Role of oxidative stress in pathophysiology of peripheral neuropathy and modulation by N-acetyl-L-cysteine in rats.

OBJECTIVES: The objectives of this study were to examine the role of reactive oxygen species and oxidative stress in peripheral neuropathy and behavioural pain responses in experimentally induced chronic constriction injury (CCI) of sciatic nerve of rat. Effect of N-acetyl-L-cysteine (NAC) administered intraperitoneally, was also investigated on CCI-induced neuropathic pain in rats. METHODS: Neuropathy was induced by CCI of the right sciatic nerve in ketamine anaesthetized rats. Effect of intraperitoneally administered NAC in rats was also investigated using nociceptive behavioural tests. Malondialdehyde, an index of oxidative stress and antioxidant enzymes was also estimated in ligated sciatic nerve. RESULTS: Behavioural tests, mechanical, thermal and cold stimuli confirmed the development of neuropathic pain after the CCI. The malondialdehyde levels of ligated sciatic nerves were significantly increased compared to non-ligated sciatic nerves (sham operated). The antioxidant enzyme reduced, glutathione was inhibited, while superoxide dismutase increased. However, catalase remained unaffected in the injured sciatic nerves. Intraperitoneal administration of NAC resulted in significant reduction of hyperalgesia in CCI-induced neuropathic rats. CONCLUSIONS: This study identifies antioxidants superoxide dismutase and reduced glutathione, and oxidative stress as important determinants of neuropathological and behavioural consequences of CCI-induced neuropathy, and NAC may be a potential candidate for alleviation of neuropathic pain.

Synergistic interaction between meloxicam and aminoguanidine in formalin-induced nociception in mice.

OBJECTIVES: The objective of this study was to examine the nature of interaction between cyclooxygenase-2 inhibitor meloxicam and inducible nitric oxide synthase inhibitor aminoguanidine in formalin-induced nociception in mice and the possible therapeutic advantage. METHODS: Antinociceptive effect of meloxicam (1, 3, 10 and 30 mg/kg, oral) and aminoguanidine (10, 30, 100 and 300 mg/kg, oral) and their combinations was examined in formalin-induced paw licking model in mice. Analysis of variance and isobolographic method were employed to identify the nature of antinociceptive interaction. RESULTS: Higher doses of meloxicam (10 and 30 mg/kg) and aminoguanidine (100 and 300 mg/kg) produced significant reduction in paw licking time (antinociceptive) in late phase of formalin-induced nociception. Combination of sub-threshold dose of meloxicam (3 mg/kg) with increasing doses of aminoguanidine (10, 30, 100 and 300 mg/kg) resulted in synergistic antinociceptive effect. Similarly, co-administration of sub-threshold dose of aminoguanidine (30 mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30 mg/kg) produced significant reduction in formalin-induced paw licking behaviour. The experimental ED(50) for combination with their confidence limits are below the confidence interval of theoretical line of additive interaction, suggesting synergistic nature of interaction between meloxicam and aminoguanidine in isobolographic analysis. CONCLUSION: Co-administration of meloxicam and aminoguanidine showed synergistic antinociceptive effect which might possibly reduce gastrointestinal toxicity associated with the use of meloxicam.