Evaluation of anticonvulsant activity of N-(4-Amino-2-methylphenyl) phthalimide

Abstract

The present studies was aimed to investigate the anticonvulsant activity of a newly synthesized phthalimide derivative, N-(4-amino-2-methylphenyl) phthaIimide, (AMP), in comparison to Valproic acid, (VPA). Maximal electroshock test (MES), Pentylenetetrazole test (PTZ) and rotorod test were used to assess the anticonvulsant and neurotoxicity of AMP in mice, respectively. In addition, in vivo microdialysis experiment on freely moving rats was performed to search for possible action of AMP on cortical amino acid neurotransmitters. The median effective dose (ED50) of AMP and VPA were 17 and 214 mg/kg body weight respectively in MES test and they were 68 and 86 mg/kg body weight respectively in PTZ model, while it was ineffective in strychnine test. The median lethal dose (LD50) of AMP and VPA were found to be 101 and 605 mg/kg body weight respectively. The median neurotoxicity dose (TD50) as measure by rotorod test were 38 and 309 mg/kg body weight for AMP and VPA respectively. Despite favorable profile in MES test, AMP was able to protect the animal in PTZ test in the dose that not only higher than its TD50 but also very closed to its LD50. Therefore it is likely that AMP may become clinically acceptable only for seizure types that correlate well with ability to protect against MES but not as a broad-spectrum AED. Microdialysis studies on awake rats revealed different profile of responses on cortical amino acid neurotransmitters exhibited by AMP and VPA. AMP (70 mg/kg) significantly decreased the level of glutamate and increased the level of glycine and GABA, while had no significant effect on aspartate level. However, AMP (100 mg/kg) was not found to produce any effect on the level cortical amino acid neurotransmitter. In contrast VPA appeared to exert its effect by a decrement of cortical glutamate. In conclusion, the present study demonstrated anticonvulsant activity of AMP against both the MES and PTZ tests. However due to unfavorable neuroprotective indices (TD50/ED50= 0.56) and low relative safety margin (LD50/ ED50= 1.49) of AMP in PTZ model, AMP is anticipated to be clinically beneficial for certain types of seizure. Reduction of glutamate in concert with increment of GABA and glycine seem to underlie anticonvulsant observed in vivo. In order to achieve a therapeutic drug which broad spectrum anticonvulsant profile with favorable toxic. Further modification of its chemical structure is needed.