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Fisetin Imparts Neuroprotection in Experimental Diabetic Neuropathy by Modulating Nrf2 and NF-κB Pathways
Reddemma Sandireddy1, Veera Ganesh Yerra1, Prashanth Komirishetti1
1Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Bala Nagar, Hyderabad, TG, 500037, India.
Abstract:
The current study is aimed to assess the therapeutic potential of fisetin, a phytoflavonoid in streptozotocin (STZ)-induced experimental diabetic neuropathy (DN) in rats. Fisetin was administered (5 and 10 mg/kg) for 2 weeks (7th and 8th week) post STZ administration. Thermal and mechanical hyperalgesia were assessed by measuring tactile sensitivity to thermal and mechanical stimuli, respectively. Motor nerve conduction velocity (MNCV) was determined using power lab system and sciatic nerve blood flow (NBF) was determined using laser Doppler system. Nerve sections were processed for TUNEL assay and NF-κB, COX-2 immunohistochemical staining. Sciatic nerve homogenate was used for biochemical and Western blotting analysis. MNCV and sciatic NBF deficits associated with DN were ameliorated in fisetin administered rats. Fisetin treatment reduced the interleukin-6 and tumour necrosis factor-alpha in sciatic nerves of diabetic rats (p < 0.001). Protein expression studies have identified that the therapeutic benefit of fisetin might be through regulation of redox sensitive transcription factors such as nuclear erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB). Our study provides an evidence for the therapeutic potential of fisetin in DN through simultaneous targeting of NF-κB and Nrf2.
Insights
Fisetin, a plant flavonoid, shows therapeutic potential for diabetic neuropathy (DN) by improving nerve function and reducing inflammation. It works by regulating key transcription factors, offering a novel treatment strategy for DN.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Diabetic neuropathy (DN) is a debilitating complication of diabetes, characterized by nerve damage and pain.
- Current treatments for DN offer limited efficacy and often come with side effects.
- Phytoflavonoids, like fisetin, are being investigated for their potential therapeutic properties.
Purpose of the Study:
- To evaluate the therapeutic efficacy of fisetin in a rat model of streptozotocin (STZ)-induced diabetic neuropathy.
- To investigate the underlying molecular mechanisms of fisetin's action in DN.
Main Methods:
- Rats were induced with STZ to model diabetes and DN.
- Fisetin was administered orally at doses of 5 and 10 mg/kg for two weeks.
- Nerve function was assessed via motor nerve conduction velocity (MNCV) and sciatic nerve blood flow (NBF).
- Histological and biochemical analyses included TUNEL assay, immunohistochemistry for NF-κB and COX-2, and Western blotting.
Main Results:
- Fisetin treatment significantly ameliorated MNCV and NBF deficits in STZ-induced diabetic rats.
- Fisetin administration reduced inflammatory markers, including interleukin-6 and tumor necrosis factor-alpha, in sciatic nerves.
- Molecular analysis revealed that fisetin's benefits are linked to the regulation of redox-sensitive transcription factors, specifically Nrf2 and NF-κB.
Conclusions:
- Fisetin demonstrates significant therapeutic potential for diabetic neuropathy.
- The mechanism involves the simultaneous regulation of NF-κB and Nrf2 pathways.
- Fisetin represents a promising natural compound for the management of DN.
