Neuroprotective effect of allopurinol and nimesulide against cerebral ischemic reperfusion injury in diabetic rats.

OBJECTIVES: The main objective of the study was to determine the neuroprotective effect of allopurinol and nimesulide against the cerebral ischemic reperfusion injury in diabetic and nondiabetic rats. MATERIALS AND METHODS: In this study, Wistar albino rats of either sex weighing 150-250 g were procured from authorized suppliers. Rats were anesthetized by giving thiopentone sodium (45 mg/kg) by i.p. Under anesthesia, midline incision was given. Common carotid arteries were identified and isolated carefully from vago-sympathetic nerve. Rats were made ischemic by occluding bicommon carotid arteries with thread for 30 min, followed by reperfusion for 4 h by removing the occlusion. The drugs allopurinol (15, 30 mg/kg) and nimesulide (20, 40 mg/kg) were administered 10 min before reperfusion. Then after 4 h reperfusion, animals were sacrificed and immediately brain was removed, homogenized, centrifuged and supernatant was collected, various enzyme estimations were done and same procedure was followed in streptozotocin (STZ: 45 mg/kg; i.p.) induced diabetic rats. RESULTS: Ischemia reperfusion (I/R) group showed significant increase in malondialdehyde (MDA), myeloperoxidase (MPO) and depletion in catalase (CAT) and superoxide dismutase (SOD) levels. Treatment with allopurinol and nimesulide significantly decreased the MDA and MPO levels whereas increased the SOD and CAT levels when compared I/R group in both non-diabetic and diabetic rats. CONCLUSIONS: These findings suggest the cerebral injury due to over production of free radicals was inhibited by allopurinol and nimesulide that exert a neuroprotective effect probably by radical scavenging and antioxidant activities.

Cardioprotective effect of tetrahydrocurcumin and rutin on lipid peroxides and antioxidants in experimentally induced myocardial infarction in rats.

The present study was undertaken to evaluate the cardioprotective potential of tetrahydrocurcumin (THC) and rutin in an in vivo rat ischemia-reperfusion (I/R) model of myocardial infarction (MI). Male wistar rats were divided into six groups receiving saline (control MI/R group), vehicle control MI/R group, THC (5 mg kg(-1) and 10 mg kg(-1)) and rutin (5 mg kg(-1) and 10 mg kg(-1)) i.p. injection respectively. At the day of the experiment, each group was subjected to acute ischemia for 30 min by occlusion of the left anterior descending coronary artery (LAD). Thereafter reperfusion was allowed for 4 h. MI/R resulted in significant cardiac necrosis, elevation in lipid peroxidation, elevation in cardiac marker enzymes AST, ALT and decline in antioxidant status catalase, reduced glutathione in the normal control MI/R group and vehicle control MI/R group. Myocardial infarction produced after MI/R was significantly reduced in tetrahydrocurcumin and rutin of the myocardial antioxidant status, infarct size reduction compared to control and vehicle control MI/R group. Furthermore, MI/R induced lipid peroxidation was significantly reduced by tetrahydrocurcumin and rutin. Cardioprotection in the treatment group was probably a result from suppression of oxidative stress. Histopathological examination further confirmed the protective effect of tetrahydrocurcumin and rutin on the MI/R heart.

Specific inhibition of poly(ADP-ribose) glycohydrolase by adenosine diphosphate (hydroxymethyl)pyrrolidinediol.

Adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD), an NH analog of ADP-ribose, was chemically synthesized and shown to be a potent and specific inhibitor of poly-(ADP-ribose) glycohydrolase. The synthetic starting material was the protected pyrrolidine, (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal. This starting pyrrolidine was phosphorylated, coupled to adenosine 5'-monophosphate, and deprotected, yielding the title inhibitor ADP-HPD. ADP-HDP was shown to inhibit the activity of poly(ADP-ribose) glycohydrolase by 50% (IC50) at 0.12 microM, a value 1000-times lower than the IC50 of the product, ADP-ribose. The NAD glycohydrolase from Bungarus fasciatus venom was less sensitive to inhibition by ADP-HPD, exhibiting an IC50 of 260 microM. ADP-HPD did not inhibit either poly(ADP-ribose) polymerase or NAD:arginine mono(ADP-ribosyl)-transferase A at inhibitor concentrations up to 1 mM. At low ADP-HPD concentration, inhibition was therefore shown to be highly specific for poly(ADP-ribose) glycohydrolase, the hydrolytic enzyme in the metabolism of ADP-ribose polymers.

Synthesis of (2R,3R,4S)-2-hydroxymethylpyrrolidine-3,4-diol from (2S)-3,4-dehydroproline derivatives.

(2R,3R,4S)-2-Hydroxymethylpyrrolidine-3,4-diol (1,4-dideoxy-1,4-imino-D-ribitol) was synthesized in five steps from N-protected (2S)-3,4-dehydroproline methyl esters. The stereoselective reaction of osmium tetraoxide with dehydroproline derivatives gave high yields of (2S,3R,4S)-3,4-dihydroxyprolines (2,3-trans-3,4-cis-3,4-dihydroxy-L-prolines) accompanied by small amounts (< 15%) of the diastereomeric (2S,3S,4R)-3,4-dihydroxyprolines (2,3-cis-3,4-cis-3,4-dihydroxy-L-prolines). The mixture of the diastereomeric glycols was converted into the isopropylidene acetals, and the isomers separated efficiently on a preparative scale. The resulting protected (2S,3R,4S)-3,4-dihydroxyproline methyl ester was reduced (LiBH4) to the 2-hydroxymethylpyrrolidine and deprotected, resulting in the production of (2R,3R,4S)-2-hydroxymethylpyrrolidine-3,4-diol in high yield and in high purity. The 1H and 13C NMR signals of the product have been unambiguously assigned using two-dimensional NMR techniques, and the identity of the title pyrrolidine confirmed by comparisons of its spectra with those reported for the authentic material.