Evaluation of anti-arthritic activity of aripiprazole through multi models: new potential of an old drug.

aim of studyThis study was conducted to investigate the anti-arthritic effect of three different doses of aripiprazole based on its previously reported anti-inflammatory activity. MATERIAL AND

methodsAripiprazole, an atypical antipsychotic, has been used in the present study in animal models. Histamine model was used to verify the documented property of aripiprazole to treat inflammation. In-silico evaluation included molecular docking that was done by Auto-Dock of Chemical Computing Group. In-vitro studies involved heat evoked BSA protein degradation and egg albumin degradation and maintenance of human RBCs membrane test, whereas in-vivo studies encompassed, formaldehyde evoked arthritis & CFA evoked arthritis. Acute histamine model was carried out for four hours. Formaldehyde provoked arthritic disease in Sprague Dawley rats was studied to appraise anti-arthritic action of three respective doses of aripiprazole at 5 mg/kg, 10 mg/kg and 15 mg/kg oral dose for 10 days while the time period for study of same activity was twenty eight days with Complete Freund adjuvant and diameter of rat hind paw, arthritic index, body weight, radiological and histopathological investigation of ankles joints were performed. Variety of inflammation causing bio-markers (interleukin-1β, interleukin-6, nuclear factor-Kβ, tumor necrosis factor-α, Cox-2, interleukin-4, interleukin-10 and PGE2) had been investigated by real time-polymerase chain reaction and ELISA.

resultsAripiprazole significantly suppressed paw edema in acute inflammatory model of histamine at dose of 15 mg/kg of aripiprazole showed significant (p < 0.0001) prevention of paw edema showing percentage inhibition of (56.10%) and diameter of 3.13 mm (± 0.046). Molecular docking analysis disclosed that aripiprazole shows binding interactions with TNF-alpha, IL6, IL-1β, NF- κB and Cox-2. It was evaluated in this study that aripiprazole showed inhibition of protein degradation and stability of human red blood cell membrane in concentration gradient manner, demonstrating maximum activity at concentration of 6400 µg/ml. Similarly, considerable (****p < 0.0001) prevention in hind paw edema and arthritic score had been shown at dose of 15 mg/kg in arthritic models that was interestingly greater than piroxicam. aripiprazole suppressed increase in paw diameter in dose dependent manner. 15 mg/kg of aripiprazole showed significant (****p < 0.0001) suppression of in paw edema showing percentage inhibition (64.14%) and paw diameter of 2.94 mm (± 0.044) in formaldehyde provoked arthritic model. Administration of 15 mg/kg of aripiprazole in CFA induced arthritic model presented significant (****p < 0.0001) suppression in paw edema showing percentage inhibition (70.58%) that was interestingly greater then piroxicam and paw diameter of 3.5 mm (± 0.105) and aripiprazole 15 mg/kg has significantly (****p < 0.0001) reduced arthritic score with suppression of edema confirmed by arthritic score 1 (± 0.00) recorded on 28th day of model. Aripiprazole had recovered body weight alteration in CFA induced arthritic model (****p < 0.0001), Radiographic and histopathological investigation displayed no substantial architectural variations in joints of rats that were given treatment. Inflammatory genes IL-1β, TNF-α, IL-6, Cox-2, NF-Kβ and PGE2 were down regulated together with remarkable rise in expression of interleukin-4 and interleukin-10 in treated animals had been revealed by aripiprazole. Significant (****p < 0.0001) downregulation of levels of PGE2 of 222.055 ng/ml (± 4.760) was detected at highest dose of aripiprazole 15 mg/kg. Whereas, a significant (****p < 0.0001) down-regulation of fold change of NF- κB, IL-1β, TNF-α, IL-6, Cox-2 in dose dependent manner was shown by aripiprazole.

conclusionAbove stated results strongly claims that aripiprazole is an effective anti-arthritic therapy as verified through molecular docking, in-vitro and in-vivo assessment and via down regulating pro-inflammatory markers and up regulation of anti-inflammatory cytokines and can be thought to be an appropriate option to repurpose the drug as anti-arthritic agent.