Quantitative gait analysis as a method to assess mechanical hyperalgesia modulated by disease-modifying antirheumatoid drugs in the adjuvant-induced arthritic rat

In the present study, azothioprine, chloroquine, D-penicillamine, methotrexate and sodium aurothiomalate (gold salt) were evaluated for possible disease-modifying effects in the adjuvant-induced arthritis model of human rheumatoid arthritis in rats. Gait analysis was used to examine the role of disease-modifying antirheumatic drugs in the development of pain. Body weights were also measured to monitor the progression of disease and the systemic antiarthritic effects of the test compounds used in this study, as well as their systemic toxicity. Our results showed that azothioprine (5 mg/kg/day), chloroquine (12.5 mg/kg/day), sodium aurothiomalate (2.5 mg/kg/day) and methotrexate (1 mg/kg/week) not only inhibited the macroscopic changes such as erythema and swelling of limbs, but also exhibited significant reversal of gait deficits seen in the untreated or saline-treated arthritic rats. No reduction in the body weights were observed in the arthritic rats treated with azothioprine, chloroquine, sodium aurothiomalate and methotrexate. D-Penicillamine (12.5 mg/kg/day), however, showed a significant reduction (P < 0.03) in the body weights of the arthritic rats over a period of 22 days; furthermore, it was unable to show any reduction in arthritic score (P < 0.1). In earlier experiments, chloroquine and methotrexate failed to suppress carageenan-induced edema, suggesting that the mode of antiarthritic action may be different from those of nonsteroidal anti-inflammatory agents. Since these disease-modifying antirheumatic drugs are reported to have an immunomodulatory role, especially the gold salt, which influences the monocyte–macrophage system, it is suggested that the observed antiarthritic effects of disease-modifying antirheumatic drugs may be partly attributed to their immunomodulatory activity

Protective Efficacy of N-(2-Hydroxyphenyl) Acetamide against Adjuvant-Induced Arthritis in Rats

Rheumatoid arthritis is a chronic inflammatory joint disease characterized by synovial proliferation and tissue destruction. Proinflammatory cytokines like interleukin-1beta (IL-1 ) and tumor necrosis factor-alpha (TNF-) play a key role in the disease process and elevate energy expenditure, which further increases the joint pain and stiffness. To explore the effects of N-(2-hydroxyphenyl) acetamide (NA-2) on the development of arthritis, clinical signs, histopathology of knee joints, nociception analysis, and the serum levels of IL-1 and TNF-were monitored. Arthritis was induced by intradermal administration of heatkilled adjuvant Mycobacterium tuberculosis H37Ra in rats. NA-2 and indomethacin treatments were started in their respective group on the same day when adjuvant was administered. Experiments were terminated when arthritic score of 4 was observed in arthritic control group. NA-2 (5 mg/kg) treatment significantly ameliorated the disease severity. Reduction in body weight and increase in paw oedema were significantly reversed in arthritic animal receiving NA-2. The nociceptive sensation was also inhibited in the NA-2 treated arthritic rats. Remission was associated with improved histology and significant decreased expression of serum proinflammatory cytokines ( &lt; 0.05 for IL-1 and TNF-). Based on our observations, it can be suggested that NA-2 possesses promising anti-arthritic property, and it can be used as a therapeutic agent for arthritis

Time course of the change in hind paw volume after the induction of arthritis

<p><b>Copyright information:</b></p><p>Taken from "Quantitative gait analysis as a method to assess mechanical hyperalgesia modulated by disease-modifying antirheumatoid drugs in the adjuvant-induced arthritic rat"</p><p>http://arthritis-research.com/content/9/5/R91</p><p>Arthritis Research & Therapy 2007;9(5):R91-R91.</p><p>Published online 11 Sep 2007</p><p>PMCID:PMC2212551.</p><p></p> Rats in all arthritic groups showed an increase in their paw volume until day 8; however, this increase in the azothioprine (AZ)-treated, chloroquine (CQ)-treated and sodium aurothiomalate (gold salt (GS))-treated arthritic rats was not significantly different from the normal control rats, and also no further increase in the paw volume was noticed in these groups. In contrast, arthritic rats treated with methotrexate (MTX) and indomethacine showed a gradual increase in their paw volume over a period of 22 days, but this increase was nonsignificant compared with normal control rats. The arthritic rats treated with D-penicillamine (D-PEN) or saline showed a significant increase in their paw volume over the period of 22 days (< 0.006). Inbox pictures, difference between the arthritic rat paw and the normal rat paw. Results expressed as mean ± standard error (= 6). AC, arthritic control; AIA, adjuvant-induced arthritis; DC, drug control; NT, no treatment; Sal + Art, saline and arthritis

Arthritis severity scores in rats during the development of adjuvant-induced arthritis

<p><b>Copyright information:</b></p><p>Taken from "Quantitative gait analysis as a method to assess mechanical hyperalgesia modulated by disease-modifying antirheumatoid drugs in the adjuvant-induced arthritic rat"</p><p>http://arthritis-research.com/content/9/5/R91</p><p>Arthritis Research & Therapy 2007;9(5):R91-R91.</p><p>Published online 11 Sep 2007</p><p>PMCID:PMC2212551.</p><p></p> Effect of azothioprine (AZ), chloroquine (CQ), D-penicillamine (D-PEN), sodium aurothiomalate (gold salt (GS)) and methotrexate (MTX) on the time course of the development and progression of arthritis, shown as the arthritis severity scores measured over a period of 22 days. Results are the mean ± standard error for six animals in each group. AIA, adjuvant-induced arthritis; DC, drug control; NT, no treatment

Time course of body weight changes in rats with adjuvant-induced arthritis

<p><b>Copyright information:</b></p><p>Taken from "Quantitative gait analysis as a method to assess mechanical hyperalgesia modulated by disease-modifying antirheumatoid drugs in the adjuvant-induced arthritic rat"</p><p>http://arthritis-research.com/content/9/5/R91</p><p>Arthritis Research & Therapy 2007;9(5):R91-R91.</p><p>Published online 11 Sep 2007</p><p>PMCID:PMC2212551.</p><p></p> Effect of disease-modifying antirheumatic drugs (DMARDs) on the body weight change of the arthritic rats, measured over a period of 22 days. Effect of D-penicillamine (D-PEN) and sodium aurothiomalate (gold salt (GS)) on body weights of adjuvant-induced arthritis (AIA) rats. Effect of azothioprine (AZ), chloroquine (CQ) and methotrexate (MTX) on body weights of AIA rats. Results are the mean ± standard error for six animals per group. AC, arthritic control; DC, drug control; NT, no treatment; Sal + Art, saline and arthritis

Time course of walking speed changes after the induction of arthritis compared with normal rats

<p><b>Copyright information:</b></p><p>Taken from "Quantitative gait analysis as a method to assess mechanical hyperalgesia modulated by disease-modifying antirheumatoid drugs in the adjuvant-induced arthritic rat"</p><p>http://arthritis-research.com/content/9/5/R91</p><p>Arthritis Research & Therapy 2007;9(5):R91-R91.</p><p>Published online 11 Sep 2007</p><p>PMCID:PMC2212551.</p><p></p> Treated arthritic rats or untreated arthritic rats showed a gradual decrease in velocity from day 2 onwards. Arthritic rats treated with azothioprine (AZ), chloroquine (CQ), sodium aurothiomalate (gold salt (GS)), methotrexate (MTX) and indomethacine, however, exhibited a reversal of the deficit in velocity seen in the untreated rats or saline-treated arthritic rats from day 12 onwards. Results are the mean ± standard error (= 6). AC, arthritic control; AIA, adjuvant-induced arthritis; DC, drug control; NT, no treatment; Sal + Art, saline and arthritis

Modulation of c-Fos and BDNF Protein Expression in Pentylenetetrazole-Kindled Mice following the Treatment with Novel Antiepileptic Compound HHL-6

Brain-derived neurotrophic factor (BDNF) and c-Fos are shown to promote epileptogenesis and are taken as a marker of neuronal activity. The present study investigated the expression of BDNF and c-Fos in mice brain with pentylenetetrazol- (PTZ-) induced generalized seizure and evaluated the effect of novel tryptamine derivative HHL-6 on the expression of these two markers. The subconvulsive dose of PTZ (50 mg/kg) was administered on alternate days in the experimental groups until the seizure scores 4-5 developed in the PTZ-control group. At the end of each experiment, animals were sacrificed, brain samples were collected and cryosectioned, and immunohistochemical analysis of BDNF and c-Fos protein was performed. Data obtained from two sections per mouse (n=12 animals/group) is presented as means ± S.E.M. The test compound HHL-6 demonstrated a potent anticonvulsant activity in the PTZ-induced seizure in mice. Significant reduction in the BDNF (P<0.003) and c-Fos (P<0.01) protein expression was observed in the HHL-6 treated group. Based on these results we suggest that one of the possible mechanisms of HHL-6 to inhibit epileptogenesis might be due to its controlling effect on the cellular and molecular expression of the factors that contribute to the development of epileptogenic plasticity in the CNS