GM1 ganglioside prevents seizures, Na+,K+-ATPase activity inhibition and oxidative stress induced by glutaric acid and pentylenetetrazole.
Monosialoganglioside (GM1) is a glycosphingolipid that protects against some neurological conditions, such as seizures and ischemia. Glutaric acidemia type I (GA-I) is an inherited disease characterized by striatal degeneration, seizures, and accumulation of glutaric acid (GA). In this study, we show that GA inhibits Na+,K+-ATPase activity and increases oxidative damage markers (total protein carbonylation and thiobarbituric acid-reactive substances-TBARS) production in striatal homogenates from rats in vitro and ex vivo. It is also shown that GM1 (50 mg/kg, i.p., twice) protects against GA-induced (4 micromol/striatum) seizures, protein carbonylation, TBARS increase, and inhibition of Na+,K+-ATPase activity ex vivo. Convulsive episodes induced by GA strongly correlated with Na+,K+-ATPase activity inhibition in the injected striatum but not with oxidative stress marker measures. Muscimol (46 pmol/striatum), but not MK-801 (3 nmol/striatum) and DNQX (8 nmol/striatum) prevented GA-induced convulsions, increase of TBARS and protein carbonylation and inhibition of Na+,K+-ATPase activity. The protection of GM1 and muscimol against GA-induced seizures strongly correlated with Na+,K+-ATPase activity maintenance ex vivo. In addition, GM1 (50-200 microM) protected against Na+,K+-ATPase inhibition induced by GA (6 mM) but not against oxidative damage in vitro. GM1 also decreased pentylenetetrazole (PTZ)-induced (1.8 micromol/striatum) seizures, Na+,K+-ATPase inhibition, and increase of TBARS and protein carbonyl in the striatum. These data suggest that Na+,K+-ATPase and GABA(A) receptor-mediated mechanisms may play important roles in GA-induced seizures and in their prevention by GM1.
Fighera
Michele Rechia
MR
Laboratório de Psicofarmacologia e Neurotoxicologia, Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil.
Royes
Luiz Fernando Freire
LF
Furian
Ana Flávia
AF
Oliveira
Mauro Schneider
MS
Fiorenza
Natália Gindri
NG
Frussa-Filho
Roberto
R
Petry
João Carlos
JC
Coelho
Rafael Correa
RC
Mello
Carlos Fernando
CF
D000818:Animals; D003292:Convulsants / Q000633:toxicity*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D005977:Glutarates / Q000008:administration & dosage / Q000633:toxicity; D007276:Injections, Intraventricular; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010433:Pentylenetetrazole / Q000633:toxicity; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D005977:Glutarates; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D017392:Thiobarbituric Acid Reactive Substances; D009118:Muscimol; D005677:G(M1) Ganglioside; D016291:Dizocilpine Maleate; D000254:Sodium-Potassium-Exchanging ATPase; C035736:glutaric acid; D010433:Pentylenetetrazole