Ibrahim Elfaki

Neuroprotective effect of nicotine against 3-nitropropionic acid (3-NP)-induced experimental Huntington's disease in rats

Nicotinic acetylcholine receptors (nAChRs) are regarded as potential therapeutic targets to control various neurodegenerative diseases. Owing to the relevance of cholinergic neurotransmission in the pathogenesis of Huntingtons disease (HD) this investigation was aimed to study the effect of nicotine, a nAChR agonist, on 3-nitropropionic acid (3-NP)-induced neurodegeneration in female Wistar rats. Systemic administration of 3-NP in rats serves as an important model of HD. The animals received subcutaneous injections of nicotine (0, 0.25, 0.50 and 1.00 mg/kg) daily for 7 days. 3-NP (25 mg/kg, i.p.) was administered daily 30 min after nicotine for the same duration. One additional group of rats served as control (vehicle only). On day 8, the animals were observed for neurobehavioral performance (motor activity, inclined plane test, grip strength test, paw test and beam balance). Immediately after behavioral studies, the animals were transcardially perfused with neutral buffered formalin (10%) and brains were fixed for histological studies. Lesions in the striatal dopaminergic neurons were assessed by immunohistochemical method using tyrosine hydroxylase (TH) immunostaining. Treatment of rats with nicotine significantly and dose-dependently attenuated 3-NP-induced behavioral deficits. Administration of 3-NP alone caused significant depletion of striatal dopamine (DA) and glutathione (GSH), which was significantly and dose-dependently attenuated by nicotine. Preservation of striatal dopaminergic neurons by nicotine was also confirmed by immunohistochemical studies. These results clearly showed neuroprotective effect of nicotine in experimental model of HD. The clinical relevance of these findings in HD patients remains unclear and warrants further studies.

Gastric antisecretory and antiulcer effects of simvastatin in rats.

Background and Aim:  Recently, statins have appeared to have additional benefits beyond their lipid lowering effects, which has led to the interest in the use of this class of drugs outside the realm of cardiovascular disease. Simvastatin (SIM) is a commonly prescribed statin with anti‐inflammatory and antioxidant properties. Excessive generation of oxygen‐derived free radicals (ODFR) and proinflammatory mediators has been implicated in the pathogenesis of gastric ulcers. This investigation aimed to study the effect of SIM on experimentally induced gastric acid secretion and ulcer formation.

Effects of subchronic versus acute in utero exposure to dexmedetomidine on foetal developments in rats.

Dexmedetomidine is a highly selective and specific alpha-2 adrenergic agonist with sedative, analgesic and sympathetic activities. This study was undertaken to investigate the effects of in utero exposure of dexmedetomidine on foetal development and postnatal behaviour in the offspring. Pregnant Sprague-Dawley rats were chronically treated with dexmedetomidine (0, 5, 10 and 20 microg/kg, subcutaneously) daily from gestation day 7 to day 19. Another group of animals received only a single acute dose of dexmedetomidine (20 microg/kg) on gestational day 19 to mimic a model for systemic analgesia during labour. Administration of dexmedetomidine did not affect the frequency of implantations. Chronic administration of 10 and 20 microg/kg of dexmedetomidine significantly reduced the body weight and crown-rump length of pups, whereas a single acute dose (20 microg/kg) did not affect these parameters. None of the pups exhibited any external malformations or skeletal abnormalities irrespective of treatment assigned. All the pups showed a normal postnatal weight gain during the developmental phase. No significant differences were observed among any of the groups with respect to behavioural performances of offspring in beam balance, grip strength and inclined plane tests as well as motor activity. In conclusion, acute exposure to dexmedetomidine at the anticipated delivery time does not exert any adverse effects on perinatal morphology of pups, their birth weight, crown-rump length, physical growth and postnatal behavioural performances. Since this study was conducted in rats, its clinical relevance in human beings remains to be unclear and warrants further studies.

Trolox ameliorates 3-nitropropionic acid-induced neurotoxicity in rats.

3-nitropropionic acid (3-NPA) is a naturally occurring neurotoxin produced by legumes of the genus Astragalus and Arthrium fungi. Acute exposure to 3-NPA results in striatal astrocytic death and variety of behavior dysfunction in rats. Oxidative stress has been reported to play an important role in 3-NPA-induced neurotoxicity. Trolox is a potent free radical chain breaking antioxidant which has been shown to restore structure and function of the nervous system following oxidative stress. This rapid and efficient antioxidant property of trolox was attributed to its enhanced water solubility as compared with alpha-tocopherol. This investigation was aimed to study the effect of trolox against 3-NPA-induced neurotoxicity in female Wistar rats. The animals received trolox (0, 40 mg, 80 mg and 160 mg/kg, orally) daily for 7 days. 3-NPA (25mg/kg, i.p.) was administered daily 30 min after trolox for the same duration. One additional group of rats served as control (vehicle only). On day 8, the animals were observed for neurobehavioral performance. Immediately after behavioral studies, the animals brains were dissected out for histological studies. Lesions in the striatal dopaminergic neurons were assessed by immunohistochemical method using tyrosine hydroxylase immunostaining. Administration of 3-NPA alone caused significant depletion of striatal dopamine and glutathione, whereas, the levels of thiobarbituric acid reactive substance (TBARS) and nitric oxide (NO) were significantly increased suggesting an elevated level of oxidative stress. Trolox significantly and dose-dependently protected animals against 3-NPA-induced neurobehavioral, neurochemical and structural abnormalities. These results clearly suggest that protective effect of trolox against 3-NPA-induced neurotoxicity is mediated through its free radical scavenging activity.

Protective effect of a cysteine prodrug and antioxidant, L-2-oxothiazolidine-4-carboxylate, against ethanol-induced gastric lesions in rats.

Earlier studies have suggested an important role of glutathione (GSH) in cytoprotection against free radicals induced oxidative damage. This study reports gastroprotective effects of a cysteine precursor, L-2-oxothiazolidine-4-carboxylate (OTC), in experimental models of gastric secretion and ulceration. Acid secretion studies (volume and acidity) were undertaken in pylorus-ligated rats whereas the gastric lesions were induced by ethanol. Different groups of animals were treated with OTC (0, 100, 200 and 400 mg/kg). The levels of gastric wall mucus, nonprotein sulfhydryls (NP-SH) and myeloperoxidase (MPO) were measured in the glandular stomach of rats following ethanol-induced gastric lesions. Both medium and high doses of OTC significantly reduced the volume and acidity of gastric secretion in pylorus-ligated rats. Pretreatment with OTC significantly and dose-dependently attenuated the formation of ethanol-induced gastric lesion. OTC significantly protected the gastric mucosa against ethanol-induced depletion of gastric wall mucus, NP-SH and MPO. The gastroprotective effects of OTC may be attributed to its ability to inhibit neutrophils activity and replenish GSH demand.

Vanillin abrogates ethanol induced gastric injury in rats via modulation of gastric secretion, oxidative stress and inflammation

Vanillin is commonly used as an additive in food, medicine and cosmetics, but its effect has not yet been studied in gastric injury. Therefore the effect of vanillin was studied in experimental gastric ulcer. Gastric secretion and acidity were studied in pylorus ligated rats. Ulcer index, levels of gastric mucus, malondialdehyde (MDA), myeloperoxidase activity (MPO), expression of nuclear factor kappa B (NF-κB) p65, and histopathological changes were determined in ethanol induced gastric ulcer. Pre treatment with vanillin significantly reduced gastric secretion (P < 0.001) and acidity (P < 0.0001) and gastric ulcer index scores (P < 0.001). and augmented the gastric mucosal defense. Vanillin significantly restored the depleted gastric wall mucus levels (P < 0.0001) induced by ethanol and also significantly attenuated ethanol induced inflammation and oxidative stress by the suppression of gastric MPO activity (P < 0.001), reducing the expression of NF-κB p65 and the increased MDA levels (P < 0.001). Vanillin was also effective in alleviating the damage to the histological architecture and the activation of mast cells induced by ethanol. Together the results of this study highlight the gastroprotective activity of vanillin in gastric ulcers of rats through multiple actions that include inhibition of gastric secretion and acidity, reduction of inflammation and oxidative stress, suppression of expression of NF-κB, and restoration of the histological architecture.

Gastric antisecretory and antiulcer activity of bovine hemoglobin

AIM To investigate gastric antisecretory and gastroprotective activity of bovine hemoglobin (B-Hb) in rats. METHODS Adult Albino-Wistar rats were divided into groups of 6 animals each. B-Hb in doses of 100, 300 and 900 mg/kg body weight was tested for gastric acid secretion and antiulcer activity. Gastric secretions were measured 6 h after pylorus ligation in rats pretreated with B-Hb. The acidity was measured by titrating gastric contents against 0.01 mol/L NaOH to pH 7. Indomethacin ulcers were produced by oral administration of 30 mg/kg bw in the rats pretreated with B-Hb one hour before indomethacin. Six hours after indomethacin stomach removed and ulcer index was recorded. Ethanol ulcer were produced by 1 mL of ethanol in the rats pretreated with B-Hb 30 min before the ethanol. One hour after ethanol stomach were cut open to score ulcers. Histological examination and analysis of gastric wall mucus, non-protein sulfhydryl groups (NP-SH), and myeloperoxidase (MPO) were carried in gastric tissue following ethanol administration. RESULTS In control rats pylorus ligation for 6 h resulted in the accumulation of 8.1 ± 0.61 mL of gastric secretion. The treatment of the rats with 100, 300 and 900 mg/kg of B-Hb produced a significant decrease in the volume of gastric secretion 5.6 ± 0.63, 5.5 ± 0.75 and 4.7 ± 0.58 mL respectively as compared to the control group [analysis of variance (ANOVA) F = 4.77, P < 0.05]. The lesion area in the control group was found to be 22.4 ± 3.2 mm(2) six hours after the administration of indomethacin. Treatment of rats with B-Hb at doses of 100 mg/kg (24.3 ± 3.29 mm(2)), 300 mg/kg (16.2 ± 1.45 mm(2)) and 900 mg/kg (12.6 ± 1.85 mm(2)) produced a dose dependent decreased the lesion scores (ANOVA F = 4.50, P < 0.05). The ulcer index following one hour after 1 mL ethanol was 7.1 ± 0.31. Pretreatment of rats with B-Hb at the doses of 100 mg/kg (2.5 ± 0.42), 300 mg/kg (2.1 ± 0.4) and 900 mg/kg (0.7 ± 0.21) significantly inhibited the formation of gastric lesions (ANOVA F = 63.26, P < 0.0001). Histological examination of gastric mucosa following ethanol showed significant lesions in the form of gastric pits with detachment of the surface epithelium; vacuolation of epithelial cells and elongation of microvessels. The changes were dose-dependently attenuated by B-Hb. The treatment of rats with ethanol significantly decreased the Alcian blue binding capacity of gastric wall mucus (480 ± 25.6 μg Alcian blue/g of tissue) as compared to control rats (667 ± 25.8 μg). Pretreatment of rats with B-Hb at the doses of 100 mg/kg (516 ± 31.6 μg/g), 300 mg/kg (558 ± 28.8 μg/g) and 900 mg/kg (654 ± 33.8 μg/g) significantly attenuated ethanol induced depletion of gastric wall mucus (ANOVA F = 8.05, P < 0.005). A significant and dose dependent increase of gastric mucosal NP-SH (ANOVA F = 19.62, P < 0.001) and decrease in MPO activity (ANOVA F = 3.1, P < 0.05) was observed in B-Hb treated rats. CONCLUSION B-Hb possesses significant gastric antisecretory and gastroprotective activity against experimentally induced gastric lesion. The gastroprotective effects of B-Hb are accompanied by inhibition of neutrophils activity, reduction of oxidative stress and maintenance of mucosal integrity.

2,3-Dimercaptopropanol, a thiol chelator, alleviates gastroduodenal ulcers in rats.

Earlier studies have implicated reactive oxygen species and transitional metals in the pathogenesis of gastric lesions. In this study, we have evaluated the effect of 2,3‐dimercaptopropanol (DMP), a thiol compound and metal chelator, on chemically induced gastroduodenal ulcers in rats. Acid secretion studies were undertaken using pylorus‐ligated rats pretreated with DMP (3–100 mg/kg, i.p.). The effect of orally administered DMP on cysteamine‐induced duodenal ulcers and ethanol‐induced gastric ulcers was also tested. The level of nonprotein sulfhydryls (NP‐SH) and gastric wall mucus was measured in the glandular stomach of rats treated with ethanol. None of the dose of DMP affected the volume or acidity of gastric secretion. Low doses of DMP (3 and 10 mg/kg) significantly reduced cysteamine‐induced duodenal ulcers, whereas the high doses (30 and 100 mg/kg) were ineffective in this model. All the doses of DMP significantly and dose dependently attenuated ethanol‐induced gastric lesions. The adverse effects of ethanol on gastric wall mucus and NP‐SH were significantly and dose dependently reversed by DMP. In conclusion, the protective effects of DMP appear to be independent of gastric acid secretion and may be associated with counteracting the oxidative stress by replenishing glutathione and reducing the pool of transition metals.