Berberine ameliorates acute hyperglycemia and hypoinsulinemia induced by ketamine/xylazine in rats: role of alpha2 adrenergic receptors, oxidative stress and inflammatory suppressing mechanisms.

Background: Xylazine is a common veterinary drug used for sedation, anesthesia, muscle relaxation and analgesia. Berberine (C₂₀H₁₈NO₄⁺) is an alkaloid compound found in different plant species with a wide range of biological and pharmacological activities. To date, no studies have examined the effects of berberine on acute hyperglycemia. Therefore, the present study was designed to investigate the effects of berberine on acute hyperglycemia and low insulin levels caused by ketamine/xylazine (K/X) administration. To clarify the involved mechanism, yohimbine (C₂₁H₂₆N₂O₃, an α2-adrenergic receptor antagonist) was used. To further elucidate the underlying mechanisms, insulin concentration, SOD activity, TAC, MDA, TNF-α, and IL-1β levels in serum were also determined.

Methods: Berberine (1.25, 5, and 20 mg/kg) and yohimbine (0.5 and 2 mg/kg) were injected intraperitoneally (IP) 25 and 20 min before acute hyperglycemia induction, respectively. IP administration of a cocktail of ketamine (100 mg/kg) and xylazine (10 mg/kg) caused acute hyperglycemia. The tail blood glucose levels and their average (30-120 min) were measured. After the last blood glucose level measurement, blood samples were taken, and the serum insulin concentration, total antioxidant capacity (TAC), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) levels were evaluated.

Results: K/X significantly (P < 0.05) increased blood glucose at 30, 60, 90, and 120 min, decreased insulin levels, and induced oxidative stress, which was accompanied by an increase in pro-inflammatory cytokines. Berberine (5 and 20 mg/kg) and yohimbine (2 mg/kg) significantly reduced blood glucose and increased insulin levels. Berberine (5 and 20 mg/kg) treatment also improved the decreased TAC content and SOD activity and restored the increased serum levels of MDA, TNF-α and IL-1β. Furthermore, coadministration of ineffective doses of berberine (1.25 mg/kg) and yohimbine (0.5 mg/kg) significantly prevented hyperglycemia and hypoinsulinemia. The synergic effect between berberine and yohimbine was observed.

Conclusion: Overall, berberine helps counteract K/X-induced hyperglycemia and hypoinsulinemia. Anti-hyperglycemic synergy between berberine and yohimbine suggests that berberine works partly by blocking α2 adrenergic receptors. In addition, oxidative stress and pro-inlammatory mediators reduction and anti-oxidative activity elevation might be involved in these metabolic effects of berberine.