Abstract
Since its first marketing as an antiepileptic drug (AED) 35 years ago in France, valproate has become established worldwide as one of the most widely used AEDs in the treatment of both generalised and partial seizures in adults and children. The broad spectrum of antiepileptic efficacy of valproate is reflected in preclinical in vivo and in vitro models, including a variety of animal models of seizures or epilepsy.
There is no single mechanism of action of valproate that can completely account for the numerous effects of the drug on neuronal tissue and its broad clinical activity in epilepsy and other brain diseases. In view of the diverse molecular and cellular events that underlie different seizure types, the combination of several neurochemical and neurophysiological mechanisms in a single drug molecule might explain the broad antiepileptic efficacy of valproate. Furthermore, by acting on diverse regional targets thought to be involved in the generation and propagation of seizures, valproate may antagonise epileptic activity at several steps of its organisation.
There is now ample experimental evidence that valproate increases turnover of γ-aminobutyric acid (GABA) and thereby potentiates GABAergic functions in some specific brain regions thought to be involved in the control of seizure generation and propagation. Furthermore, the effect of valproate on neuronal excitation mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors might be important for its anticonvulsant effects. Acting to alter the balance of inhibition and excitation through multiple mechanisms is clearly an advantage for valproate and probably contributes to its broad spectrum of clinical effects.
Although the GABAergic potentiation and glutamate/NMDA inhibition could be a likely explanation for the anticonvulsant action on focal and generalised convulsive seizures, they do not explain the effect of valproate on nonconvulsive seizures, such as absences. In this respect, the reduction of γ-hydroxybutyrate (GHB) release reported for valproate could be of interest, because GHB has been suggested to play a critical role in the modulation of absence seizures.
Although it is often proposed that blockade of voltage-dependent sodium currents is an important mechanism of antiepileptic action of valproate, the exact role played by this mechanism of action at therapeutically relevant concentrations in the mammalian brain is not clearly elucidated.
By the experimental observations summarised in this review, most clinical effects of valproate can be explained, although much remains to be learned at a number of different levels about the mechanisms of action of valproate. In view of the advances in molecular neurobiology and neuroscience, future studies will undoubtedly further our understanding of the mechanisms of action of valproate.
Similar content being viewed by others
References
Löscher W, editor. Valproate. Basel: Birkhäuser, 1999
Löscher W. Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 1999; 58: 31–59
Burton BS. On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J 1882; 3: 385–95
Meunier H, Carraz G, Meunier Y, et al. Propriétés pharmacodynamiques de l’acide n-dipropylacétique. 1er mémoire: propriétés antiépileptiques. Thérapie 1963; 18: 435–8
Löscher W. The discovery of valproate. In: Löscher W, editor. Valproate. Basel: Birkhäuser, 1999: 1–3
Carraz G, Fau R, Chateau R, et al. Communication à propos des premiers essais cliniques sur l’activité anti-épileptique de l’acide n-dipropylacétiques (sel de Na). Ann Med Psychol (Paris) 1964; 122: 577–85
Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults: The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med 1992; 327: 765–1
Richens A, Davidson DL, Cartlidge NE, et al. A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy: the Adult EPITEG Collaborative Group. J Neurol Neurosurg Psychiatry 1994; 57: 682–7
Verity CM, Hosking G, Easter DJ. A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy: the Paediatric EPITEG Collaborative Group. Dev Med Child Neurol 1995; 37: 97–108
Heller AJ, Chesterman P, Elwes RD, et al. Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995; 58: 44–50
de Silva M, Macardle B, Mcgowan M, et al. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996; 347: 709–13
Brodie MJ, Mumford JP. Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy: 012 Study Group. Epilepsy Res 1999; 34: 199–205
Christe W, Kramer G, Vigonius U, et al. A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997; 26: 451–60
Fountain NB, Dreifuss FE. The future of valproate. In: Löscher W, editor. Valproate. Basel: Birkhäuser, 1999: 265–76
Davis R, Peters DH, Mctavish D. Valproic acid: a reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1994; 47: 332–72
Sarisjulis N, Dulac O. Valproate in the treatment of epilepsies in children. In: Löscher W, editor. Valproate. Basel: Birkhäuser, 1999: 131–52
Schmidt D, Bourgeois B. A risk-benefit assessment of therapies for Lennox-Gastaut syndrome. Drug Saf 2000; 22: 467–77
Vassella F, Rudeberg A, Da Silva V, et al. Double-blind study on the anti-convulsive effect of phenobarbital and valproate in the Lennox syndrome [in German]. Schweiz Med Wochenschr 1978; 108: 713–6
Dyken PR, DuRant RH, Minden DB, et al. Short term effects of valproate on infantile spasms. Pediatr Neurol 1985; 1: 34–7
Schmidt D. Adverse effects and interactions with other drugs. In: Löscher W, editor. Valproate. Basel: Birkhäuser, 1999: 223–64
Cotariu D, Zaidman JL, Evans S. Neurophysiological and biochemical changes evoked by valproic acid in the central nervous system. Progr Neurobiol 1990; 34: 343–54
Johannessen CU. Mechanisms of action of valproate: a commentary. Neurochem Int 2000; 37: 103–10
Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002; 16(10): 695–714
Browne TR, Holmes GL. Epilepsy. N Engl J Med 2001; 344: 1145–51
McNamara JO. Emerging insights into the genesis of epilepsy. Nature 1999; 399: A15–22
Proposal for revised clinical and electroencephalographic classification of epileptic seizures: the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981; 22: 489–501
Annegers JF, Rocca WA, Hauser WA. Causes of epilepsy: contributions of the Rochester Epidemiology Project. Mayo Clin Proc 1996; 71: 570–5
Löscher W. Animal models of epilepsy and epileptic seizures. In: Eadie MJ, Vajda F, editors. Antiepileptic drugs: handbook of experimental pharmacology. Berlin: Springer, 1999: 19–62
Löscher W. New visions in the pharmacology of anticonvulsion. Eur J Pharmacol 1998; 342: 1–13
Löscher W, Rogawski MA. Epilepsy. In: Lodge D, Danysz W, Parsons CG, editors. Ionotropic glutamate receptors as therapeutic targets. Johnson City (TN): Graham Publ., 2002: 91–132
Löscher W. Valproic acid. In: Frey H-H, Janz D, editors. Anti-epileptic drugs. Berlin: Springer Verlag, 1985: 507–36
Hönack D, Löscher W. Intravenous valproate: onset and duration of anticonvulsant activity against a series of electroconvulsions in comparison with diazepam and phenytoin. Epilepsy Res 1992; 13: 215–21
Löscher W, Fisher JE, Nau H, et al. Marked increase in anticonvulsant activity but decrease in wet-dog shake behaviour during short-term treatment of amygdala-kindled rats with valproic acid. Eur J Pharmacol 1988; 150: 221–32
Löscher W, Fisher JE, Nau H, et al. Valproic acid in amygdalakindled rats: alterations in anticonvulsant efficacy, adverse effects and drug and metabolite levels in various brain regions during chronic treatment. J Pharmacol Exp Ther 1989; 250: 1067–78
Löscher W, Hönack D. Comparison of anticonvulsant efficacy of valproate during prolonged treatment with one and three daily doses or continuous (“controlled release”) administration in a model of generalized seizures in rats. Epilepsia 1995; 36: 929–37
Altrup U, Gerlach G, Reith H, et al. Effects of valproate in a model nervous system (buccal ganglia of Helix pomatia). I: antiepileptic actions. Epilepsia 1992; 33: 743–52
Wamil AW, Löscher W, Mclean MJ. Trans-2-en-valproic acid limits action potential firing frequency in mouse central neurons in cell culture. J Pharmacol Exp Ther 1997; 280: 1349–56
Silver JM, Shin C, McNamara JO. Antiepileptogenic effects of conventional anticonvulsants in the kindling model of epilepsy. Ann Neurol 1991; 29: 356–63
Bolanos AR, Sarkisian M, Yang Y, et al. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology 1998; 51: 41–8
Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J Neurosurg 1999; 91: 593–600
Hashimoto R, Hough C, Nakazawa T, et al. Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J Neurochem 2002; 80: 589–97
Li R, El-Mallahk RS. A novel evidence of different mechanisms of lithium and valproate neuroprotective action on human SY5Y neuroblastoma cells: caspase-3 dependency. Neurosci Lett 2000; 294: 147–50
Mora A, Gonzalez-Polo RA, Fuentes JM, et al. Different mechanisms of protection against apoptosis by valproate and Li+. Eur J Biochem 1999; 266: 886–91
Thurston JH, Hauhart RE. Valproate doubles the anoxic survival time of normal developing mice: possible relevance to valproate-induced decreases in cerebral levels of glutamate and aspartate, and increases in taurine. Life Sci 1989; 45: 59–62
Manji HK, Moore GJ, Rajkowska G, et al. Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry 2000; 5: 578–93
Perucca E, Gram L, Avanzini G, et al. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998; 39: 5–17
Balfour JA, Bryson HM. Valproic acid: a review of its pharmacology and therapeutic potential in indications other than epilepsy. CNS Drugs 1994; 2: 144–73
Vajda FJ, Donnan GA, Phillips J, et al. Human brain, plasma, and cerebrospinal fluid concentration of sodium valproate after 72 hours of therapy. Neurology 1981; 31: 486–7
Nau H, Löscher W. Valproic acid and metabolites: pharmacological and toxicological studies. Epilepsia 1984; 25(1): 14–22
Semmes RL, Shen DD. Comparative pharmacodynamics and brain distribution of E-delta2-valproate and valproate in rats. Epilepsia 1991; 32: 232–41
Löscher W. Pharmacological, toxicological and neurochemical effects of delta2(E)-valproate in animals. Pharm Weekbl 1992; 14: 139–43
Deckers CL, Czuczwar SJ, Hekster YA, et al. Selection of anti-epileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia 2000; 41: 1364–74
Brodie MJ, Yuen AWC. Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 1997; 26: 423–32
Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated ash: risk/benefit considerations in adults and children. Epilepsia 1999; 40: 985–1
Faught E, Morris G, Jacobson M, et al. Adding lamotrigine to valproate: incidence of rash and other adverse effects. The Postmarketing Antiepileptic Drug Survey (PADS) Group. Epilepsia 1999; 40: 1135–40
Voskuyl RA, Ter Keurs HE, Meinardi H. Actions and interactions of dipropylacetate and penicillin on evoked potentials of excised prepiriform cortex of guinea pig. Epilepsia 1975; 16: 583–92
Piredda S, Yonekawa W, Whittingham TS, et al. Effects of antiepileptic drugs on pentylenetetrazole-induced epileptiform activity in the in vitro hippocampus. Epilepsia 1986; 27: 341–6
Tian LM, Alkadhi KA. Valproic acid inhibits the depolarizing rectification in neurons of rat amygdala. Neuropharmacology 1994; 33: 1131–8
Bruckner C, Stenkamp K, Meierkord H, et al. Epileptiform discharges induced by combined application of bicuculline and 4-aminopyridine are resistant to standard anticonvulsants in slices of rats. Neurosci Lett 1999; 268: 163–5
Bruckner C, Heinemann U. Effects of standard anticonvulsant drugs on different patterns of epileptiform discharges induced by 4-aminopyridine in combined entorhinal cortex-hippocampal slices. Brain Res 2000; 859: 15–20
Fueta Y, Avoli M. Pattern- and age-dependency of the antiepileptic effects induced by valproic acid in the rat hippocampus. Can J Physiol Pharmacol 1991; 69: 1301–4
Fueta Y, Siniscalchi A, Tancredi V, et al. Extracellular magnesium and anticonvulsant effects of valproate in young rat hippocampus. Epilepsia 1995; 36: 404–9
Dreier JP, Heinemann U. Late low magnesium-induced epileptiform activity in rat entorhinal cortex slides becomes insensitive to the anticonvulsant valproic acid. Neurosci Lett 1990; 119: 68–70
Zhang CL, Dreier JP, Heinemann U. Paroxysmal epileptiform discharges in temporal lobe slices after prolonged exposure to low magnesium are resistant to clinically used anticonvulsants. Epilepsy Res 1995; 20: 105–11
Sokolova S, Schmitz D, Zhang CL, et al. Comparison of effects of valproate and trans-2-en-valproate on different forms of epileptiform activity in rat hippocampal and temporal cortex slices. Epilepsia 1998; 39: 251–8
Zhang YF, Gibbs III JW, Coulter DA. Anticonvulsant drug effects on spontaneous thalamocortical rhythms in vitro: valproic acid, clonazepam, and alpha-methyl-alpha-phenylsuccinimide. Epilepsy Res 1996; 23: 37–53
Macdonald RL. Cellular actions of antiepileptic drugs. In: Eadie MJ, Vajda FJE, editors. Antiepileptic drugs: pharmacology and therapeutics. Berlin: Springer, 1999: 123–50
Sypert GW, Reynolds AF. Single pyramidal-tract fiber analysis of neocortical propagated seizures with reference to inactivation responses. Exp Neurol 1974; 45: 228–40
Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990; 42: 223–86
Mutani R, Doriguzzi T, Fariello R, et al. Azione antiepilettica del sale di sodio dell’acido N-dipropilacetico: studio sperimentale sul gatto. Riv Patol Nerv Ment 1968; 89: 24–33
Salt TE, Tulloch IF, Walter DS. Anti-epileptic properties of sodium valproate in rat amygdaloid kindling. Br J Pharmacol 1980; 68(1): 134P
Ito T, Hori M, Yoshida K, et al. Effect of anticonvulsants on thalamic afterdischarge in rats and cats. Jpn J Pharmacol 1977; 27: 823–31
Mutani R, Fariello R. Effetti dell’acido n-dipropilacetico (Depakine) sull’attività del focus epilettogeno da cobalto. Riv Patol Nerv Ment 1969; 90: 40–9
Fariello R, Mutani R. Modificazioni dell’attività del focus epilettogeno cortico-monotorio da alluminia indotte dal sale di sodio n-dipropylacetico (DPA). Acta Neurol (Napoli) 1970; 25: 116–22
van Duijn H, Beckmann MK. Dipropylacetic acid (Depakine) in experimental epilepsy in the alert cat. Epilepsia 1975; 16: 83–90
Maresova D, Mares P. Influence of valproate and carbamazepine on symmetrical cortical penicillin foci in the rat. Physiol Bohemoslov 1985; 34: 562–6
Löscher W, Hönack D. Effects of the competitive NMDA receptor antagonist, CGP 37849, on anticonvulsant activity and adverse effects of valproate in amygdala-kindled rats. Eur J Pharmacol 1993; 234: 237–45
Mares P, Maresova D, Pohl M, et al. Effect of anticonvulsant drugs on thalamo-cortical and hippocampo-cortical self-sustained after-discharges in the rat. Physiol Bohemoslov 1984; 33: 179–87
Marescaux C, Micheletti G, Vergnes M, et al. A model of chronic spontaneous petit mal-like seizures in the rat: comparison with pentylenetetrazol-induced seizures. Epilepsia 1984; 25: 326–31
Löscher W, Nau H, Marescaux C, et al. Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-en-valproic acid in different animal models of epilepsy. Eur J Pharmacol 1984; 99: 211–8
Macdonald RL, Bergey GK. Valproic acid augments GABA-mediated postsynaptic inhibition in cultured mammalian neurons. Brain Res 1979; 170: 558–62
Olpe HR, Steinmann MW, Pozza MF, et al. Valproate enhances GABA-A mediated inhibition of locus coeruleus neurons in vitro. Naunyn Schmiedeberg’s Arch Pharmacol 1988; 338: 655–7
Baldino F, Geller HM. Effect of sodium valproate on hypothalamic neurons in vivo and in vitro. Brain Res 1981; 219: 231–7
Zeise ML, Kasparaow S, Zieglgansberger W. Valproate suppresses N-methyl-D-aspartate evoked, transient depolarizations in the rat neocortex in vitro. Brain Res 1991;544: 345–8
Czuczwar SJ, Frey H-H, Löscher W. Antagonism of N-methyl-D,L-aspartic acid-induced convulsions by antiepileptic drugs and other agents. Eur J Pharmacol 1985; 108: 273–80
Musshoff U, Madeja M, Düsing R, et al. Valproate affects glutamate but not GABA receptors [abstract]. Eur J Neurosci 1996; Suppl. 9: 205
Chapman A, Keane PE, Meldrum BS, et al. Mechanism of anticonvulsant action of valproate. Progr Neurobiol 1982; 19: 315–59
Kerwin RW, Taberner PV. The mechanism of action of sodium valproate. Gen Pharmacol 1981; 12: 71–5
Farrant M, Webster RA. Neuronal activity, amino acid concentration and amino acid release in the substantia nigra of the rat after sodium valproate. Brain Res 1989; 504: 49–56
Rohlfs A, Rundfeldt C, Koch R, et al. A comparison of the effects of valproate and its major active metabolite E-2-envalproate on single unit activity of substantia nigra pars reticulata neurons in rats. J Pharmacol Exp Ther 1996; 277: 1305–14
Löscher W. Valproate enhances GABA turnover in the substantia nigra. Brain Res 1989; 501: 198–203
Löscher W, Ebert U. Basic mechanisms of seizure propagation: targets for rational drug design and rational polypharmacy. Epilepsy Res 1996; Suppl. 11: 17–44
Gale K. Progression and generalization of seizure discharge: anatomical and neurochemical substrates. Epilepsia 1988; 29Suppl. 2: S15–34
McLean MJ, Macdonald RL. Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 1986; 237: 1001–11
Van den Berg RJ, Kok P, Voskuyl RA. Valproate and sodium currents in cultured hippocampal neurons. Exp Brain Res 1993; 93: 279–87
Albus H, Williamson R. Electrophysiologic analysis of the actions of valproate on pyramidal neurons in the rat hippocampal slice. Epilepsia 1998; 39: 124–39
Willow M, Kuenzel EA, Catterall WA. Inhibition of voltagesensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol Pharmacol 1984; 25: 228–34
Francis J, Burnham WM. [3H]Phenytoin identifies a novel anticonvulsant-binding domain on voltage-dependent sodium channels. Mol Pharmacol 1992; 42: 1097–103
Zona C, Avoli M. Effects induced by the antiepileptic drug valproic acid upon the ionic currents recorded in rat neocortical neurons in cell culture. Exp Brain Res 1990; 81: 313–7
Vreugdenhil M, Vanveelen CWM, Vanrijen PC, et al. Effect of valproic acid on sodium currents in cortical neurons from patients with pharmaco-resistant temporal lobe epilepsy. Epilepsy Res 1998; 32: 309–20
Vreugdenhil M, Wadman WJ. Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis. Epilepsia 1999; 40: 1512–22
Vreugdenhil M, Bruehl C, Voskuyl RA, et al. Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons. Proc Natl Acad Sci U S A 1996; 93: 12559–63
Taverna S, Mantegazza M, Franceschetti S, et al. Valproate selectively reduces the persistent fraction of Na+ current in neocortical neurons. Epilepsy Res 1998; 32: 304–8
Fariello RG, Varasi M, Smith MC. Valproic acid: mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press, 1995: 581–604
Morre M, Keane PE, Vernières JC, et al. Valproate: recent findings and perspectives. Epilepsia 1984; 25Suppl. 1: S5–9
Franceschetti S, Hannon B, Heinemann U. The action of valproate on spontaneous epileptiform activity in the absence of synaptic transmission and on evoked changes in [Ca2+]0 and [K+]0 in the hippocampal slice. Brain Res 1986; 386: 1–11
Roderfeld H-J, Altrup U, Düsing R, et al. Effects of the antiepileptic drug valproate on cloned voltage-dependent potassium channels [abstract]. Pflügers Arch 1994; 426 Suppl.: R32
Coulter DA, Huguenard JR, Prince DA. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann Neurol 1989; 25: 582–93
Kelly KM, Gross RA, Macdonald RL. Valproic acid selectively reduces the low-threshold (T) calcium current in rat nodose neurons. Neurosci Lett 1990; 116: 1–2
Crowder JM, Bradford HF. Common anticonvulsants inhibit Ca2+ uptake and amino acid neurotransmitter release in vitro. Epilepsia 1987; 28: 378–82
Perlman BJ, Goldstein DB. Membrane-disordering potency and anticonvulsant action of valproic acid and other short-chain fatty acids. Mol Pharmacol 1984; 26: 83–9
Rumbach L, Mutet C, Cremel G, et al. Effects of sodium valproate on mitochondrial membranes: electron paramagnetic resonance and transmembrane protein movement studies. Mol Pharmacol 1986; 30: 270–3
Godin Y, Heiner L, Mark J, et al. Effects of di-n-propylacetate, an anticonvulsive compound, on GABA metabolism. J Neurochem 1969; 16: 869–73
Simler S, Ciesielski L, Maitre M, et al. Effect of sodium n-dipropylacetate on audiogenic seizures and brain γ-aminobutyric acid level. Biochem Pharmacol 1973; 22: 1701–8
Schechter PJ, Tranier Y, Grove J. Effect of n-dipropylacetate on amino acid concentrations in mouse brain: correlations with anti-convulsant activity. J Neurochem 1978;31: 1325–7
Martin DL, Olsen RW, Martin DL, et al., editors. GABA in the nervous system: the view at fifty years. Philadelphia (PA): Lippincott Williams & Wilkins, 2000
Löscher W. GABA and the epilepsies: experimental and clinical considerations. In: Bowery NG, Nisticò G, editors. GABA: basic research and clinical applications. Rome: Pythagora Press, 1989: 260–300
Avoli M. Epilepsy. In: Martin DL, Olsen W, editors. GABA in the nervous system: the view at fifty years. Philadelphia (PA): Lippincott Williams & Wilkins, 2000: 293–316
Simler S, Randrianarisoa H, Lehman A, et al. Effects du di-n-propylacétate sur les crises audiogènes de la souris. J Physiol (Paris) 1968; 60: 547
Sieghart W. Unraveling the function of GABA(A) receptor subtypes. Trends Pharmacol Sci 2000; 21: 411–3
Möhler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002; 300: 2–8
Rudolph U, Crestani F, Möhler H. GABA(A) receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol Sci 2001; 22: 188–94
Iadarola MJ, Gale K. Dissociation between drug-induced increases in nerve terminal and non-nerve terminal pools of GABA in vivo. Eur J Pharmacol 1979; 59: 125–9
Löscher W, Vetter M. In vivo effects of aminooxyacetic acid and valproic acid on nerve terminal (synaptosomal) GABA levels in discrete brain areas of the rat: correlation to pharmacological activities. Biochem Pharmacol 1985; 34: 1747–56
Iadarola MJ, Gale K. Cellular compartments of GABA in brain and their relationship to anticonvulsant activity. Mol Cell Biochem 1981; 39: 305–30
Löscher W. GABA in plasma, CSF and brain of dogs during acute and chronic treatment with γ-acetylenic GABA and valproic acid. In: Okada Y, Roberts E, editors. Problems in GABA research: from brain to bacteria. Amsterdam: Exerpta Medica, 1982: 102–9
Petroff OA, Rothman DL, Behar KL, et al. Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures. Seizure 1999; 8: 120–7
Petroff OA, Rothman DL. Measuring human brain GABA in vivo: effects of GABA-transaminase inhibition with vigabatrin. Mol Neurobiol 1998; 16: 97–121
Löscher W. Valproate induced changes in GABA metabolism at the subcellular level. Biochem Pharmacol 1981; 30: 1364–6
Phillips NI, Fowler LJ. The effects of sodium valproate on γ-aminobutyrate metabolism and behavior in naive and ethanolamine-O-sulphate pretreated rats and mice. Biochem Pharmacol 1982; 31: 2257–61
Löscher W. Effect of inhibitors of GABA aminotransferase on the metabolism of GABA in brain tissue and synaptosomal fractions. J Neurochem 1981; 36: 1521–7
Löscher W. In vivo administration of valproate reduces the nerve terminal (synaptosomal) activity of GABA aminotransferase in discrete brain areas of rats. Neurosci Lett 1993; 160: 177–80
Larsson OM, Gram L, Schousboe I, et al. Differential effects of gamma-vinyl GABA and valproate on GABA-transaminase from cultured neurons and astrocytes. Neuropharmacology 1986; 25: 617–25
Taberner PV, Charington CB, Unwin JW. Effects of GAD and GABA-T inhibitors on GABA metabolism in vivo. Brain Res Bull 1980; 5 Suppl. 2: 621–5
Nau H, Löscher W. Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and GABA metabolism in the mouse. J Pharmacol Exp Ther 1982; 220: 654–9
Wikinski SI, Acosta GB, Rubio MC. Valproic acid differs in its in vitro effect on glutamic acid decarboxylase activity in neonatal and adult rat brain. Gen Pharmacol 1996; 27: 635–8
Bolanos JP, Medina JM. Evidence of stimulation of the gamma-aminobutyric acid shunt by valproate and E-delta-2-valproate in neonatal rat brain. Mol Pharmacol 1993; 43: 487–90
Löscher W, Frey H-H. Zum Wirkungsmechanismus von valproinsäure. Arzneimittel Forschung 1977; 27: 1081–2
Luder AS, Parks JK, Frerman F, et al. Inactivation of beef brain α-ketoglutarate dehydrogenase complex by valproic acid and valproic acid metabolites. J Clin Invest 1990; 86: 1574–81
Gram L, Larsson OM, Johnsen AH, et al. Effects of valproate, vigabatrin and aminooxyacetic acid on release of endogenous and exogenous GABA from cultured neurons. Epilepsy Res 1988; 2: 87–95
Ekwuru MO, Cunningham JR. Phaclofen increases GABA release from valproate treated rats. Br J Pharmacol 1990; 99 Suppl.: 251P
Ueda Y, Willmore LJ. Molecular regulation of glutamate and GABA transporter proteins by valproic acid in rat hippocampus during epileptogenesis. Exp Brain Res 2000; 133: 334–9
Biggs CS, Pearce BR, Fowler LJ, et al. The effect of sodium valproate on extracellular GABA and other amino acids in the rat ventral hippocampus: an in vivo microdialysis study. Brain Res 1992; 594: 138–42
Rowley HL, Marsden CA, Martin KF. Differential effects of phenytoin and sodium valproate on seizure-induced changes in gamma-aminobutyric acid and glutamate release in vivo. Eur J Pharmacol 1995; 294: 541–6
Wolf R, Tscherne U, Emrich HM. Suppression of preoptic GABA release caused by push-pull-perfusion with sodium valproate. Naunyn Schmiedeberg’s Arch Pharmacol 1988; 338: 658–63
Timmermann W, Westerink BHC. Brain microdialysis of GABA and glutamate: what does it signify? Synapse 1997; 27: 242–61
Ticku MK, Davis WC. Effect of valproic acid on [3H]diazepam and [3H]dihydroxypicrotoxinin binding sites at the benzodiazepine-GABA receptor ionophore complex. Brain Res 1981; 223: 218–22
Miller LG, Greenblatt DJ, Barnhill JG, et al. “GABA shift” in vivo: enhancement of benzodiazepine binding in vivo by modulation of endogenous GABA. Eur J Pharmacol 1988; 148: 123–30
Koe BK, Kondratas E, Russo LL. [3H]Ro 15-1788 binding to benzodiazepine receptors in mouse brain in vivo: marked enhancement by GABA agonists and other CNS drugs. Eur J Pharmacol 1987; 142: 373–84
Nutt DJ, Cowen PJ, Little HJ. Unusual interactions of benzodiazepine receptor antagonists. Nature 1982; 295: 436–8
Gent JP, Bentley M, Feely M, et al. Benzodiazepine cross-tolerance in mice extends to sodium valproate. Eur J Pharmacol 1986; 128: 9–15
Liljequist S, Engel JA. Reversal of anticonflict action of valproate by various GABA and benzodiazepine antagonists. Life Sci 1984; 34: 2525–31
Morag M, Myslobodsky M. Benzodiazepine antagonists abolish electrophysiological effects of sodium valproate in the rat. Life Sci 1982; 30: 1671–7
Myslobodsky M, Feldon J, Lerner T. Anticonflict action of sodium valproate: interaction with convulsant benzodiazepine (Ro 5-3663) and imidazodiazepine (Ro 15-1788). Life Sci 1983; 33: 317–21
Shephard RA, Stevenson D, Jenkinson S. Effects of valproate on hyponeophagia in rats: competitive antagonism with picrotoxin and non-competitive antagonism with RO 15-1788. Psychopharmacology (Berl) 1985; 86: 313–7
Shephard RA, Hamilton MS. Chlordiazepoxide and valproate enhancement of saline drinking by nondeprived rats: effects of bicuculline, picrotoxin and Rol5-1788. Pharmacol Biochem Behav 1989; 33: 285–90
Ong J, Kerr DI. Recent advances in GABAB receptors: from pharmacology to molecular biology. Acta Pharmacol Sin 2000; 21: 111–23
Caddick SJ, Hosford DA. The role of GABAB mechanisms in animal models of absence seizures. Mol Neurobiol 1996; 13: 23–32
Czuczwar SJ, Patsalos PN. The new generation of GABA enhancers: potential in the treatment of epilepsy. CNS Drugs 2001; 15: 339–50
Lloyd KG, Thuret F, Pilc A. Upregulation of gamma-amino-butyric (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock. J Pharmacol Exp Ther 1985; 235: 191–9
Motohashi N. GABA receptor alterations after chronic lithium administration: comparison with carbamazepine and sodium valproate. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16: 571–9
DeFeudis FV. Gamma-aminobutyric acid-ergic analgesia: implications for gamma-aminobutyric acid-ergic therapy for drug addiction. Drug Alcohol Depend 1984; 14: 101–11
Whittle SR, Turner AJ. Effects of the anticonvulsant sodium valproate on γ-aminobutyrate and aldehyde metabolism in ox brain. J Neurochem 1978; 31: 1453–9
Vayer P, Cash CD, Maitre M. Is the anticonvulsant mechanism of valproate linked to its interaction with the cerebral γ-hydroxybutyrate system? Trends Pharmacol Sci 1988; 9: 127–9
Whittle SR, Turner SJ. Effects of anticonvulsants on the formation of γ-hydroxybutyrate from γ-aminobutyrate in rat brain. J Neurochem 1982; 38: 848–51
Snead OI. γ-Hydroxybutyrate model of generalized absence seizures: further characterization and comparison with other absence models. Epilepsia 1988; 29: 361–77
Snead OCI, Bearden LJ, Pegram V. Effect of acute and chronic anticonvulsant administration on endogenous γ-hydroxybutyrate in rat brain. Neuropharmacology 1980; 19: 47–52
Dixon JF, Hokin LE. The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates. Proc Natl Acad Sci U S A 1997; 94: 4757–60
Nilsson M, Hansson E, Ronnback L. Interactions between valproate, glutamate, aspartate, and GABA with respect to uptake in astroglial primary cultures. Neurochem Res 1992; 17: 327–32
Biggs CS, Pearce BR, Fowler LJ, et al. Regional effects of sodium valproate on extracellular concentrations of 5-hydroxytryptamine, dopamine, and their metabolites in the rat brain: an in vivo microdialysis study. J Neurochem 1992; 59: 1702–8
Horton RW, Anlezark GM, Sawaya MCB, et al. Monoamine and GABA metabolism and the anticonvulsant action of di-n-propylacetate and ethanolamine-O-sulphate. Eur J Pharmacol 1977; 41: 387–97
Ichikawa J, Meltzer HY. Valproate and carbamazepine increase prefrontal dopamine release by 5-HT1A receptor activation. Eur J Pharmacol 1999; 380: R1–3
Dreifuss FE. Valproic acid: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4thed. New York: Raven, 1995: 641–8
Jones EA, Basile AS. Does ammonia contribute to increased GABA-ergic neurotransmission in liver failure? Metab Brain Dis 1998; 13: 351–60
Nathanson JA. Cyclic nucleotides and nervous system function. Physiol Rev 1977; 57: 157–256
Lust WD, Kupferberg HJ, Yonekawa WD, et al. Changes in brain metabolites induced by convulsants or electroshock: effects of anticonvulsant agents. Mol Pharmacol 1978; 14: 347–56
McCandless DW, Feussner GK, Lust WD, et al. Metabolite levels in brain following experimental seizures: the effects of isoniazid and sodium valproate in cerebellar and cerebral cortical layers. J Neurochem 1979; 32: 755–60
Frey H-H, Löscher W. Distribution of valproate across the interface between blood and cerebrospinal fluid. Neuropharmacology 1978; 17: 637–42
Shen DD. Valproate: absorption, distribution, and excretion. In: Löscher W editor. Valproate. Basle: Birkhäuser, 1999: 77–90
Huai-Yun H, Secrest DT, Mark KS, et al. Expression of multi-drug resistance-associated protein (MRP) in brain micro-vessel endothelial cells. Biochem Biophys Res Commun 1998; 243: 816–20
Cutrer FM, Limmroth V, Moskowitz MA. Possible mechanisms of valproate in migraine prophylaxis. Cephalalgia 1997; 17: 93-100
Acknowledgements
The author’s own experiments were supported by grants from the Deutsche Forschungsgemein-schaft (Bonn, Germany). The author would like to thank Dr Manuela Gernert for help with the figure and Sanofi (Paris, France) for supporting the writing of this manuscript (the company had no significant influence on the contents of the manuscript).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Löscher, W. Basic Pharmacology of Valproate. Mol Diag Ther 16, 669–694 (2002). https://doi.org/10.2165/00023210-200216100-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00023210-200216100-00003