الفهرس 
GENERAL INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Epilepsy continues to be a neurological disorder awaiting safer drugs with improved antiepileptic effectiveness. N-methyl-D-aspartate (NMDA) receptor antagonists appear to enhance the anticonvulsant activity of antiepileptic drugs in several models of epilepsy. Besides, organoids that are formed from several cell types may serve as a developed model for toxicity screening. Therefore, the current study evaluates the augmenting effect of magnesium nano, a non-competitive NMDA receptor antagonist, on valproate (VPA) against pentylenetetrazol (PTZ)-induced convulsions in vivo. We also used the 3D brain and liver organoids to evaluate the toxic effect of these compounds on the human cells. Rats were pretreated with valp, Mg nano, Mg micro, valp + Mg nano or Valp + Mg micro for four weeks, then they were treated with PTZ for 24 hrs while, organoids were treated with valp or valp + Mg nano for 24 hrs then incubated with PTZ for an extra 24 hrs. as the in vivo model. At the end of the experiment blood and tissue samples were collected to investigate the effect of these compounds on some neurotransmitters and monoamines in addition to brain oxidative stress, liver and kidney biomarkers. We also evaluated the toxic effect of these compounds in vitro by the assessment of the viability, cleaved caspase, apoptosis, and ROS production. The in vivo data elucidate that PTZ + Valp + Mg nano showed a significant decrease in excitatory neurotransmitters glutamate comparing with PTZ only treated group. And the in vitro results showed that the treatment of the brain organoids with PTZ 30 µM/ml for 24 hrs., Valproate 100 mg/ml and Mg compound nanoparticles 100 µg/ml caused a significant decrease in the ATP production level and increasing in the number of the dead cells in comparison with the normal control organoid, at the same time cleaved caspase and apoptosis showed these drugs increased the number of cells that dais through apoptosis. Because the ROS production experiment showed that these drugs increased the ROS production and the Nanoparticles had the highest, and at the same time similar have been noticed in the in vivo data as a significant increase in MDA, NO, and GSH in brain tissue by the treatment of PTZ +6 ValP +Mg nano comparing with the control group. We explained this toxic effect through as, reactive metabolites that include reactive oxygen species (ROS), reactive nitrogen species, and reactive sulfur species these reactive species because of deleterious complications such as lipid peroxidation which can cause damage to the cellular membrane and trigger second messengers that lead to apoptosis. Also, Toxicity in the liver organoids was demonstrated by reduced cell viability, decreased ATP, and increased reactive oxygen species (ROS). And the rat convulsion model, results revealed elevated serum ALT and AST levels. Both the in vitro and in vivo data demonstrated the potentially toxic effects of valp+Mg nano on the liver tissues. from the presented data we could conclude that Mg nano has an augmenting anticonvulsant effect however, it might induce oxidative effect so we recommend the usage of a good antioxidant.