Intrastriatal malonate administration induces convulsive behaviour in rats

Area of Science:

• Biochemistry
• Neuroscience
• Metabolic Disorders

Background:

• Malonic acidemia is an inherited metabolic disorder characterized by the accumulation of malonate.
• Malonate is a competitive inhibitor of succinate dehydrogenase (SDH; EC 1.3.99.1), a key enzyme in the mitochondrial electron transport chain.

Purpose of the Study:

• To investigate the behavioral effects of unilateral intrastriatal administration of malonate in adult male Wistar rats.
• To explore the relationship between succinate dehydrogenase inhibition and the observed behavioral outcomes.

Main Methods:

• Unilateral intrastriatal injections of varying doses of malonate (0.6, 1.8, or 6 micromol) were administered to adult male Wistar rats.
• Behavioral responses, including exploratory activity and rotational behavior, were recorded.
• In vitro assays were performed to determine the inhibitory potency (Ki) of malonate and methylmalonate on succinate dehydrogenase in striatal mitochondrial fractions.

Main Results:

• Low doses of malonate (1.8 micromol) led to decreased exploratory activity and ipsiversive rotational behavior.
• High doses of malonate (6 micromol) induced contralateral rotational behavior and convulsive episodes.
• Malonate competitively inhibited SDH in vitro (Ki=0.034+/-0.008 mmol/L). Methylmalonate, a weaker SDH inhibitor (Ki=4.22+/-1.3 mmol/L), caused more convulsions and no ipsiversive rotation at equimolar doses.

Conclusions:

• The in vitro potency of succinate dehydrogenase inhibition by malonate and methylmalonate does not directly correlate with their in vivo convulsant potential.
• Malonate administration induces distinct behavioral changes in rats, including motor deficits and seizures, highlighting its neurotoxic effects.
• These findings suggest complex mechanisms underlying the neurological manifestations of malonic acidemia beyond simple SDH inhibition.