Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.19 (GABA transaminase)
 808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA-agonist muscimol on dural plasma protein ([125I]-bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg-1,i.v.) in anaesthetized Sprague-Dawley rats. 2. Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (< or = 10 mg kg-1, i.p.) dose-dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6 +/- 1.4 mg kg-1, i.p., and 58 +/- 18 micrograms kg-1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2 +/- 1.4 mg kg-1, i.p. and 385 +/- 190 micrograms kg-1, i.p. for valproate or muscimol, respectively). 3. Valproate (6.6 mg kg-1, i.p.) or muscimol (58 micrograms kg-1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. 4. The GABAA-antagonist bicuculline (0.01 mg kg-1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB-receptor antagonist, phaclofen (0.01-1 mg kg-1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration. 5. Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline-reversible mechanism. This suggests that GABAA receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats.6. We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.
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PMID:Peripheral GABAA receptor-mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation. 856 34

Valproic acid has been shown to be effective in migraine prophylaxis. Its method of action is believed to be the inhibition of gamma-aminobutyric acid transaminase. The therapeutic dose needed to prevent migraine headaches has been examined in several studies, yet the optimum dose has not been found. In this case report, valproic acid was given to a 24-year-old woman with chronic headaches at 1000 mg per day. Her headaches resolved for 2 months. She tapered herself off of the medication, and her headaches returned. She was restarted at 500 mg per day of valproic acid and again, her headaches resolved. She preferred being on the lower dose which she found as effective as the higher dose. Her case makes two interesting points. The first is that lower dosages of valproic acid may be as effective as higher ones in headache prophylaxis. The second is that more studies looking at dose ranges are needed to correlate effectiveness with daily requirements.
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PMID:High-dose versus low-dose valproic acid as a prophylactic medication. 882 9

Valproate, one of the major antiepileptic drugs used today, has besides its wide use in both generalized and partial epilepsies, several new approved indications including the treatment of bipolar disorders, neuropathic pain, and as a migraine prophylaxis. This wide spectrum of activities is reflected by several different mechanisms of action, which are discussed in this review. With regard to the antiepileptic effect of VPA, a special emphasis is put on the effect on the GABAergic system and the effect on enzymes like succinate semialdehyde dehydrogenase (SSA-DH), GABA transaminase (GABA-T), and alpha-ketoglutarate dehydrogenase, related to the tricarboxylic acid (TCA) cycle and thereby cerebral metabolism. In vitro studies have shown that VPA is a potent inhibitor of SSA-DH. In brain homogenates, GABA-T is inhibited at high concentrations only. Besides affecting the GABA-shunt, VPA might also inhibit the TCA cycle at the alpha-ketoglutarate dehydrogenase step. The effect of VPA on excitatory neurotransmission and on excitatory membranes are mechanisms likely to be responsible for the 'mood-stabilizing' effect as well as in the treatment of migraine. GABA-mediated responses may be involved in neuropathic pain. But still there are many aspects of the mechanisms of action of VPA that remain unknown.
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PMID:Mechanisms of action of valproate: a commentatory. 1081 95