Protective effect of N,N'-dialkylated analogs of 4,4'-diaminodiphenylsulfone in a model of intrastriatal quinolinic acid induced-excitotoxicity

Abstract

The bacteriostatic agent 4,4'-diaminodiphenylsulfone or dapsone (DDS) and some of its N,N'-dialkylated analogs have shown anticonvulsant and neuroprotective properties in different experimental models. In this study, we tested the ability of five DDS analogs (N,N'-dimethyldapsone, N,N'-diethyldapsone, N,N'-dipropyldapsone, N,N'-dibutyldapsone and N,N'-ditosyldapsone) to attenuate quinolinic acid-induced toxicity in vivo. Male Wistar rats were treated with either DDS or analogs (12.5mg/kg and equimolar doses respectively) 30 min before quinolinic acid intrastriatal stereotaxic injection (240 nmol/μl). Six days after injury, circling behavior was evaluated by counting ipsilateral turns for 1h after apomorphine challenge (1mg/kg, sc). Twenty-four hours later, rats were sacrificed and their corpora striata were dissected out to determine GABA content. Hemotoxicity of the analogs was assessed as the ability to produce methemoglobin (MHb) in vivo. Blood was sampled from tail vein within 18 h after drugs administration. Methemoglobin levels were determined by visible spectrophotometry and mean profiles of MHb-percentage versus time were obtained. All of the analogs tested decreased the number of ipsilateral turns/hour, reducing up to 67% the turns counting (p<0.05) when compared to those induced in animals receiving quinolinic acid with no treatment. N,N'-dimethylated, N,N'-diethylated and N,N'-dibutylated analogs significantly prevented the decrease of intrastriatal GABA content (p<0.05). Methemoglobin produced by the administration of analogs was significantly lower than the levels of the group receiving dapsone (p<0.05). The neuroprotective effect of analogs and their diminished hemotoxicity make them potential candidates for therapeutic applications.