Vitis labrusca leaf extract prevents pentylenetetrazol-induced oxidative damage but not seizures in rats.

Epilepsy is a disorder of the central nervous system characterized by recurrent seizures. It is a very common disease in which approximately 30% of patients do not respond favorably to treatment with anticonvulsants. Oxidative stress is associated with neuronal damage arising from epileptic seizures. The present study investigated the possible anticonvulsant and antioxidant effects of a leaf extract of Vitis labrusca in an animal model of seizures induced by pentylenetetrazole (PTZ). The animals received injections of V. labrusca extract (10, 30 and 100 mg/kg) or vehicle and, 30 minutes later, they received an injection of PTZ, and were then observed for 30 minutes. The latency time and tonic—clonic seizure time were registered. Oxidative damage in lipids and proteins was quantified in the cerebellum, cerebral cortex and hippocampus. It was observed that the leaf extract were capable of reducing lipid peroxidation and protein oxidation caused by PTZ at all doses tested.

Pharmacological evidence that alpha-ketoisovaleric acid induces convulsions through GABAergic and glutamatergic mechanisms in rats.

Neurological dysfunction is common in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the pathophysiology of this disorder are poorly known. In the present study we investigated the effect of intrastriatal administration of the alpha-keto acids accumulating in MSUD on the behavior of adult rats. After cannula placing, rats received unilateral intrastriatal injections of alpha-ketoisocaproic acid (KIC, 8 micromol), alpha-ketoisovaleric acid (KIV, 8 micromol), alpha-keto-beta-methylvaleric acid (KMV, 6 micromol) or NaCl. KIV elicited clonic convulsions in a dose-response manner, whereas KIC and KMV did not induce seizure-like behavior. Convulsions provoked by KIV were prevented by intrastriatal preadministration of muscimol (46 pmol) and MK-801 (3 nmol), but not by the preadministration of DNQX (8 nmol). These results indicate that among the keto acids that accumulate in MSUD, KIV is the only metabolite capable of causing convulsions in the present animal model and indicates that KIV is an important excitatory metabolite. Moreover, the participation of GABAergic and glutamatergic NMDA mechanisms in the KIV-induced convulsant behavior is suggested, since KIV-induced convulsions are attenuated by muscimol and MK-801. The authors suggest that KIV may play an important role in the convulsions observed in MSUD, and highlight its relevance to the understanding of the pathophysiology of the neurological dysfunction of MSUD patients.

Inhibition of synaptosomal [3H]glutamate uptake and [3H]glutamate binding to plasma membranes from brain of young rats by glutaric acid in vitro.

Synaptosomes and plasma membrane preparations from brain of 30-day-old rats were incubated with glutaric acid at final concentrations ranging from 10 nM to 1 mM for the determination of glutamate uptake and binding, respectively. [3H]Glutamate uptake into synaptosomes was inhibited by approximately 50% by 1 mM glutaric acid, corresponding to the concentration found in brain of glutaric acidemic children. In addition, in the presence of extracellular Na+ concentrations, the same dose of glutaric acid decreased by about 30% [3H]glutamate binding to brain plasma membranes. The results indicate that the inhibition of both glutamate uptake into synaptosomes and glutamate binding to plasma synaptic membranes by the metabolite could result in elevated concentrations of the excitatory neurotransmitter in the synaptic cleft, potentially causing excitotoxicity to neural cells, a fact that may be related to the brain damage characteristic of glutaric acidemia type I.