Target Validation Information
Target ID T13259
Target Name Succinate semialdehyde dehydrogenase, mitochondrial
Target Type
Successful
Drug Potency against Target VANILLIN Drug Info IC50 = 15600 nM [527869]
1-(4-hydroxyphenyl)prop-2-en-1-one Drug Info IC50 = 350 nM [527869]
Action against Disease Model Chlormerodrin An effect of diuretics on cellular metabolism has been shown. In order to examine further the direct effect of diuretics on renal mitochondria, their effect on isolated cortical(C) and outer medullary (OM) mitochondrial respiration was examined. Oxygen cons uMption rate (QO2) was measured in a Gilson oxygraph utilizing either glutamate-malate or succinate as substrate. QO2,expressed in nanoatoms of O2 per milligram of protein per minute, was always higher in C than OM: 140.7 +/- 2.8 VS. 121.2 +/- 2.4 (P less than 0.001) with glutamate-malate and 181.1 +/- 6.3 vs. 129.7+/- 5.2 (P less than 0.001) with succinate. A dose-response curve was constructed for each of the following: sodi uM ethacrynate, furosemide, chlorothiazide, acetazolamide and chlormerodrin. All diuretics inhibited C and OM equally. The 50% inhibitory molar concentration for EA was 6.2 times 10(-4); for furosemide 1.5 times 10(-3); for chlorothiazide 8.1 times 10(-3); for acetazolamide 10.8 times10(-3); and for chlomerodrin 3.1 times 10(-5). Neither cysteine nor dithiothreitol inhibited the effect of EA. The effect of chlormerodrin was abolished by cysteine. These results demonstrate that while a difference exists between C and OM mitochondria during control studies, each of the diuretics examined exerted an equal inhibitory effect on mitochondrial respiration from both C and OM. Mercurials are the most potent inhibitors and pres uMably exert their effect by reacting with sulfhydryl groups. They are followed in potency by ethacrynic acid, furosemide, chlorothiazide and acetazolamide. [552270] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations The succinic semialdehyde dehydrogenase (SSADH) null mouse represents a viable animal model for h uMan SSADH deficiency and is characterized by markedly elevated levels of both gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acid (GABA) in brain, blood, and urine. GHB is known to induce absence-like seizures and absence seizures have been reported to occur in childrenwith SSADH deficiency. We tested the hypothesis that the phenotype of the SSADH(-/-) mouse shows absence-like seizures because of the inordinately high levels of GHB in the brain of this mutant animal. Sequential electrocorticographic (ECoG) and prolonged video ECoG recordings from chronically implanted electrodes were done on SSADH(-/-), SSADH(+/-), and SSADH(+/+) mice from postnatal day (P) 10 to (P) 21. Spontaneous, recurrent absence-like seizures appeared in the SSADH(-/-) during the second week of life and evolved into generalized convulsive seizures late in the third week of life that were associated with an explosive onset of status epilepticus which was lethal. The seizures in SSADH null mice were consistent with typical absence seizures in rodent with 7 Hz spike-and-wave discharge (SWD) recorded from thalamocortical circuitry, the onset/offset of which was time-locked with ictal behavior characterized by facial myoclonus, vibrissal twitching and frozen immobility. The absenceseizures became progressively more severe from P14 to 18 at which time they evolved into myoclonic and generalized convulsive seizures that progressed into a lethal status epilepticus. The absence seizures in SSADH(-/-) were abolished by ethosuximide (ETX) and the GABA(B)R antagonist CGP 35348. The seizure phenotype in the SSADH(-/-) recapitulates that observed in h uMan SSADH deficiency. Hence, SSADH(-/-) may be used to investigate the molecular mechanisms that underpin the pathogenesis of absence and generalized tonic-clonic seizures associated with SSADH deficiency. As well, the SSADH(-/-)may represent a unique animal model of the transition from absence to myoclonic and generalized convulsive seizures that is observed in up to 80% of patients with juvenile absence epilepsy. [552270]
References
Ref 552270Effect of diuretics on oxidative phosphorylation of dog kidney mitochondria. J Pharmacol Exp Ther. 1975 Sep;194(3):614-23.
Ref 527869Bioorg Med Chem Lett. 2006 Feb;16(3):592-5. Epub 2005 Nov 14.Inhibition of GABA shunt enzymes' activity by 4-hydroxybenzaldehyde derivatives.
Ref 527869Bioorg Med Chem Lett. 2006 Feb;16(3):592-5. Epub 2005 Nov 14.Inhibition of GABA shunt enzymes' activity by 4-hydroxybenzaldehyde derivatives.

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