Ethosuximide

An anticonvulsant

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Background

Ethosuximide is an anticonvulsant.^1,2,3,4,5 It increases glucose, fructose-1,6-bisphosphate, and pyruvate levels in rat brain when administered at a dose of 200 mg/kg.¹ Ethosuximide (400 mg/kg) reduces the severity of audiogenic seizures in a rat model of barbiturate withdrawal-induced convulsions.² It also inhibits tonic hindlimb extension induced by pentylenetetrazole or brainstem stimulation (ED₅₀s = 35 and 70 mg/kg, respectively), as well as leptazol-induced clonic seizures (ED₅₀ = 230 mg/kg), in rats.^3,4 Ethosuximide reduces resting tremor by 60% in a macaque model of Parkinson's disease induced by MPTP when administered at a dose of 150 mg/animal for 5 days.⁵ Formulations containing ethosuximide have been used in the treatment of petit mal seizures.

1.Nahorski, S.R.Biochemical effects of the anticonvulsants trimethadione, ethosuximide and chlordiazepoxide in rat brainJ. Neurochem.19(8)1937-1946(1972) 2.Norton, P.R.The effects of drugs on barbiturate withdrawal convulsions in the ratJ. Pharm. Pharmacol.22(10)763-766(1970) 3.Consroe, P.F., and Wolkin, A.L.Anticonvulsant interaction of cannabidiol and ethosuximide in ratsJ. Pharm. Pharmacol.29(8)500-501(1977) 4.Chiu, P., and Burnham, W.M.The effect of anticonvulsant drugs on convulsions triggered by direct stimulation of the brainstemNeuropharmacology21(4)355-359(1982) 5.Gomez-Mancilla, B., Latulippe, J.F., Boucher, R., et al.Effect of ethosuximide on rest tremor in the MPTP monkey modelMov. Disord.7(2)137-141(1992)

Protocol

Kinase experiment:

Vehicle- and Ethosuximide-treated Tau V337M worms are lysed and separated into soluble and insoluble fractions. Fractions are separated by SDS-PAGE and western blotted using anti-human Tau T46 and anti-actin antibodies. The abundance of Tau protein in each fraction is quantified by densitometry and normalized against beta-actin. Total Tau levels in lysates are expressed as the percentage of actin-normalized Tau relative to vehicle control lysates; Tau levels in sequentially extracted fractions are expressed as the percentage of actin-normalized Tau relative to the sum of both fractions (soluble+RIPA) combined[1].

Cell experiment:

Neuronal stem cells from the forebrain Cortex of a 3-day-old rat are used in this study. The cells are differentiated by withdrawal of basic ?broblastic growth factor (bFGF) and exposed to Ethosuximide at two concentrations of 0.1 μM and 1 μM. Before drug treatment, the cells are rinsed once with PBS, and the medium is replaced with fresh, bFGF-free DMEM/F12 medium containing different concentration of Ethosuximide. Medium exchange is done every day for 6 days with medium containing Ethosuximide. Then, cells are ?xed for immunocytochemistry[2].

参考文献:

[1]. Chen X, et al. Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression. Mol Neurodegener. 2015 Sep 29;10:51.
[2]. Sondossi K, et al. Analysis of the antiepileptic, ethosuximide impacts on neurogenesis of rat forebrain stem cells. Fundam Clin Pharmacol. 2014 Oct;28(5):512-8.