Combinational effect of curcumin and metformin against gentamicin‐induced nephrotoxicity: Involvement of antioxidative, anti‐inflammatory and antiapoptotic pathway

Abstract

Gentamicin (GM) is an antibiotic related to aminoglycoside group that is used in treating Gram‐negative bacterial infections. However, treatment with gentamicin is considered to be limited as it induces an oxidative stress‐mediated apoptosis in kidney which causes a nephrotoxicity. Metformin is a well‐known biguanide that is used for treating diabetes mellitus, especially type 2. Supplement with plant metabolites or natural antioxidants produce a protective activity against many types of diseases in vivo. Curcumin is a main medicinal constituent of Curcuma longa, has reported for number of biological effects, such as antioxidant, anti‐inflammatory, and antitumor. The study aims at evaluating the metformin and curcumin alone or in combination on nephrotoxicity induced by GM. The outcome of the study shows that both metformin and curcumin, when used unaided, were effectively decreasing GM‐induced nephrotoxicity. The two drugs combination was showed synergistic effect in ameliorating a GM‐induced kidney injury, as supported by expressively improved renal dysfunction. Metformin and curcumin showed strong protection against oxidative stress in GM treated animals through decreasing the activities and expression of various antioxidative enzymes. Moreover, combination of two drugs showed an anti‐inflammatory response through reducing a level of pro‐inflammatory cytokines including tumor necrosis factor‐alpha, interleukin 1‐beta, and interleukin 6 in GM intoxicated group of animals. Furthermore, GM agitated apoptosis was affectedly diminished by the combinational treatment of metformin and curcumin via down‐regulating activity of cleaved Caspase‐3 and pro‐apoptotic factor Bax, whereas increasing anti‐apoptotic factor Bcl‐2 signaling pathways. The above results suggested that combinational treatment of metformin and curcumin might be have a synergizing effect and substantial potential against nephrotoxicity induced by GM. Practical applications Curcumin and metformin combination exhibited substantial synergistic effect against GM‐induced nephrotoxicity through reducing oxidative stress, inflammation, as well as apoptosis in kidney cells. Therefore, the method of combination of curcumin and metformin might be functional to treat or inhibit GM prompted nephrotoxicity in future.

Natural products: potential treatments for cisplatin-induced nephrotoxicity

“…Inhibits oxidative stress, apoptosis and inflammation, activates ERK pathway, decreases cisplatin concentration, and lowers its accumulation [255] Combination of hUCMSCs and resveratrol can better protect renal podocyte function, reduction of blood glucose and renal injury for diabetic nephropathy [256]; resveratrol (RES) and quercetin (QUR) can protect against APAPinduced nephrotoxicity [ -Curcumin Inhibits oxidative stress, apoptosis, inflammation, increases NAMPT and SIRT levels, inhibits M1 macrophage, and increases M2 macrophage polarization [260][261][262] Curcumin and dexmedetomidine was effective in reducing oxidative stress and renal histopathologic injury in I/R rat model [261]; combination of curcumin and metformin might be functional to treat or inhibit nephrotoxicity [262] mechanisms because the coadministration of alkaloids with drugs that are substrates of DMEs and/or ETs may cause herb-drug interactions [115]. In addition, dehydropyrrolizidine alkaloid (DHPA) can induce chronic disease, which may accumulate over a long period of time and develop slowly until liver failure.…”

Cinnamic acid ameliorate gentamicin-induced liver dysfunctions and nephrotoxicity in rats through induction of antioxidant activities

“…These free radicals cause deleterious effects on biomolecules such as proteins, lipids, and nucleic acids [2]. The main implications of GM induced ROS overproduction is the promotion of inflammation and suppression of the endogenous antioxidant system [2,10]. Therefore, numerous preclinical and clinical studies have focused on antioxidants or drugs with promising anti-oxidative, anti-inflammatory, and renoprotective effects in the past decade [4,10,11,12].…”

Purified Sika deer antler protein attenuates GM-induced nephrotoxicity by activating Nrf2 pathway and inhibiting NF-κB pathway

“…Gentamicin (GM) is an aminoglycoside drug, used to treat bacterial infections for those caused by Gram-negative organisms 4 . Despite its vast therapeutic benefits as an antibiotic drug, its clinical use is limited majorly because of its nephrotoxicity effect 5 . Because GM can cause nephrotoxicity, it is necessary to reduce the dosage of gentamicin or replace it with other drugs.…”