Co-administration Of Curcumin Research Articles

Nephro-Protective Effects of Curcumin, Rosemary and Propolis against Gentamicin Induced Toxicity in Guinea Pigs: Morphological and Biochemical Study

The kidney is a common target for toxic xenobiotics due to its capacity to extract and concentrate toxic substances by highly specialized cells and also, due to its large blood flow. Objective: The present work aimed to evaluate the effectiveness of different natural materials (curcumin, rosemary and propolis) against the histological and also biochemical alterations of gentamicin induced nephrotoxicity in guinea pigs. Materials and methods: 48 guinea pigs were used for this study and divided into 8 groups. The first 4 groups were control groups, the 5th group was the experimental and administered gentamicin at a dose of 100 mg/kg body wt for 10 days, and in the 6th , 7th , and 8th groups, gentamicin was co-administered with curcumin, rosemary, and propolis at the doses of 200 mg, 220 mg, and 100 mg/kg body wt respectively. The animals were sacrificed and the kidneys were dissected and specimens were obtained. The specimens were processed for light microscopic examinations. Blood samples were obtained for assessment of urea, creatinine and uric acid levels. Results: In gentamicin treated animals, there were structural changes. The proximal convoluted tubules showed degenerated epithelial lining with disruption of their brush borders and presence of epithelial debris inside their lumens. The renal corpuscle appeared with degeneration of the glomerulus and disrupted Bowman's capsule. The afferent arteriole showed thickening in its wall and degeneration of endothelial lining with extensive perivascular infiltration of inflammatory cells. Massive interstitial hemorrhage was seen. Also, the serum urea, creatinine, and uric acid were elevated. Co-administration of curcumin, rosemary, and propolis significantly improved the structural changes in the kidney and the blood urea, creatinine and uric acid were significantly declined. Conclusion: It can be concluded that, the gentamicin has adverse effects on the kidney. Different natural materials as curcumin, rosemary, and propolis were able to protect the kidney against these effects. So, the patients should be advised to take one of these materials while they are treated by gentamicin.

The Novel Heterocyclic Trioxirane [(1,3,5-Tris Oxiran-2-yl)Methyl)-1,3,5-Triazinane-2,4,6-Trione (TATT)] Exhibits a Better Anticancer Effect than Platinum-Based Chemotherapy by Induction of Apoptosis and Curcumin Further Enhances its Chemosensitivity

The heterocyclic trioxirane compound [1,3,5-tris((oxiran-2-yl)methyl)-1,3,5-triazinane-2,4,6-trione (TATT)] is a synthetic compound which has been used as an experimental anticancer agent in human clinical trials. Curcumin, an active natural compound in turmeric and curry, is an ingredient commonly used in the traditional diet of many Asian countries. In the present study, we observed that TATT exhibited a better anticancer effect on chemoresistant human colorectal cancer HT-29 cells and displayed less cytotoxicity on normal human umbilical vein endothelial cells, compared with FDA-approved anticancer drugs (cisplatin, carboplatin, or oxaliplatin) using MTT assay. TATT also induced a stronger apoptotic effect than that seen with the three studied anticancer drugs, as characterized by externalization of phosphatidylserine using flow cytometry. Administration of caspase 8-specific inhibitor (z-IETD-fmk) and mitochondrial permeability transition pore inhibitor (cyclosporin A) demonstrated that TATT-induced apoptosis proceeded via both extrinsic and intrinsic signaling pathways. It is noteworthy that coadministration of curcumin further significantly increased TATT-induced cytotoxicity, externalization of phosphatidylserine (representing early apoptosis), and the percentages of cells at the sub-G1 phase (representing late apoptosis), producing an additivity and/or synergistic effect, and vice versa. Suppression of nuclear NF-κB was involved in curcumin-enhanced chemosensitivity of TATT. Overall, our data indicate that TATT exerts a chemotherapeutic effect on colorectal cancer cells and coadministration of curcumin enhances the treatment effect of TATT.

Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics

Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination.

Perifosine sensitizes curcumin‐induced anti‐colorectal cancer effects by targeting multiple signaling pathways both in vivo and in vitro

Our study shows that coadministration of curcumin and an orally bioactive alkylphospholipid perifosine results in a significant increase in colorectal cancer cell apoptosis and a marked inhibition of cell growth both in vitro and in vivo. This novel combinatorial regimen leads to changes of multiple cell signaling pathways including inactivation of Akt and nuclear factor-κB as well as activation of c-Jun N-terminal kinases and endoplasmic reticulum stress. Further, perifosine and curcumin synergistically increase intracellular level of reactive oxygen species and ceramide, and downregulate the expression of cyclin D1 and Bcl-2 in colorectal cancer cells. These changes at molecular level together account for the cancer cell apoptosis and growth inhibition. We conclude that perifosine sensitizes colorectal cancer cells to curcumin by modulating multiple signaling pathways. Adding perifosine with curcumin may represent an effective therapy regimen against colorectal cancers, and possible other aggressive tumors.

Effects of curcumin on the pharmacokinetics of talinolol in human with ABCB1 polymorphism

This study was to investigate the effect of concomitantly administered curcumin on the pharmacokinetics of talinolol and association with ABCB1 C3435T genetic polymorphism.A two-phase, randomized, single-blind, crossover study was carried out in 18 healthy male volunteers with different genotypes of ABCB1, including C3435C (CC, n = 6), C3435T (CT, n = 6) and T3435T (TT, n = 6). The pharmacokinetics of talinolol were measured after co-administration of placebo or 1000 mg curcumin capsules once daily for 14 days.The AUC0–48 h and AUC0–∞ of talinolol were increased by 67.0% (95% CI: 1.09~2.25; p = 0.002) and 80.8% (95% CI: 0.92~2.69; p = 0.005) respectively with curcumin co-administration. The Cmax of talinolol was significantly higher after curcumin administration as compared with placebo (p = 0.029).The CL/F of talinolol was decreased by 25.9% (p = 0.005) during the curcumin-treated phase. No significant change in tmax and t1/2 of talinolol were observed between the placebo- and curcumin-treated phases. AUC0–48, AUC0–∞, Cmax of talinolol were extensively increased and CLoral/F decreased in TT subjects.Co-administration of curcumin significantly increased the plasma concentration of talinolol in healthy volunteers. The effect of curcumin on talinolol was associated with ABCB1 genotypes (C3435T).

Epithelial Proinflammatory Response and Curcumin-Mediated Protection from Staphylococcal Toxic Shock Syndrome Toxin-1

Staphylococcus aureus initiates infections and produces virulence factors, including superantigens (SAgs), at mucosal surfaces. The SAg, Toxic Shock Syndrome Toxin-1 (TSST-1) induces cytokine secretion from epithelial cells, antigen presenting cells (APCs) and T lymphocytes, and causes toxic shock syndrome (TSS). This study investigated the mechanism of TSST-1-induced secretion of proinflammatory cytokines from human vaginal epithelial cells (HVECs) and determined if curcumin, an anti-inflammatory agent, could reduce TSST-1-mediated pathology in a rabbit vaginal model of TSS. TSST-1 caused a significant increase in NF-κB-dependent transcription in HVECs that was associated with increased expression of TNF- α, MIP-3α, IL-6 and IL-8. Curcumin, an antagonist of NF-κB-dependent transcription, inhibited IL-8 production from ex vivo porcine vaginal explants at nontoxic doses. In a rabbit model of TSS, co-administration of curcumin with TSST-1 intravaginally reduced lethality by 60% relative to 100% lethality in rabbits receiving TSST-1 alone. In addition, TNF-α was undetectable from serum or vaginal tissue of curcumin treated rabbits that survived. These data suggest that the inflammatory response induced at the mucosal surface by TSST-1 is NF-κB dependent. In addition, the ability of curcumin to prevent TSS in vivo by co-administration with TSST-1 intravaginally suggests that the vaginal mucosal proinflammatory response to TSST-1 is important in the progression of mTSS.

Therapeutic role of curcumin in prevention of biochemical and behavioral aberration induced by alcoholic neuropathy in laboratory animals

Painful peripheral neuropathy induced by chronic ethanol consumption is a major medico-socioeconomical problem. The objective of present investigation was to study the effect of curcumin (20, 40 and 80mg/kg; p.o.) in alcohol-induced neuropathy in rats. Ethanol (35% v/v, 10g/kg; p.o.) was administered for 10 weeks which showed a significant decrease in thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia and nerve conduction velocity. It caused enhanced malondialdehyde, oxidative-nitrosative stress, total calcium levels, inflammatory mediators (TNF-α and IL-1β levels) along with DNA damage. Co-administration of curcumin and α-tocopherol for 10 weeks significantly and dose-dependently improved nerve functions, biochemical as well as molecular parameters and DNA damage in sciatic nerve of ethanol treated rats. Hence, it was concluded that curcumin is of potent therapeutic value in the amelioration of alcoholic neuropathy in rats and acts by inhibition of pro-inflammatory mediators like TNF-α and IL-1β.

Curcumin, an active component of turmeric in the prevention and treatment of ulcerative colitis: preclinical and clinical observations

Inflammatory bowel disease (IBD) comprising of ulcerative colitis (UC) and Crohn's disease (CD) is a major ailment affecting the small and large bowel. In clinics, IBD is treated using 5-amninosalicylates, antibiotics, the steroids and immunomodulators. Unfortunately, the long term usages of these agents are associated with undue side effects and compromise the therapeutic advantage. Accordingly, there is a need for novel agents that are effective, acceptable and non toxic to humans. Preclinical studies in experimental animals have shown that curcumin, an active principle of the Indian spice turmeric (Curcuma longa Linn) is effective in preventing or ameliorating UC and inflammation. Over the last few decades there has been increasing interest in the possible role of curcumin in IBD and several studies with various experimental models of IBD have shown it to be effective in mediating the inhibitory effects by scavenging free radicals, increasing antioxidants, influencing multiple signaling pathways, especially the kinases (MAPK, ERK), inhibiting myeloperoxidase, COX-1, COX-2, LOX, TNF-α, IFN-γ, iNOS; inhibiting the transcription factor NF-κB. Clinical studies have also shown that co-administration of curcumin with conventional drugs was effective, to be well-tolerated and treated as a safe medication for maintaining remission, to prevent relapse and improve clinical activity index. Large randomized controlled clinical investigations are required to fully understand the potential of oral curcumin for treating IBD.

Protective effect of curcumin against arsenic-induced apoptosis in murine splenocytes in vitro

Arsenic is a potent environmental pollutant and immunotoxic agent. Curcumin is a natural anti-oxidant used to treat a broad variety of diseases. Here, the effects were investigated of curcumin on sodium arsenite-induced apoptosis in murine splenocytes in vitro. Cells were exposed to sodium arsenite (NaAsO2, 5 µM) with and without curcumin (5 and 10 µg/ml) and incubated at 37°C for 12 h. NaAsO2 caused a decrease in cell viability and induction of apoptosis. These outcomes were concurrent with increases in the numbers of cells with reactive oxygen species generation, loss of mitochondrial transmembrane potential, an increase in the frequency of cells with sub-G1 DNA content, and DNA fragmentation. Co-administration of curcumin with the NaAsO2 caused significant recoveries in cell viability values and mitigation of the induced apoptosis-related molecular changes. A significant protection against apoptosis parameters in murine splenocytes simultaneously treated with NaAsO2 and curcumin suggested a protective efficacy of curcumin. From the results it is concluded that the immuno-modulation exerted by curcumin might be attributed to its multifaceted effects including its anti-oxidative and anti-apoptotic properties. These findings have implications not only for the under-standing of the toxicity of arsenic to murine splenocytes in vitro but are also potentially important for developing preventive and/or corrective strategies against/during chronic arsenicosis.

Pharmacokinetic and pharmacodynamic interactions of valproate, phenytoin, phenobarbitone and carbamazepine with curcumin in experimental models of epilepsy in rats

The present study investigates the interaction of curcumin with four antiepileptic drugs (AEDs) in male Wistar rats. In the first protocol, seizures were induced using pentylenetetrazole (PTZ) and valproate was injected intraperitoneally (i.p.) in therapeutic and sub-therapeutic doses 30min before PTZ administration. Curcumin was co-administered with sub-therapeutic dose of valproate 60min before PTZ injection. In the second protocol, seizures were induced by maximal-electroshock. Phenytoin, phenobarbitone and carbamazepine were injected in their therapeutic and sub-therapeutic doses 120, 60 and 30min, respectively, before seizure induction. Curcumin was administered along with sub-therapeutic doses of phenytoin, phenobarbitone and carbamazepine, 60min before induction of seizures. Behavioral parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were assessed and the serum levels of the AEDs were estimated. The AEDs in their therapeutic doses produced complete protection against seizures. However, sub-therapeutic doses of these AEDs failed to completely protect against seizures. Co-administration of curcumin with sub-therapeutic dose of valproate significantly increased the latency to myoclonic jerks. The percentage protection against seizures with sub-therapeutic doses of valproate, phenytoin, phenobarbitone and carbamazepine was also enhanced by concomitant curcumin administration. Both PTZ and MES induced seizures caused significant impairment of cognitive functions. Co-administration of curcumin with these AEDs in their sub-therapeutic doses prevented the impairment of learning and memory due to seizures whereas no such improvement was observed in the groups administered the sub-therapeutic doses of the AEDs alone. Additionally, curcumin reversed the oxidative stress due to seizures. However, curcumin co-administration did not cause any significant alteration in the serum levels of the AEDs. The results thus suggest the potential of curcumin as an adjunct to these AEDs in epilepsy with the advantage of increasing the efficacy, reducing the dose and side effects of the AEDs.

Protective Effect of Curcumin and its Combination with Piperine (Bioavailability Enhancer) Against Haloperidol-Associated Neurotoxicity: Cellular and Neurochemical Evidence

Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects, particularly the irregular movements of chorionic type. This limitation presents a marked therapeutic challenge. The present study investigates the molecular etiology of haloperidol neurotoxicity and the role of curcumin, a well-known anti-oxidant, in ameliorating these adverse effects. The redox status of haloperidol-treated brains along with NO, TNF-α, NF-kappaB p65 subunit, caspase-3, and monoamine neurotransmitters were measured in the striatum of rat brain. Chronic treatment with haloperidol (5mg/kg, i.p., 21days) produced orofacial dyskinetic movements which were coupled with marked increase in oxidative stress parameters, TNF-α, caspase-3 activity in cytoplasmic lysate and active p65 sub unit of NF-kappaB in nuclear lysates of the striatum. Neurochemically, chronic administration of haloperidol resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin. The prototype atypical anti-psychotic, clozapine (10mg/kg, i.p., 21days) produced mild oxidative stress but did not alter any other parameters. Interestingly, co-administration of curcumin (25 and 50mg/kg, i.p., 21days) dose-dependently prevented all the behavioral, cellular, and neurochemical changes associated with the chronic administration of haloperidol. Curcumin per se (50mg/kg) did not show any side effects. Co-administration of piperine significantly enhanced the effect of curcumin (25mg/kg) but not of curcumin (50mg/kg). Collectively, the data indicated the potential of curcumin as an adjunct to haloperidol treatment and provided initial clues to the underlying molecular mechanisms in haloperidol neurotoxicity. This study also provides a rationale for the combination of piperine and curcumin.

Curcumin ameliorates cognitive dysfunction and oxidative damage in phenobarbitone and carbamazepine administered rats

The antiepileptic drugs, phenobarbitone and carbamazepine are well known to cause cognitive impairment on chronic use. The increase in free radical generation has been implicated as one of the important mechanisms of cognitive impairment by antiepileptic drugs. Curcumin has shown antioxidant, anti-inflammatory and neuro-protective properties. Therefore, the present study was carried out to investigate the effect of chronic curcumin administration on phenobarbitone- and carbamazepine-induced cognitive impairment and oxidative stress in rats. Pharmacokinetic interactions of curcumin with phenobarbitone and carbamazepine were also studied. Vehicle/drugs were administered daily for 21days to male Wistar rats. Passive avoidance paradigm and elevated plus maze test were used to assess cognitive function. At the end of study period, serum phenobarbitone and carbamazepine, whole brain malondialdehyde and reduced glutathione levels were estimated. The administration of phenobarbitone and carbamazepine for 21days caused a significant impairment of learning and memory as well as an increased oxidative stress. Concomitant curcumin administration prevented the cognitive impairment and decreased the increased oxidative stress induced by these antiepileptic drugs. Curcumin co-administration did not cause any significant alteration in the serum concentrations of both phenobarbitone as well as carbamazepine. These results show that curcumin has beneficial effect in mitigating the deterioration of cognitive functions and oxidative damage in rats treated with phenobarbitone and carbamazepine without significantly altering their serum concentrations. The findings suggest that curcumin can be considered as a potential safe and effective adjuvant to phenobarbitone and carbamazepine therapy in preventing cognitive impairment associated with these drugs.

Antidepressant activity of curcumin: involvement of serotonin and dopamine system

Curcumin is a major active principle of Curcuma longa, one of the widely used preparations in the Indian system of medicine. It is known for its diverse biological actions. The present study was designed to investigate the involvement of monoaminergic system(s) in the antidepressant activity of curcumin and the effect of piperine, a bioavailability enhancer, on the bioavailability and biological effects of curcumin. Behavioral (forced swim test), biochemical (monoamine oxidase (MAO) enzyme inhibitory activity), and neurochemical (neurotransmitter levels estimation) tests were carried out. Curcumin (10-80 mg/kg, i.p.) dose dependently inhibited the immobility period, increased serotonin (5-hydroxytryptamine, 5-HT) as well as dopamine levels (at higher doses), and inhibited the monoamine oxidase enzymes (both MAO-A and MAO-B, higher doses) in mice. Curcumin (20 mg/kg, i.p.) enhanced the anti-immobility effect of subthreshold doses of various antidepressant drugs like fluoxetine, venlafaxine, or bupropion. However, no significant change in the anti-immobility effect of imipramine and desipramine was observed. Furthermore, combination of subthreshold dose of curcumin and various antidepressant drugs resulted in synergistic increase in serotonin (5-HT) levels as compared to their effect per se. There was no change in the norepinephrine levels. The coadministration of piperine (2.5 mg/kg, i.p.), a bioavailability enhancing agent, with curcumin (20 and 40 mg/kg, i.p.) resulted in potentiation of pharmacological, biochemical, and neurochemical activities. The study provides evidences for mechanism-based antidepressant actions of curcumin. The coadministration of curcumin along with piperine may prove to be a useful and potent natural antidepressant approach in the management of depression.