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. 2018 May 11:9:471.
doi: 10.3389/fphar.2018.00471. eCollection 2018.

Gemcabene, a First-in-Class Hypolipidemic Small Molecule in Clinical Development, Attenuates Osteoarthritis and Pain in Animal Models of Arthritis and Pain

Rai A K Srivastava  1 , Joseph A Cornicelli  2 , Bruce Markham  3 , Charles L Bisgaier  1
Affiliations

Gemcabene, a First-in-Class Hypolipidemic Small Molecule in Clinical Development, Attenuates Osteoarthritis and Pain in Animal Models of Arthritis and Pain

Rai A K Srivastava et al. Front Pharmacol. .

Abstract

Our clinical studies have demonstrated that gemcabene, a small molecule in late-stage clinical development, lowers pro-inflammatory acute-phase protein, C-reactive protein (CRP). This observation was further confirmed in a cell-based study showing inhibition of cytokine-induced CRP production. Based on these observations, in the present study, we tested the hypothesis that gemcabene may possess anti-inflammatory activities in animal models of inflammatory disease. Efficacy of gemcabene was investigated in rat models of carrageenan-induced thermal hyperalgesia (CITH), monosodium iodoacetate (MIA)-induced osteoarthritis (OA), and IL-6/IL-6sR-induced inflammation. We also evaluated efficacy of gemcabene in collagen antibody-induced joint swelling and arthritis in BALB/c mice. In CITH rat model, gemcabene administration attenuated paw withdrawal latency (60% at 30 mg/kg/d and 97% at 100 mg/kg/d) and showed improvement in joint swelling (-50% at 30 mg/kg/d) in MIA model of OA. These findings were further corroborated by IL-6/IL-6sR knee injection model in rat, showing 63 and 71% reduction in hind paw weight distribution at 10 and 30 mg/kg/d doses, respectively. In mouse model of monoclonal antibody-induced arthritis, a dose-dependent attenuation of joint swelling was observed. These results demonstrate that the anti-inflammatory activity of gemcabene previously observed in cell-based and in clinical studies also occurred in animal models of inflammation-induced arthritis and hyperalgesia. Thus, in addition to hypolipidemic efficacy, the anti-inflammatory activity of gemcabene may have additional benefits to patients with elevated vascular inflammation.

Keywords: CRP; IL-1β; IL6; NF-kB; gemcabene; hyperalgesia; inflammation; osteoarthritis.

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Figures

FIGURE 1
FIGURE 1
Structure of test substance.
FIGURE 2
FIGURE 2
Efficacy of reference agents in the collagen antibody-induced joint swelling and arthritis mouse model. Methotrexate (4 mg/kg), cyclosporine A, and anti-TNF-α antibody (83.33 μg) were evaluated in this study. BALB/c mice (n = 5) were administered by oral gavage (methotrexate and cyclosporine) or intraperitoneal injection (anti-TNF-α antibody). The details are provided in the “Materials and Methods” section. The results of day 9 treatment are only shown. Data presented show changes in the footpad and ankle swelling and are expressed as mean ± SEM. ∗Significantly different compared to vehicle control.
FIGURE 3
FIGURE 3
Effect of gemcabene on carrageenan-induced thermal hyperalgesia in the male Sprague Dawley rats. To induce inflammation, male Sprague Dawley rats were anesthetized and given an intraplantar injection of carrageenan (2 mg) in saline (0.1 mL). Rats (8/group) were injected with either saline (baseline) or carrageenan (control and drug treated) into the hind paw. For measurement of PWL responses, tests were done 1-h post drug administration (3.5 h post saline/carrageenan injection). Dose-related effects of gemcabene on paw withdrawal latency (PWL) was determined following exposure to radiant heat. ∗Significantly different from Carrageenan control. p < 0.05 as determined by one-way ANOVA/Tukey’s. Data are expressed as Mean ± SEM.
FIGURE 4
FIGURE 4
Collagen antibody-induced joint swelling and arthritis in female BALB/c mice. Joint swelling and arthritis were induced in BALB/c mice by collagen antibody injection. Mice were dosed orally with vehicle (0.5% hydroxypropyl methylcellulose/0.25% Tween-80), or gemcabene at 30, 100, or 200 mg/kg in vehicle, 1 h prior to LPS injection, and then q.d. thereafter for the duration of the study. Change in footpad and ankle swelling was measured as described in the “Experimental Procedure” section. ∗Indicates statistical significance (p < 0.05). Data are expressed as Mean ± SEM.
FIGURE 5
FIGURE 5
Effect of gemcabene on monosodium iodoacetate (MIA)-induced change in hind paw weight distribution. (A) MIA was injected into the right knee and saline into the left knee of all rats on Day 0. On day 14 the rats were assessed on an incapacitance tester and then given gemcabene (10, 30, or 100 mg/kg, po). Two, 4, and 6 h later, the rats were reassessed. Statistically significant differences were determined by one-way ANOVA followed by Dunnett’s multiple comparisons procedure. Data are expressed as mean ± SEM, N = 8 rats per group. (B) MIA and saline were injected on day 0. Gemcabene (30 mg/kg) was given p.o., 0.5 h before MIA injection. Gemcabene was then given b.i.d for 28 days. Changes in hind paw weight distribution were determined on Days 7, 14, and 28. Statistically significant differences were determined by one-way ANOVA with the Dunnett’s multiple comparisons procedure (∗p < 0.05). Data are expressed as mean ± SEM. N = 12 rats per group. (C) 28 days dose-response study. MIA and saline were injected on day 0. Gemcabene (3, 10, or 30 mg/kg) was given PO, 0.5 h before MIA injection. gemcabene was then given b.i.d for 28 days. Changes in hind paw weight distribution were determined on days 7, 14, and 28. (D) Rats were treated with MIA as shown in A for 14 days followed by acute treatment with the reference agents. Only 4 h time points are shown. Data presented show pain alleviation compared to vehicle control (100% pain, 0% comfort). Statistically significant differences were determined by one-way ANOVA with the Dunnett’s multiple comparisons procedure (∗p < 0.05). Data are expressed as mean ± SEM. N = 12 rats per group. ∗∗p < 0.01.
FIGURE 6
FIGURE 6
Effect of emcabene on medial tibial plateau erosion area in the rat MIA model of OA. (A) MIA and saline were injected on day 0. Gemcabene (30 mg/kg) was given p.o., 0.5 h before MIA injection and was then given b.i.d for 28 days. Erosion analysis was performed on day 28. There were no statistically significant differences as determined by t-test (p = 0.179). N = 12 rats per group. (B) Effect of Gemcabene (3, 10, and 30 mg/kg) on medial tibial plateau erosion area in the rat MIA model of OA. MIA and saline were injected on day 0. Gemcabene (3, 10, or 30 mg/kg) was given p.o., 0.5 h before MIA injection and was then given b.i.d for 28 days. Erosion analysis was performed on day 28. Only the 10 mg/kg group was statistically significant as determined by one-way ANOVA, Dunnett’s multiple comparisons procedure (p < 0.05). N = 12 rats per group. (C) Percent erosion distribution from experiment in (A) with 30 mg/kg/d dose. (D) Percent erosion distribution from experiment in (B) with dose-response (10, 30, and 100 mg/kg). Data are expressed as Mean ± SEM.
FIGURE 7
FIGURE 7
Effect of gemcabene on change in hind paw weight distribution in the rat IL-6/IL-6sR knee injection model. (A) Experiment 1 Baseline incapacitance readings were taken on Day –1. IL-6/IL-6sR and PBS were injected on day 0. Gemcabene (10, 30, or 100 mg/kg) was given p.o. 3 h before IL-6/IL-6sR injection. Changes in hind paw weight distribution were determined 1, 3, and 6 h post-injection (4, 6, and 9 h post-gemcabene dose). Statistically significant differences were determined by one-way ANOVA followed by the Hochberg’s procedure (∗p < 0.001). Data are expressed as mean ± SEM. N = 10 rats per group. (B) Experiment 2 was carried out same way as experiment 1, but at only two doses, 10 and 30 mg/kg. The results show reproducibility of the findings.
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