammasome. Preclinical research has shown that flavonoids have strong neuroprotective benefits, and few clinical evidence also points to the potential of flavonoids to improve nerve function and lessen neuropathic pain in diabetic patients. The current review emphasises how flavonoids may be used as a treatment strategy to target inflammation in DPN caused by the NLRP3 inflammasome. By targeting important inflammatory pathways, flavonoids provide a new way to slow the progression of this debilitating illness. Further investigation into the mechanisms, clinical translation, and novel drug delivery techniques could enhance the therapeutic efficacy of diabetic peripheral neuropathy.

Keywords: Diabetic peripheral neuropathy; Drug delivery; Flavonoids; Hyperglycemia; Inflammasome; NLRP3.

Flavonoid intervention in Diabetic Neuropathy and its role in NLRP3 Inflammasome

Fig. 1

Pharmacokinetic properties of flavonoids and factors affecting the bioavailability and approaches to improve the therapeutic efficacy. The flavonoids are converted to glycosides in the small intestine by metabolic processes after ingestion. The bacterium in the colon transforms a significant portion of the flavonoids that are consumed into phenolic acids. After first pass metabolism and get further metabolized in the liver via phase I and phase II metabolism followed by excretion via kidneys or reach the target tissues. Various factors, including low solubility, low metabolism in the liver, colon, and small intestine, degradation with increase in pH and increased rate of degradation, reduces the bioavailability of flavonoids.

Fig. 2

Flavonoids and their mechanism of action in Diabetic Neuropathy. In diabetic neuropathy, the picture illustrates how the various flavonoid subclasses—flavones, flavanones, flavonols, isoflavones, flavanonols, and anthocyanins—work. It draws attention to how they might lessen oxidative stress, inhibit pro-inflammatory cytokines, enhance nerve function, and lessen neuronal damage. Under each category, particular flavonoids help improve neuroprotection in diabetes and reduce neuropathic pain.

Fig. 3

Mechanism of action of Flavonoids in Diabetic Neuropathy. The illustration shows how flavonoids affect NLRP3 components in diabetic neuropathy. Inflammasome priming, ASC oligomerisation, NLRP3 assembly, caspase-1 activation, ROS generation, and the release of pro-inflammatory cytokines IL-1β and IL-18 are all inhibited by flavonoids. These activities reduce neuronal damage and inflammation.