Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase
| Autor: | Melissa Taylor, Markus Grompe, Wolfgang Froestl, Maneesh Gupta, Cornelis Jakobs, Boris M. Hogema, Ramon Diaz-Arrastia, Teodoro Bottiglieri, O. Carter Snead, T. Burlingame, Henry Senephansiri, K. Michael Gibson, Ruud B.H. Schutgens |
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| Rok vydání: | 2001 |
| Předmět: |
Phenytoin
Succinic semialdehyde dehydrogenase deficiency medicine.medical_specialty Taurine Ataxia Genotype Hydroxybutyrates Biology Vigabatrin chemistry.chemical_compound Epilepsy Mice Seizures Internal medicine Glial Fibrillary Acidic Protein Genetics medicine Animals DNA Primers Mice Knockout Base Sequence Brain medicine.disease Aldehyde Oxidoreductases Immunohistochemistry Succinate-semialdehyde dehydrogenase Endocrinology Biochemistry chemistry Receptors GABA-B Phenobarbital Anticonvulsants medicine.symptom Succinate-Semialdehyde Dehydrogenase medicine.drug |
| Zdroj: | Nature genetics. 29(2) |
| ISSN: | 1061-4036 |
| Popis: | Succinate semialdehyde dehydrogenase (ALDH5A1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-/- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-/- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1-/- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity. |
| Databáze: | OpenAIRE |
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