Abstract
There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects.
Highlights
Epilepsy is one of the most common neurological diseases which affect around 1% of the population, including people of all ages[1]
We suppose that alkyl derivatives of 1,2,4-triazole-3-thione, that combine antioxidant and VGSC blocking activities, may be of great interest due to their potent anticonvulsant effect and their possible use in other disorders resulted from the extensive reactive oxygen species (ROS) production and excessive sodium channel activity
We showed for the first time that the investigated 1,2,4-triazole-based compounds possess anticonvulsant and antioxidant properties combined in a single molecule
Summary
Epilepsy is one of the most common neurological diseases which affect around 1% of the population, including people of all ages[1] It is characterised by recurrent episodes of seizures which result from the abnormal (i.e. excessive) electrical discharges within the nerve cells. ROS-induced damage to biomolecules is often observed in surgically resected samples of human brain, suggesting contribution of the oxidative stress to neuronal hyperexcitability and neurodegeneration[3,5]. Molecular markers of oxidative damage are increased in blood samples obtained from patients suffering from temporal lobe epilepsy[3] As it has been shown in an animal model, damage of mitochondrial DNA and excessive production of H2O2 in the inner membrane of mitochondria occur in hippocampal cells even three months after a single event of status epilepticus (SE). The death of neurons in hippocampus is often a characteristic feature of acquired epilepsy[6]
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