Abstract
Epilepsy is a common chronic neurological disorder disease, and there is an urgent need for the development of novel anticonvulsant drugs. In this study, the anticonvulsant activities and neurotoxicity of 12 cinnamic acid derivatives substituted by fluorine, chlorine, bromine, and trifluoromethyl groups were screened by the maximal electroshock seizure (MES) and rotarod tests (Tox). Three of the tested compounds (compounds 3, 6 and 12) showed better anticonvulsant effects and lower neurotoxicity. They showed respective median effective dose (ED50) of 47.36, 75.72 and 70.65 mg/kg, and median toxic dose (TD50) of them was greater than 500 mg/kg, providing better protective indices. Meanwhile, they showed a pentylenetetrazol (PTZ) ED50 value of 245.2, >300 and 285.2 mg/kg in mice, respectively. Especially, the most active compound 3 displayed a prominent anticonvulsant profile and had lower toxicity. Therefore, the antiepileptic mechanism of 3 on glycosylation changes in chronic epilepsy in mice was further investigated by using glycomics techniques. Lectin microarrays results showed that epilepsy was closely related to abnormal glycosylation, and 3 could reverse the abnormal glycosylation in scPTZ-induced epilepsy in mice. This work can provide new ideas for future discovery of potential biomarkers for evaluation of antiepileptic drugs based on the precise alterations of glycopatterns in epilepsy.
Highlights
Mankind has been suffering from epilepsy for thousands of years, and today epilepsy is still one of the most difficult diseases to overcome
Cinnamic derivatives are aromatic acids which widely distributed in plants such as cinnamon, cereals, legumes, fruits and vegetables [10,11]
Over the past 30 years a large number of studies have found that cinnamic acid and its derivatives have a variety of biological activities including anticancer, anti-inflammatory, anti-hepatotoxicity, antimicrobial, antivirus, etc. [12,13,14,15,16,17]
Summary
Mankind has been suffering from epilepsy for thousands of years, and today epilepsy is still one of the most difficult diseases to overcome. 70 million people in the world suffer from epilepsy, of which thirty percent of patients with epilepsy cannot be cured [1]. Infectious diseases, congenital malformations and genetic abnormalities can lead to epilepsy [2]. The antiepileptic drugs is the most commonly used method for the treatment of epilepsy in clinic, and the commonly used anti-epileptic drugs included phenytoin, carbamazepine, phenobarbital, sodium valproate, etc. Some of anti-epileptic drugs greatly alleviate the suffering of many patients with epilepsy, but there are still problems that cannot be ignored.
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