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

comparative study between influence of rosiglitazone; a peroxisome proliferator-activated receptor gamma [PPARS] agonist, and corticosteroids on experimentally induced asthma in guinea pigs

Dugs used currently to treat asthma have limitations partly due to their undesired effects. PPARgamma agonists including rosiglitazone may offer additional therapeutic advantages to current treatment. The aim of the present study was to assess the anti-inflammatory potential of a PPARi agonist, rosiglitazone, locally delivered by means of nebulization in a guinea pig model of asthma, in comparison with that of the corticosteroid budesonide. Five groups of guinea pigs were used, five animals each. The first group was Sham -sensitized guinea pigs; the other four groups were sensitized by ovalbumin [OVA] by allergen solution containing 100 micrograms OVA and 100 mg Al [OH]3 per ml saline. 0.5 ml was injected intraperitoneally, while another 0.5 ml of the solution was divided over seven intracutaneous injection sites. The second group was OVA-sensitized and exposed to inhalation of saline. The third, fourth and fifth group were OVA albumin-sensetized. The third group was treated with vehicle inhalation, The fourth group was treated with rosiglitazone and the fifth group was treated with budesonide. Animals in the last 3 groups were exposed to allergen provocation procedure [Ag challenge] from weeks 4 to 5 after OVA sensitization. Assessment of asthma was done by studying the effect of rosiglitazone and budesonide on airway hyper responsiveness [AHR] to acetylcholine [Ach], inflammatory cellular changes in bronchoalveolar lavage and histopathological changes. The effect of rosiglitazone and budesonide pretreatment on histamine induced contraction of isolated OVA sensitized guinea pig tracheal spiral strips was also investigated. In addition, the direct effect of rosiglitazone and budesonide incubation on histamine induced contraction of isolated guinea pig tracheal spiral strips was examined. The results revealed that one week pre-treatment with rosiglitazone [20 minutes inhalation in a dose of 300 microg/ Kg/ day] and budesonide [20 minutes inhalation in a dose of 2mg/ Kg/ day] resulted in significant reduction in airway hyperreactivity to inhaled Ach, inflammatory cellular content in bronchoalveolar lavage fluid [BALF] and improvement in histopathological changes of asthmatic lung. There was no significant difference between both drugs as regard improvement of AHR, reduction in thickness of the interalveolar septum, decrease in total leucocytic count [TLC], count of lymphocytes and macrophages. However, budesonide caused significant reduction in eosinophils and macrophages count in comparison to rosiglitazone. In addition, rosiglitazone had a direct relaxant effect on airway smooth muscle. The results provided evidence for the therapeutic potential of inhaled PPARi agonist, rosiglitazone, in the treatment of airway asthmatic inflammation. In addition PPARgamma agonists had a direct relaxant effect on the isolated tracheal smooth muscle