Amelioration of Diabetes mellitus by modulation of GLP-1 via targeting alpha-glucosidase using Acacia tortilis polysaccharide in Streptozotocin-Nicotinamide induced diabetes in rats.

BACKGROUND: Polysaccharides decrease the glucose level by inhibiting α-glucosidase enzyme which further increases the level of GLP-1 (Glucagon-like peptide 1) to increase the insulin level as per earlier reports. OBJECTIVE: Similar hypothesis was designed in present study to investigate the α-glucosidase enzyme inhibition and involvement of GLP-1 in antidiabetic mechanism of Acacia tortilis polysaccharides (AEATP) in diabetic rats. Isolated polysaccharides were analyzed for their chemical nature by using HPLC and FTIR method. MATERIALS AND METHODS: Male albino wistar rats were divided into control, diabetic, diabetic + voglibose, diabetic + glimepiride, diabetic+250, 500, 1000 mg/kg of AEATP, diabetic + glimepiride + voglibose, diabetic + glimepiride+ 250, 500 and 1000 mg/kg AEATP, diabetic + GLP-1 antagonist+250, 500 and 1000 mg/kg AEATP. Plasma glucose, insulin and active GLP-1 levels were measured 15 min after OGTT. Fasting blood glucose, Plasma triglycerides, glycated hemoglobin (HbA1c), Fasting insulin, pancreatic insulin content, ileum and colon GLP-1 content were assessed at 5th week. Association of alpha-glucosidase was also assessed with GLP-1 and insulin. RESULTS: AEATP significantly attenuated hyperglycemia by increasing insulin level in plasma and pancreas and increased active GLP-1 as well as insulin level in diabetic rats after OGTT. GLP-1 content was significantly increased in ileum and colon by inhibiting alpha-glucosidase. Involvement of GLP-1 in antihyperglycemic effect of AEATP was confirmed by using GLP-1 antagonist. Moreover, AEATP significantly improved dyslipidemia in diabetic rats. HPLC analysis of A. tortilis polysaccharide comprised four specific monosaccharides (Rhamnose, Glucuronic acid, glucose and galactose) and FTIR spectrum shown band at 3430.6 cm-1 (O-H stretching), 2940.3 cm-1 (C-H linkage), 1630.4 cm-1 (carbonyl stretching), 1410 cm-1 (uronic acid) and 1030.5 cm-1 (glycosidic linkage). CONCLUSION: It can be concluded that antidiabetic effect of AEATP is through the modulation of GLP-1 level in plasma and intestinal tissue via alpha glucosidase inhibition.

Antidiabetic activity of Acacia tortilis (Forsk.) Hayne ssp. raddiana polysaccharide on streptozotocin-nicotinamide induced diabetic rats.

The present study was designed to investigate the antidiabetic activity of aqueous extract of Acacia tortilis polysaccharide (AEATP) from gum exudates and its role in comorbidities associated with diabetes in STZ-nicotinamide induced diabetic rats. Male albino Wistar rats were divided into control, diabetic control, glimepiride treated (10 mg/kg), and diabetic rats treated with 250, 500, and 1000 mg/kg dose of AEATP groups and fasting blood glucose, glycated hemoglobin, total cholesterol, triglyceride, LDL, VLDL, HDL, SGOT, and SGPT levels were measured. STZ significantly increased fasting blood glucose level, glycated hemoglobin, total cholesterol, triglyceride, LDL, VLDL, SGOT, and SGPT levels, whereas HDL level was reduced as compared to control group. After 7 days of administration, 500 and 1000 mg/kg dose of AEATP showed significant reduction (P < 0.05) in fasting blood glucose level compared to diabetic control. AEATP has also reduced total cholesterol, triglyceride, LDL, VLDL, SGOT, and SGPT levels and improved HDL level as compared to diabetic control group. Our study is the first to report the normalization of fasting blood glucose level, lipid profile, and liver enzyme in AEATP treated diabetic rats. Thus, it can be concluded that AEATP may have potentials for the treatment of T2DM and its comorbidities.

Involvement of cyclic adenosine diphosphoribose receptor activation in ischemic preconditioning induced protection in mouse brain.

The present study has been designed to expound the significance of cyclic adenosine diphosphoribose receptor activation in ischemic preconditioning induced reversal of ischemia and reperfusion induced cerebral injury in mice. Bilateral carotid artery occlusion of 17 min followed by reperfusion for 24 h was employed in present study to produce ischemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using Morris water-maze test. Rota-rod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor co-ordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min (ischemic preconditioning) prevented markedly ischemia-reperfusion-induced cerebral injury measured in terms of infarct size, loss of memory and motor coordination. 8-Bromo-cyclic adenosine diphosphate ribose (2 mg/kg, ip), an antagonist of cyclic ADP-ribose receptor, attenuated the neuroprotective effect of ischemic preconditioning. It is concluded that neuroprotective effect of ischemic preconditioning may be due to the adenosine diphosphoribose receptor activation.

Diethyl dithiocarbamic acid, a possible nuclear factor kappa B inhibitor, attenuates ischemic postconditioning-induced attenuation of cerebral ischemia-reperfusion injury in mice.

The present study was designed to pharmacologically investigate the possible role of nuclear factor kappa B (NF-kappaB) in the reversal of global cerebral injury induced by ischemia and reperfusion after ischemic postconditioning. Bilateral carotid artery occlusion for 17 min followed by reperfusion for 24 h was employed to produce ischemia- and reperfusion-induced cerebral injury in mice. Cerebral infarct size was measured by using triphenyltetrazolium chloride staining. Memory was evaluated using the Morris water maze test. The rotarod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced a marked increase in cerebral infarct size, impairment of memory, and motor coordination. A set of 5 episodes of carotid artery occlusion for a period of 10 s and reperfusion of 10 s (ischemic postconditioning) significantly prevented ischemia-reperfusion-induced cerebral infarct size and behavioral deficits measured in terms of loss of memory and motor coordination. Diethyl dithiocarbamic acid sodium salt trihydrate (DDA) (100 mg/kg, i.p.), an inhibitor of NF-kappaB, given 30 min before ischemia attenuated the beneficial effects of ischemic postconditioning. It may be concluded that the beneficial effects of ischemic postconditioning on global cerebral ischemia- and reperfusion-induced cerebral injury and behavioral deficits may involve activation of the NF-kappaB-linked pathway.

Nuclear factor-kappa-B inhibitor modulates the development of opioid dependence in a mouse model of naloxone-induced opioid withdrawal syndrome.

The present study was designed to investigate the effect of diethyl dithiocarbamic acid sodium salt trihydrate (DDA), a selective inhibitor of nuclear factor-kappa-B, on the development of morphine dependence in a mouse model of naloxone-induced opioid withdrawal syndrome. Morphine (5 mg/kg, intraperitoneally) was administered twice daily for a period of 5 days, after which a single injection of naloxone (8 mg/kg, intraperitoneally) precipitated an opioid withdrawal syndrome in mice. Behavioral observations were made for a period of 30 min immediately after naloxone treatment. Withdrawal syndrome was quantitatively assessed in terms of withdrawal severity score and the frequency of jumping, rearing, forepaw licking, and circling. DDA markedly and dose-dependently (P<0.01) attenuated the morphine-naloxone-induced experimental opioid withdrawal syndrome. However, DDA administration did not alter locomotor activity, thus ruling out any sedative action of DDA per se. Further, DDA pretreatment did not alter the acute analgesic effect of morphine. The results suggest that nuclear factor-kappa-B is involved in the development of opioid dependence and the precipitation of its withdrawal syndrome, and thus, may serve as a viable pharmacological target to tackle the problem of opioid addiction.

Implication of mast cell degranulation in ischemic preconditioning-induced prevention of cerebral injury.

The present study has been designed to pharmacologically investigate the role of mast cell degranulation in ischemic preconditioning-induced reversal of global ischemia- and reperfusion-induced cerebral injury in mice. Bilateral carotid artery occlusion of 17 min followed by reperfusion for 24 h was employed in present study to produce ischemia- and reperfusion-induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using Morris water-maze test. Rota-rod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor coordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min (ischemic preconditioning) prevented markedly ischemia-reperfusion-induced cerebral injury measured in terms of infarct size, loss of memory and motor coordination. Sodium cromoglycate (10 mg/kg, i.p.), a mast cell stabilizer attenuated the neuroprotective effect of ischemic preconditioning. It is concluded that neuroprotective effect of ischemic preconditioning may be due to the degranulation of mast cells.