Anticonvulsant effects of 1, alpha-hydroxy-vitamin D in comparison to the conventional antiepileptic drug phenytoin in the pilocarpine model of epilepsy in rats

Conventional antiepileptic drugs fail to adequately control seizures and exhibit unfavorable side effects. Vitamin D3 [Cholecalciferol], has its essential role in calcium and phosphorus metabolism, and is involved in regulating the functions of the central nervous system. Moreover, it has long been known that chronic treatment with antiepileptic drugs impairs mineral homeostasis in epileptic patients, leading to marked hypocalcaeinia and reduced plasma levels of vitamin D which in turn may increase seizure]. to test the possible role of the neurosteroid hormone 1, alpha-hydroxy vitamin D3 [1, alpha vit. D3], an active form of Vitamin D3 in epilepsy and its interactions with the conventional antiepileptic drug phenytoin in the pilocarpine induced seizures in rats two experiments were performed. Experiment 1 was conducted to measure seizures severity, oxidative markers and calcium level in the pilocarpine model of epilepsy: live groups of rats were used. 1-Control group received saline intraperitoneal [i.p.] only, 2-control epileptic group received pilocarpine 320 mg/kg i.p., 3-vitamine D3 treated group received 1, alpha-H vit. D3 40 ng/kg i.p. one hour before pilocarpine, 4-Phenytoin treated group received 11.2mg/kg phenytoin i.p., 2 hours before pilocarpine and 5-both 1, alpha-H vit. D3 and phenytoin treated group in the same doses mentioned before. Experiment 2 was conducted to test the effect of chronic treatment for one week with 1, alpha-H vit. D3, phenytoin or both on oxidative markers, calcium level and behavioral tests in rats. Overall, compared to the saline-treated control animals, the 1, alpha-H vit. D3 -treated rats demonstrated reduced severity of pilocarpine induced seizures, with decreased levels of oxidative markers. Co-administration of 1, alpha-H vit. D3 with phenytoin resulted in a significant reduction of seizure severity and duration. Furthermore, 1.alpha-H vit. D3 potentiated the anticonvulsant activity of phenytoin and reduced its undesirable effects as regard increase in oxidative markers and memory impairment that were induced by phenytoin. These findings show that Vitamin 0 plays a direct anticonvulsant role in the brain and suggest that the Vitamin D may represent a new anticonvulsant drug increasing the efficacy of conventional antiepileptic drugs

ATP-sensitive potassium channel blockers, glimepiride and glibenclamide reduces ischemia reperfusion-induced renal injury in rats by inhibition of neutrophil aggregation: comparative study of glimepiride versus glibenclamide and diazoxide

Renal ischemia is a complex neutrophils-mediated syndrome in which ATP-sensitive potassium channels are involved. Fall in intracellular ATP concentration induces opening of these channels resulting in massive influx of neutrophils .This exerts a crucial role in the patho-physiology of post-ischemic renal failure. Our study has used the ischemia reperfusion [I/R] model to asses the role of ATP-dependant potassium channel modulation, comparing the protective effects of glimepiride and glibenclamide on renal I/R inflammatory injury and neutrophil aggregation. As this protective effect in renal I/R stands in sharp contrast to the harmful effects on the cardiac tissues, our study evaluates the harmful effects of both sulfonylurea drugs on normal hearts and on ischemic reperfused hearts subjected to ischemic preconditioning protection afforded by diazoxide. One hundred and fourteen [114] adult albino rats were used; 72 of them were used for the in renal I/R study and 42 rats for the cardiac I/R experiment. In renal I/R study, rats were unilaterally nephrectomized, then all rats except the Sham operated control group, were subjected to renal I/R by ischemia 45 min and reperfusion 4 and 24 h, then divided into five groups: [1] renal ischemia-reperfusion, [2] renal I/R + solvent control, [3] renal I/R + diazoxide, [4] renal I/R + glibenclamide, [5] renal I/R + glimepiride. At the end of each reperfusion period, mean arterial pressure, urine volume, serum creatinine and urea, were measured. Then kidneys and lungs were taken for histological examination and determination of TNF-alpha levels, superoxide anion production and myloperoxidase activity. Cardiac I/R study, cardiac ischemia reperfusion model by left coronary artery ligation was used for evaluating the side effects of both sulfonylureas on both normal and ischemic preconditioning rat's hearts. Renal ischemia reperfusion induced marked renal dysfunction associated with significant increase in arterial pressure, TNF-alpha levels, superoxide anion production, and myloperoxidase activity. Treatment with glibenclamide or glemipiride, illustrated significant improvement in the reperfusion-induced injury in both kidney and lung, but glemipiride has no effect on superoxide anion production. However glibenclamide induced a significant improvement in these measurements as compared to glimepiride group. Before coronary artery ligation, neither diazoxide nor glimepiride pretreatment influenced significantly the electrocardiographic parameters [heart rates, T-waves voltages and ST segment elevation] in comparison with control group. On the other hand, glibenclamide supplementation induced a significant elevation in all these parameters. After left coronary artery ligation, reperfusion of the ischemic hearts caused a significant elevation in the measured electrocardiographic parameters. These elevations were significantly ameliorated by pretreatment with diazoxide. Administration of glibenclamide significantly abolished the protective effects of diazoxide, while pretreatment with glimepiride didn't abolish it. In conclusion, glimepiride offered some promise for therapy of renal I/R with minimizing the undesirable cardiac side effects

possible protective role of lisinopril as a pro-apoptotic agent in cyclosporin A induced nephrotoxicity in rats

The study was carried out on 40 male albino rats, which were divided into five groups: Group 1, normal control group, group 2, saline treated group, group 3, cyclosporin A treated group [rats received saline 0.2 ml for one week orally daily, then received cyclosporin A [20 mg/kg/day] intraperitoneally daily for another week], group 4, lisinopril plus cyclosporin A treated group [treatment with lisinopril [10 mg/kg/day] orally for one week, then co-administration, of both lisinopril and cyclosporin A for another one week using the aforementioned doses] and group 5, lisinopril-treated group [rats received lisinopril [10 mg/kg/day] orally for two weeks]. At the end of the study, blood samples were withdrawn from rats of all groups for determination of serum creatinine. Afterwards, rats were sacrificed and the kidneys were obtained. Sections from the kidney were stained by hematoxylin and oesin and immunohistochemically using anti-Bcl-2 antibodies for assessment of both necrosis and apoptosis, respectively. Cyclosporin A administration for one week significantly raised the serum creatinine level. Also, it produced histopathological changes confined to the proximal convoluted tubules in the form of moderate to severe focal necrosis, and produced strong Bcl-2 cytoplasm immunostaining. Treatment with lisinopril for one week, then co-administration, of both lisinopril and cyclosporin A, decreased significantly the cyclosporin A-induced elevation of serum creatinine, decreased the focal necrosis in the proximal convoluted tubules [Chi square=13.3], and produced weak Bcl-2 cytoplasm immunostaining [Chi square=7.27]. This denotes that the ACE inhibitor ameliorated the toxic insult induced by CsA by favoring induction of apoptosis as denoted by diminishing the Rcl-2 cytoplasmnostaining. From the above data, it could be concluded that lisinopril has a proapoptotic effect in the kidney after cyclosporin A-induced nephrotoxicity