Probucol attenuates lipopolysaccharide-induced leukocyte recruitment and inflammatory hyperalgesia: effect on NF-кB activation and cytokine production

Abstract

Probucol 4,4'- (Isopropylidenedithio)bis(2,6-di-tert-butylphenol) is a synthetic molecule clinically used for prevention and treatment of hypercholesterolemia and atherosclerosis. Recent studies have shown that the beneficial effects of probucol mainly derive from its anti-inflammatory and antioxidant properties. Gram-negative bacteria are common infectious agents and their wall components, e.g. lipopolysaccharide (LPS), are important elicitors of inflammation. LPS is sensed by tissue resident cells and it triggers a Toll-like receptor 4/MyD88-dependent signaling cascade resulting in endothelial activation, leukocyte recruitment and nociception. Therefore the present study aimed to investigate the anti-inflammatory and analgesic effects of probucol in models of LPS-induced acute inflammation. Probucol at 0.3-30mg/kg was administrated to male Swiss mice per oral 1h before intraplantar or intraperitoneal lipopolysaccharide stimulus. Probucol at 3mg/kg reduced lipopolysaccharide-induced mechanical and thermal hyperalgesia. These effects were accompanied by reduced leukocyte influx and cytokine production in both paw skin and peritoneum exudate. Unexpectedly, probucol did not alter lipopolysaccharide-induced tissue oxidative stress at anti-inflammatory /analgesic dose. On the other hand, probucol inhibited lipopolysaccharide-induced nuclear factor kappa B (NF-кB) activation in paw tissue as well as NF-кB activity in cultured macrophages in vitro, reinforcing the inhibitory effect of probucol over the NF-кB signaling pathway. In this sense, we propose that probucol acts on resident immune cells, such as macrophages, targeting the NF-кB pathway. As a result, it prevents the amplification and persistence of the inflammatory response by attenuating NF-кB-dependent cytokine production and leukocyte recruitment explaining its analgesic effects as well.

Effect of probucol on autophagy and apoptosis in the penile tissue of streptozotocin-induced diabetic rats

“…Increasing evidence has shown that probucol can effectively reduce inflammation by inhibiting the NF-κB pathway and reducing the release of inflammatory cytokines, such as TNF-α. 16 17 18 …”

Paeoniflorin relieves LPS-induced inflammatory pain in mice by inhibiting NLRP3 inflammasome activation via transient receptor potential vanilloid 1

“…injected daily with PF (≥98% purity by HPLC analysis, P0038, Sigma–Aldrich, St. Louis, MO, USA) or the same volume of sterilized saline (vehicle of PF) continuously for 1 week, separately. Two hours after last injection on the seventh day, LPS (200 ng/20 µL) ( Escherichia coli 0111: B4) (L2630, Sigma–Aldrich) or the same volume of sterilized saline (vehicle of LPS) was injected into the plantar surface of right hind paw using a microsyringe with a 30‐gauge needle, respectively 16 . After 5 h, mice were sacrificed by cervical dislocation and samples were collected for further evaluation.…”

Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington’s Disease

“…Probucol (Sigma, St. Louis, MO, USA; 30 mg/kg/day) was diluted in carboxymethylcellulose (CMC), 1 mg/mL. The probucol dose was chosen based on previous studies that reported neuroprotective effects of this compound [ 48 – 50 ]. YAC128 and wild-type (WT) mice were randomly divided into four experimental groups (with equal numbers of males and females included in each group, 10 mice/group): 1 (WT vehicle), 2 (YAC128 vehicle), 3 (WT probucol), and 4 (YAC128 probucol).…”