Anticonvulsant activity and effects of amide 1C on the central nervous system

Abstract

Amide 1C is a newly synthesized valproic acid analog, being synthesized in an attempt to obtain a new compound with higher potency and less toxicity than its parent compound. Anticonvulsant activity, lethality and neurotoxicity of Amide 1C were investigated in mice using valproic acid (VPA) as a reference drug. Additionally, microdialysis technique was used to study the effect of Amide 1C on cortical amino acid neurotransmitters of anesthetized rats. The evaluation of anticonvulsant activity was performed in mice using two standard screening models, the maximal electroshock seizures (MES) and pentylenetetrazol (PTZ) tests. In MES test, Amide 1C was found to be orally and intraperitoneally effective showing the maximal protection around 15 min after pretreatment while the corresponding value for VPA was 30 min. Like VPA, an intraperitoneal administration of Amide 1C exhibited protection in MES, PTZ and bicuculline tests but was ineffective in the strychnine test. The median effective doses (ED₅₀) of Amide 1C were 81, 33 and 214 mg/kg BW. In MES, PTZ and bicuculline tests, respectively, while corresponding values for VPA were 218, 93 and 395 mg/kg BW., respectively. These results indicated that Amide 1C exhibited a greater potency and a more rapid action than those of VPA. In toxicity testing, although the median lethal dose (LD₅₀) of Amide 1C was lower than that of VPA, the relative safety margin (LD₅₀/ED₅₀) of Amide 1C were substantially higher than those of VPA, about 2 times higher, in both MES and PTZ tests. Minimal neurological deficit assessed by rotorod test and expressed as the median neurotoxic dose (TD₅₀) were 318 and 386 mg/kg BW. For Amide 1C and VPA respectively. Therefore a wider therapeutic of Amide 1C than VPA can be anticipated as the protective indice (PI = TD₅₀/ED₅₀) were 3.86 and 9.48 mg/kg BW. for Amide 1C while they were 177 and 4.15 mg/kg BW. for VPA in MES and PTZ test respectively. Furthermore, no significant depressant effect on motor activity was demonstrated by the ED₅₀ of Amide 1C, though Amide 1C in the dose of 100 mg/kg BW. was able to prolong the barbiturate sleeping time. With regards to possible mechanisms of Amide 1C, microdialysis study in anesthetized rats indicated that neither inhibitory (GABA and glycine) nor excitatory (aspartate and glutamate) cortical amino acid neurotransmitters were altered by Amide 1C. The present study demonstrated a promising prospect for Amide 1C as a candidate for a potent and broad spectrum antiepileptic drug with higher margin of safety and lower side effects. However, extensive studies are needed to elucidate its precise mechanism of action as well as pharmacological and toxicological profiles.