CD80 blockade enhance glucocorticoid-induced leucine zipper expression and suppress experimental autoimmune encephalomyelitis.

Designing mimetic of the interface functional groups of known receptor-ligand complexes is an attractive strategy for developing potential therapeutic agents that interfere with target protein-protein interactions. The CD80/CD86-CD28/CD152 costimulatory interactions transmit signals for CD4(+) T cell activation and suppression and are critically involved in the initiation, progression, and reactivation of the immunopathology in multiple sclerosis. Differences in the pattern, levels, and kinetics of expression of CD80/CD86 molecules in conjunction with differences in the strength of the signals delivered upon binding CD28 or CD152 determine the outcome of the immune response. A temporal up-regulation of surface expression of CD80 relative to CD86 on APCs and CNS-infiltrating cells has been shown to correlate with disease progression in experimental autoimmune encephalomyelitis an animal model for multiple sclerosis. Hence blockade of the CD80 costimulatory axis has therapeutic potential in multiple sclerosis. In this study, we report the efficacy of a novel CD80-blocking agent CD80-competitive antagonist peptide (CD80-CAP) in suppressing clinical disease and relapse in experimental autoimmune encephalomyelitis. The CD80-CAP mediates protection by inhibiting proinflammatory cytokines and skewing toward anti-inflammatory response presumably by enhancing the expression of glucocorticoid-induced leucine zipper in activated CD4(+) T cells.

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.

Ameliorative effect of combined administration of inducible nitric oxide synthase inhibitor with cyclooxygenase-2 inhibitors in neuropathic pain in rats.

OBJECTIVES: The objective of this study was to examine the effects of rofecoxib, meloxicam, both cyclooxygenase-2 (COX-2) inhibitors and aminoguanidine hydrochloride, an inducible nitric oxide synthase (iNOS) inhibitor and their combinations in neuropathic pain in rats. METHODS: Neuropathy was induced by chronic constriction injury (CCI) of right sciatic nerve under ketamine anesthesia in rats. Effect of ED(50) of aminoguanidine hydrochloride, rofecoxib and meloxicam administered orally was investigated using behavioral tests. Effect of combinations of aminoguanidine hydrochloride with rofecoxib and meloxicam was also investigated in neuropathic pain employing behavioral tests. RESULTS: Behavioral tests, mechanical, thermal and cold stimuli confirmed the development of neuropathic pain after CCI. Aminoguanidine hydrochloride, rofecoxib and meloxicam when administered alone, produced significant increase in paw withdrawal threshold to mechanical stimuli at 6 h in ipsilateral hind paw after CCI. Co-administration of aminoguanidine hydrochloride (30 mg/kg) with rofecoxib (1.31 mg/kg) and meloxicam (1.34 mg/kg) was also found to produce significant increase in paw withdrawal latencies to mechanical stimuli at 6 h. Combined administration of aminoguanidine hydrochloride with meloxicam and rofecoxib produced significant rise in pain threshold for mechanical hyperalgesia in ipsilateral hind paw when compared with the groups treated with aminoguanidine hydrochloride, meloxicam and rofecoxib alone. CONCLUSION: Co-administration of meloxicam and rofecoxib with aminoguanidine hydrochloride may be an alternative approach for the treatment of neuropathic pain.

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.

Nitric oxide and its modulators in chronic constriction injury-induced neuropathic pain in rats.

This study was conducted to examine the role of nitric oxide (NO) in peripheral neuropathy induced by chronic constriction injury of sciatic nerve of rats by using NO precursor, NO donors and nitric oxide synthase (NOS) inhibitors. Chronic constriction injury of sciatic nerve of rats resulted in peripheral neuropathy as confirmed by nociceptive behavioural tests using mechanical, thermal and cold allodynia. NO precursor, L-arginine and NO donors sodium nitroprusside, S-nitroso-N-acetylpenicillamine potentiated the hyperalgesia and allodynia significantly suggesting proalgesic effect in neuropathic rats. Intracerebroventricular (i.c.v.) administration of rats with NOS inhibitors such as L-N(G)-nitroarginine methyl ester, N-iminoethyl lysine and 7-nitroindazole did not show any effect but i.p. administration of NOS inhibitors aminoguanidine, L-N(G)-nitroarginine methyl ester and 7-nitroindazole caused alleviation of pain. The study confirms the involvement of endogenously synthesized and exogenously administered NO in chronic constriction injury-induced neuropathy in rats. Significant increase in the levels of nitrate and nitrite in ligated sciatic nerve suggest that local up regulation of NO in the production and maintenance of neuropathic pain. In conclusion, initial attempt to manipulate L-arginine: NO pathway is indicative of therapeutic potential of these interventions in the management of neuropathic pain.

Synergistic anti-inflammatory interaction between meloxicam and aminoguanidine hydrochloride in carrageenan-induced acute inflammation in rats.

Interaction studies with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) inhibitor have been conducted to assess the nature of interaction and the possible therapeutic advantage. The interaction between meloxicam--a selective COX-2 inhibitor--and aminoguanidine hydrochloride--a selective iNOS inhibitor-- was examined in carrageenan-induced paw edema in rats. Appropriate statistical method was applied to detect the nature of anti-inflammatory interaction. Different doses of meloxicam (1, 3, 10 and 30 mg/kg) or aminoguanidine hydrochloride (10, 30, 100 and 300 mg/kg) were administered orally to adult male albino rats. Higher doses of meloxicam (3, 10 and 30 mg/kg) showed statistically significant anti-inflammatory effect. However, aminoguanidine hydrochloride did not show any anti-inflammatory activity. Combination of sub-threshold dose of meloxicam (1 mg/kg) with increasing doses of aminoguanidine hydrochloride (30, 100 and 300 mg/kg) resulted in synergistic anti-inflammatory effect. Combined therapy with sub-threshold dose of aminoguanidine hydrochloride (30 mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30 mg/kg) also resulted in synergistic anti-inflammatory effect. The possible mechanism of interaction could be the stimulation of COX-2 activity by nitric oxide (NO) by combining with heme component. These results suggest that co-administration of meloxicam and aminoguanidine hydrochloride may be an alternative in clinical control of inflammation.

Interaction of inducible nitric oxide synthase and cyclooxygenase-2 inhibitors in formalin-induced nociception in mice.

Studies with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 inhibitor were conducted to assess their synergistic antinociceptive effect and possible therapeutic advantage. The antinociceptive interaction of rofecoxib, a selective cyclooxygenase-2 inhibitor, with aminoguanidine hydrochloride, a selective iNOS inhibitor, was examined in the formalin-induced paw-licking model in mice. Analysis of variance (ANOVA) and the isobolographic method were used to identify the nature of the antinociceptive interaction. Different doses of rofecoxib (1, 3, 10 and 30 mg/kg) and aminoguanidine hydrochloride (10, 30, 100 and 300 mg/kg) alone were administered orally to adult male albino mice (20-30 g). Only high doses of rofecoxib (10 and 30 mg/kg) and aminoguanidine hydrochloride (100 and 300 mg/kg) showed a statistically significant antinociceptive effect. Combination of a subthreshold dose of rofecoxib (1 mg/kg) with increasing doses of aminoguanidine hydrochloride (30, 100 and 300 mg/kg) resulted in potentiated antinociception (P<0.05). Combined therapy with a subthreshold dose of aminoguanidine hydrochloride (30 mg/kg) with increasing doses of rofecoxib (1, 3, 10 and 30 mg/kg) also resulted in significant antinociception (P<0.05). These results suggest that rofecoxib and aminoguanidine hydrochloride act synergistically in their antinociceptive action in mice. A possible mechanism of interaction is that nitric oxide (NO) stimulates the activity of cyclooxygenase-2 by combining with its heme component. Furthermore, the present results suggest that combination therapy with rofecoxib and aminoguanidine hydrochloride may provide an alternative for the clinical control of pain.