Malonic acidaemia is an inborn error of metabolism that accumulates malonate, a competitive succinate dehydrogenase (SDH; EC 1.3.99.1) inhibitor. The present study investigated the behavioural effects of unilateral intrastriatal administration of malonate (0.6, 1.8 or 6 micromol) in adult male Wistar rats (n=10-13). Low doses of malonate (1.8 micromol) decreased exploratory activity and caused ipsiversive rotational behaviour. High doses of malonate (6 micromol) induced contralateral rotational behaviour and convulsive episodes. Malonate competitively inhibited SDH in mitochondrion-enriched fractions from striatum ( Ki=0.034+/-0.008 mmol/L). Interestingly, methylmalonate, which is a weaker SDH inhibitor than malonate (Ki=4.22+/-1.3 mmol/L), induced more convulsions than malonate at equimolar doses and did not cause ipsiversive rotational behaviour. It is suggested that the potency of SDH inhibition in vitro does not correlate positively with the convulsant potential of these inhibitors in vivo.

Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1 immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.

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