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INTRODUCTION: The use of valproic acid (VPA) in the treatment of some psychiatric and neurological disorders such as bipolar disorder, migraines, and epilepsy is associated with hyperammonemia. However, the mechanism of this negative effect of VPA is unclear. In this study, we investigate gene glutamate-ammonia ligase (GLUL) polymorphisms for the glutamine synthetase (GS) enzyme, a key enzyme that catalyzes the removal of ammonia by incorporating it with glutamate to form glutamine, and we investigate whether it has a relationship with the emergence of hyperammonemia during VPA-based therapy. PATIENTS AND METHODS: We enrolled 180 Egyptian epilepsy patients in this study. Patient history, general and neurological examination and blood samples from arm veins were taken. Real time TaqMan PCR polymorphism for three polymorphism SNPs (rs2296521, rs10911021 and rs12136955) of GLUL was done. We assessed the relationship between the patient features, including three GLUL polymorphisms, and the development of hyperammonemia during VPA-based therapy. RESULTS: We found that the ammonia levels showed a positive correlation with VPA treatment duration (p = 0.015) and a negative correlation with carbamazepine total dose per day (p = 0.027) and with WBCs count (p = 0.026). Also, female patients having rs2296521 SNPs with the A allele and patients having rs10911021 SNPs with the C allele were at high risk for elevated plasma ammonia levels. Moreover, patients having rs12136955 SNPs with the A allele or associated hypertension as a co-morbidity were at high risk for elevated plasma ammonia levels. CONCLUSION: Female patients who have rs2296521 with the A allele, rs10911021 with the C allele, or rs12136955 with the A allele, are independent risk factors for elevated plasma ammonia levels during VPA-based therapy. Moreover, carbamazepine combined therapy may protect against the development of hyperammonemia in VPA-treated patients.
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The current study investigated the effects of stevia extracts on a PTZ-induced epileptic rat model and its potential mechanism. Thirty male Sprague-Dawley rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/kg, i.p. every other day) for 2 weeks, and (3) PTZ+ Stevia group: received PTZ and stevia (200 mg/kg orally daily) for 4 weeks (2 weeks before the start of PTZ treatment and 2 weeks with PTZ administration). The first jerk latency and the seizure score were assessed in rats. Also, brain tissue samples were collected by the end of the experiment, and oxidative stress markers (catalase, MDA, and total antioxidant capacity (TAC)) were measured by biochemical analysis in hippocampal brain homogenates. Also, in the hippocampus, the expression of IL6 and Bcl-2 at the mRNA level and expression of Sirt-1, P53, caspase-3, GFAP, and NF-kB in CA3 hippocampal region by immunohistochemistry was investigated. PTZ substantially increased the seizure score and decreased the seizure latency. Also, PTZ significantly increased MDA, GFAP, IL-6, NF-kB, caspase-3, and p53 and significantly reduced Sirt-1, TAC, and Bcl-2 in hippocampal tissues compared to the control group (p < 0.01). However, Stevia Rebaudiana Bertoni (Stevia R.) significantly attenuated the PTZ-induced seizures, improved oxidative stress markers, downregulated GFAP, IL-6, NF-kB, caspase-3, and p53, and upregulated Sirt-1 and Bcl-2 in the CA3 hippocampal region (p < 0.01). In conclusion, Stevia R. exhibits neuroprotective and antiepileptic actions in PTZ-induced epilepsy due to its antioxidant, anti-apoptotic, and anti-inflammatory effects. Additionally, the Sirt-1 pathway might be involved in the antiepileptic and neuroprotective effects of stevia in PTZ-kindled epileptic rat model.