Evaluation of anticonvulsant activity of valproyl hydroxamic acid

Abstract

Valpropyl hydroxamic (VHA) is a novel derivative of valpromide, the primary amide of valproic acid, being synthesized in an attempt to obtain a new compound with higher potency and less toxicity than valproic acid (VPA). Anticonvulsant activity, lethality and neurotoxicity of VHA in comparison to VPA were investigated in mice. In addition, in vitro degradation using rat brain and liver homogenate was performed to search for possible mode of action of VHA The evaluation of anticonvulsant activity was performed in mice using the maximal electroshock seizure (MES) and chemically induced seizure tests. In MES test, VHA was found to be intraperitoneally effective showing the maximal protection around 15 min after pretreatment while the corresponding value for VPA was 30 min. Intraperitoneal administration of VHA demonstrated a higher protection than VPA in MES and bicuculline but was effective as VPA in PTZ tests. The median effective dose (ED50) of VHA were 114, 97 and 153 mg/kg BW. in MES, PTZ and bicuculline tests respectively, while corresponding values for VPA were 211, 99 and 382 mg/kg BW. VHA weakly blocked the effect of strychnine exhibiting ED50 of 441 mg/kg BW., while VPA was ineffective. Like VPA, VHA was also active orally demonstrating ED50 approximately 2 times higher than its ED50 by intraperitoneal route in MES test. The observation that VHA was not degraded to VPA by brain or liver homogenate as well as that VHA was able to protect the animal against MES test giving the ED50 of 102 μM when being administered intracerebroventricularly indicate that VHA is an active anticonvulsant molecule. However, the anticonvulsant activity of VHA seemed to be short-lived as reflected by a rapid increase of ED50 values of 114 mg/kg BW. at pretreated time of 15 min to 207, 466 and 832 mg/kg BW. at 1, 3 and 6 hour(s). respectively. Inactivation by cytochrome P450 seemed to be part of rapid decline in anticonvulsant activity as the ED of VHA at pretreated time of 15 min was reduced to 83 mg/kg BW when VHA was given after an inhibitor of cytochrome P450, SKF-525A. However this finding did not exclude any other paths of inactivation of VHA which remain to be determined. With regards to toxicity in terms of lethality, the LD50 of VHA (840 mg / kg B.W.) is slightly higher that of VPA. The median neurotoxicity dose (TD50) as measured by rotorod test were 189 and 260 mg / kg BW. for VHA and VPA respectively. Therefore, both of them exhibited the protective index (PI =TD50, ED50) of about 1-2 in both MES and PTZ tests. Furthermore. ED50 of VHA had no significant depressant effect on locomotor activity though prolongation of barbiturate sleeping time was exhibited by VHA in the dose of 120 mg/kg B.W. Additionally, VHA seemed to have rather low potential to induce tolerance. The present studies, VHA demonstrated better anticonvulsant activity with approximately the same profile of toxicity as VPA. Further modification of the structure of VHA is needed in order to improve its unfavorable short-lived anticonvulsant activity.