Dharmveer Singh Arya

Naringin ameliorates pentylenetetrazol-induced seizures and associated oxidative stress, inflammation, and cognitive impairment in rats: Possible mechanisms of neuroprotection

Oxidative stress and cognitive impairment are associated with PTZ-induced convulsions. Naringin is a bioflavonoid present in the grapefruit. It is a potent antioxidant, and we evaluated its effect on PTZ-induced convulsions. Rats were pretreated with normal saline, naringin (20, 40, and 80 mg/kg, i.p.), or diazepam (5mg/kg, i.p.) 30 min prior to the administration of PTZ. The administration of PTZ induced myoclonic jerks and generalized tonic-clonic seizures (GTSs). We observed that naringin significantly prolonged the induction of myoclonic jerks dose-dependently. Naringin (80 mg/kg, i.p.) pretreatment protected all rats, and this protective effect was annulled by the GABAA receptor antagonist, flumazenil. In addition, naringin reduced brain MDA and TNF-α levels and conserved GSH. The pretreatment also enhanced the performance of rats in the passive avoidance task. Our observations highlight the antioxidant, antiinflammatory, and anticonvulsant potential of naringin. Also, naringin modulates the GABAA receptor to produce anticonvulsant effects and to ameliorate cognitive impairment.

Hydroalcoholic extract of Emblica officinalis protects against kainic acid-induced status epilepticus in rats: Evidence for an antioxidant, anti-inflammatory, and neuroprotective intervention

Context: Emblica officinalis (Euphorbiaceae), commonly known as amla, is traditionally used for central nervous system (CNS) disorders. Objective: In the present study, the effect of standardized hydroalcoholic extract of E. officinalis fruit (HAEEO), an Indian medicinal plant with potent antioxidant activity, was studied against kainic acid (KA)-induced seizures, cognitive deficits and on markers of oxidative stress. Materials and methods: Rats were administered KA (10 mg/kg, i.p.) and observed for behavioral changes, incidence, and latency of convulsions over 4 h. The rats were thereafter sacrificed for estimation of oxidative stress parameters: thiobarbituric acid-reactive substances (TBARS) and glutathione (GSH). The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) was also determined in the rat brain. Results: Pretreatment with HAEEO (500 and 700 mg/kg, i.p.) significantly (P < 0.001) increased the latency of seizures as compared with the vehicle-treated KA group. HAEEO significantly prevented the increase in TBARS levels and ameliorated the fall in GSH. Furthermore, HAEEO dose-dependently attenuated the KA-induced increase in the TNF-α level in the brain. HAEEO also significantly improved the cognitive deficit induced by KA, as evidenced by increased latency in passive avoidance task. Discussion and conclusion: HAEEO at the dose of 700 mg/kg, i.p., was most effective in suppressing KA-induced seizures, cognitive decline, and oxidative stress in the brain. These neuroprotective effects may be due to the antioxidant and anti-inflammatory effects of HAEEO.

Anti-Inflammatory Effect of Emblica officinalis in Rodent Models of Acute and Chronic Inflammation: Involvement of Possible Mechanisms

Emblica officinalis, commonly known as amla in Ayurveda, is unarguably the most important medicinal plant for prevention and treatment of various ailments. The present study investigated the anti-inflammatory activity of hydroalcoholic extract of Emblica officinalis (HAEEO). Acute inflammation in rats was induced by the subplantar injection of carrageenan, histamine, serotonin, and prostaglandin E2 and chronic inflammation was induced by the cotton pellet granuloma. Intraperitoneal (i.p.) administration of HAEEO at all the tested doses (300, 500, and 700 mg/kg) significantly (P < 0.001) inhibited rat paw edema against all phlogistic agents and also reduced granuloma formation. However, at the dose of 700 mg/kg, HAEEO exhibited maximum anti-inflammatory activity in all experimental models, and the effects were comparable to that of the standard anti-inflammatory drugs. Additionally, in paw tissue the antioxidant activity of HAEEO was also measured and it was found that HAEEO significantly (P < 0.001) increased glutathione, superoxide dismutase, and catalase activity and subsequently reduced lipid peroxidation evidenced by reduced malondialdehyde. Taken all together, the results indicated that HAEEO possessed potent anti-inflammatory activity and it may hold therapeutic promise in the management of acute and chronic inflammatory conditions.

912 Naringin attenuates insulin resistance, β-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes via up-regulating PPARγ, heat shock protein-27 and -72

Objectives: Naringin, a bioflavonoid isolated from grapefruit, is well known to possess lipid-lowering and insulin-like properties. We assessed whether naringin treatment ameliorates insulin resistance (IR), &bgr;-cell dysfunction, hepatic steatosis and kidney damage in high-fat diet (HFD)-streptozotocin (STZ)-induced type 2 diabetic rats. Design and Methods: Wistar albino male rats were fed a HFD (55 % energy from fat and 2 % cholesterol) to develop IR and on the 10th day injected with a low dose of streptozotocin (40 mg/kg i.p.) to induce type 2 diabetes. After confirmation of hyperglycaemia (>13·89 mmol/l) on the 14th day, different doses of naringin (25-100 mg/kg per d) and rosiglitazone (5 mg/kg per d) were administered orally for the next 28 d while maintaining the HFD. Results: Naringin significantly decreased IR, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, TNF-&agr;, IL-6, CRP and concomitantly increased adiponectin and &bgr;-cell function in a dose-dependent manner. Naringin increased PPAR&ggr; expression in liver and kidney; phosphorylated tyrosine insulin receptor substrate 1 in liver; and heat shock protein-27 and 72 in pancreas, liver and kidney. In contrast, NF-&kgr;B expression in these tissues along with sterol regulatory element binding protein-1c and liver X receptor- expressions in liver were significantly diminished. Additionally, microscopic observations validated that naringin effectively rescues &bgr;-cells, hepatocytes and kidney from HFD-STZ-mediated oxidative damage and pathological alterations. Conclusions: This seminal study provides evidence that naringin ameliorates IR, dyslipidaemia, &bgr;-cell dysfunction, hepatic steatosis and kidney damage in type 2 diabetic rats by partly regulating oxidative stress, inflammation and dysregulated adipocytokines production through up-regulation of PPAR&ggr;, HSP-27 and 72.

942 SESAMOL AMELIORATES DIET-INDUCED CARDIOMETABOLIC SYNDROME IN RATS VIA UP-REGULATING PPAR γ AND PPAR α

Objectives: Increased oxidative stress and inflammation in obesity are the central and causal components in the pathogenesis and progression of cardiometabolic syndrome (CMetS). The aim of the study was to determine the potential role of sesamol (a natural powerful antioxidant and anti-inflammatory phenol derivative of sesame oil) in chronic high-cholesterol/high-fat diet (HFD)-induced CMetS in rats and to explore the molecular mechanism. Design and methods: Rats were fed with HFD (55% calorie from fat and 2% cholesterol) for 60 days to induce obesity, dyslipidemia, insulin resistance (IR), hepatic steatosis and hypertension. On the 30th day, rats with total cholesterol>150 mg/dl were considered hypercholesterolemic and administered sesamol 2, 4 and 8 mg/kg per day for the next 30 days. Results: Sesamol treatment decreased IR, hyperinsulinemia, hyperglycemia, dyslipidemia, TNF-&agr;, IL-6, leptin, resistin, highly sensitive C-reactive protein (hs-CRP), hepatic transaminases and alkaline phosphatase, along with normalization of adiponectin, nitric oxide and arterial pressures in a dose-dependent fashion. Increased TBARS, nitrotyrosine and decreased antioxidant enzyme activities were also amended in HFD rats. Similarly, sesamol normalized hepatic steatosis and ultrastructural pathological alteration in hepatocytes, although the effect was more pronounced at 8 mg/kg. Furthermore, hepatic PPAR&ggr;, PPAR&agr; and e-NOS protein expressions were increased, whereas LXR&agr;, SERBP-1c, P-JNK and NF-&kgr;B expression were decreased by sesamol treatment. Conclusions: These results suggest that sesamol attenuates oxidative stress, inflammation, IR, hepatic steatosis and hypertension in HFD-fed rats via modulating PPAR&ggr;, NF-&kgr;B, PJNK, PPAR&agr;, LXR&agr;, SREBP-1c and e-NOS protein expressions, thereby preventing CMetS. Thus, the present study demonstrates the therapeutic potential of sesamol in alleviating CMetS.