International Journal of Pharmaceutical Investigation, 2021, 11, 3, 312-318.
Published: October 2021
Type: Original Article
Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, INDIA.
Department of Pharmacology, Bharat Institute of Technology-Pharmacy, Hyderabad, Telangana, INDIA.
Shrinivas Krishnarao Kulkarni
Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, INDIA.
Satyanarayana Siddhi Venkata Padi
Department of Pharmacology, Jangaon Institute of Pharmaceutical Sciences, Jangaon, Telangana, INDIA.
Background: Neuropathic pain, a chronic debilitating painful condition, is frequently difficult to manage with the conventional analgesics. Emerging evidence indicates potential role of peroxisome proliferator-activated receptor (PPAR)-γ, a subfamily of nuclear receptors, in regulating inflammation and oxidative stress at transcription level. Therefore, we investigated whether activation of PPAR-γ attenuate established neuropathic pain and to delineate underlying mechanisms. Methods: Neuropathy was induced by chronic constriction injury of sciatic nerve in rats. Behavioral tests were performed to assess pain hypersensitivity and the markers of inflammation and nitroso-oxidative stress were estimated in sciatic nerve. Results: Chronic administration of pioglitazone (10 and 30 mg/kg, i.p.) for 2 weeks starting 14 days after nerve injury did not induce hypoalgesia in contralateral paws and had no effect on locomotor activity. However, pioglitazone significantly mitigated cold allodynia and thermal hyperalgesia in ipsilateral paws after nerve injury. In addition, pioglitazone reduced plasma extravasation and pro-inflammatory cytokines, TNF-α and IL-1β, following nerve injury. These effects of pioglitazone are parallel with the significant reduction in lipid peroxidation, protein carbonyls, nitrite levels as well as marked improvement in GSH and activities of SOD, catalase in injured nerves. BADGE, a PPAR-γ antagonist (30 mg/kg, i.p.) reversed the effects of pioglitazone in chronic constriction injury (CCI) rats. Conclusion: Together, the present results demonstrate that activation of PPAR-γ receptor-dependently exerted antiallodynic and antihyperalgesic effects through inhibition of inflammation and nitroso-oxidative stress in mononeuropathic rats and supporting a key role of PPAR-γ activation in extenuating existing neuropathic pain.
Keywords: BADGE, Chronic constriction injury, Nerve injury, Neuroinflammation, Neuropathic pain, Pain hypersensitivity, Pioglitazone, PPAR-γ agonist .