Posted by Ame Sans Vie on October 1, 2003, at 10:00:12
In reply to Re: Amphetamines and NDMA antagonism, posted by Ramon Paz on October 1, 2003, at 2:04:54
According to one study I have below, Rilutek is certainly neuroprotective, but does not act via NMDA receptors: "The results indicate that when given alone, riluzole has a behavioral profile resembling that of competitive NMDA receptor antagonists. However, coadministration of riluzole with NMDA/AMPA receptor ligands suggests that this assumption is incorrect, and that riluzole affects glutamatergic transmission by a more indirect mechanism."
I have however been wondering about Rilutek as GABA-enhancing med for some time now. A lot of very interesting things I've come across below... the first thing that really strikes me as interesting is this line in the second abstract: "... riluzole-induced potentiation was inhibited by the lactone antagonist alpha-isopropyl-alpha-methyl-gamma-butyrolactone (alpha-IMGBL)." So if its effects were attenuated by a lactone inhibitor (gamma butyrolactone, no less), then I have to wonder whether part of its M.O.A. is through GHB (or similar) receptors... I may be totally wrong about this, but it sounds possible. After all, it's said to possess anxiolytic, sedative, and anaesthetic qualities... remind you of anything? :-)
1. Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder.
Coric V, Milanovic S, Wasylink S, Patel P, Malison R, Krystal JH.
Clinical Neuroscience Research Unit, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, CT 06519, New Haven, USA.
2. Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function.
He Y, Benz A, Fu T, Wang M, Covey DF, Zorumski CF, Mennerick S.
Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
The antiepileptic drug riluzole is a use-dependent blocker of voltage-gated Na(+) channels and selectively depresses action potential-driven glutamate over gamma-aminobutyric acid (GABA) release. Here we report that in addition to its presynaptic effect, riluzole at higher concentrations also strongly potentiates postsynaptic GABA(A) responses both in cultured hippocampal neurons and in Xenopus oocytes expressing recombinant receptors. Although peak inhibitory postsynaptic currents (IPSCs) of autaptic hippocampal neurons were inhibited, 20-100 microM riluzole significantly prolonged the decay of IPSCs, resulting in little change in total charge transfer. The effect was dose-dependent and reversible. Riluzole selectively increased miniature IPSC fast and slow decay time constants, without affecting their relative proportions. Miniature IPSC peak amplitude, rise time and frequency were unaffected, indicating a postsynaptic mechanism. In the Xenopus oocyte expression system, riluzole potentiated GABA responses by lowering the EC(50) for GABA activation. Riluzole directly gated a GABA(A) current that was partially blocked by bicuculline and gabazine. Pharmacological experiments suggest that the action of riluzole did not involve a benzodiazepine, barbiturate, or neurosteroid site. Instead, riluzole-induced potentiation was inhibited by the lactone antagonist alpha-isopropyl-alpha-methyl-gamma-butyrolactone (alpha-IMGBL). While most anticonvulsants either block voltage-gated Na(+) channels or potentiate GABA(A) receptors, our results suggest that riluzole may define an advantageous class of anticonvulsants with both effects.
3. Riluzole, a novel antiglutamate, blocks GABA uptake by striatal synaptosomes.
Mantz J, Laudenbach V, Lecharny JB, Henzel D, Desmonts JM.
Department of Anesthesiology, Hospital Bichat, Paris, France.
The effect of riluzole (2-amino-6-trifluoro-methoxybenzothiazole, a novel antiglutamate agent) on the uptake of [3H]GABA (gamma-aminobutyric acid) by striatal synaptosomes was investigated in rats. Both nipecotic acid (a classical blocker of GABA uptake) and riluzole were found to inhibit [3H]GABA uptake in a dose-related fashion (IC50 = 3.6 x 10(-6) M and 4.3 x 10(-5) M for nipecotic acid and riluzole, respectively). These results indicate that, in addition to its antiglutamate properties, riluzole probably also promotes synaptic GABA accumulation, which might contribute to the anticonvulsant and/or anesthetic properties of this pharmacological agent.
4. Riluzole antagonizes the anxiogenic properties of the beta-carboline FG 7142 in rats.
Stutzmann JM, Cintrat P, Laduron PM, Blanchard JC.
Rhone-Poulenc Sante, Centre de Recherches de Vitry, France.
The possible anxiolytic activity of riluzole, a drug which interferes with glutamic acid neurotransmission, was studied in rats using operant conflict procedures. In both "anxiolytic" and "anxiogenic" procedures, riluzole alone did not possess any anticonflict or proconflict effect at doses of 2 and 4 mg/kg PO. Riluzole over the same dose-range was able to antagonize the well known proconflict effect of the beta-carboline derivative FG 7142, an inverse agonist at the GABA-benzodiazepine-chloride ionophore receptor complex. This effect could be related to the possible interaction of riluzole with glutamic acid neurotransmission, since it has been demonstrated previously that beta-carbolines such as DMCM and beta-CCM were able to deplete the levels of aspartic and glutamic acids in rodent cortex, perhaps by enhancing release of amino acid neurotransmitters. If one subscribes to the hypothesis that the anxiety induced by beta-carboline derivatives is related to depression, riluzole might be of value in the treatment of anxiety related to depression.
5. The pharmacology and mechanism of action of riluzole.
Doble A.
Vitry-Alfortville Research Centre, Rhone-Poulenc Rorer SA, Vitry-sur-Seine, France.
The excitotoxic hypothesis of neurodegeneration has stimulated much interest in the possibility of using compounds that will block excitotoxic processes to treat neurologic disorders. Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission in the CNS. Riluzole inhibits the release of glutamic acid from cultured neurons, from brain slices, and from corticostriatal neurons in vivo. It is thought these effects may be partly due to inactivation of voltage-dependent sodium channels on glutamatergic nerve terminals, as well as activation of a G-protein-dependent signal transduction process. Riluzole also blocks some of the postsynaptic effects of glutamic acid by noncompetitive blockade of N-methyl-D-aspartate (NMDA) receptors. In vivo, riluzole has neuroprotective, anticonvulsant, and sedative properties. In a rodent model of transient global cerebral ischemia, a complete suppression of the ischemia-evoked surge in glutamic acid release has been observed. In vitro, riluzole protects cultured neurons from anoxic damage, from the toxic effects of glutamic-acid-uptake inhibitors, and from the toxic factor in the CSF of patients with amyotrophic lateral sclerosis.
6. Protective effects of riluzole on dopamine neurons: involvement of oxidative stress and cellular energy metabolism.
Storch A, Burkhardt K, Ludolph AC, Schwarz J.
Department of Neurology, University of Ulm Medical School, Ulm, Germany. alexander.storch@medizin.uni-ulm.de
Riluzole is neuroprotective in patients with amyotrophic lateral sclerosis and may also protect dopamine (DA) neurons in Parkinson's disease. We examined the neuroprotective potential of riluzole on DA neurons using primary rat mesencephalic cultures and human dopaminergic neuroblastoma SH-SY5Y cells. Riluzole (up to 10 microM:) alone affected neither the survival of DA neurons in primary cultures nor the growth of SH-SY5Y cells after up to 72 h. Riluzole (1-10 microM:) dose-dependently reduced DA cell loss caused by exposure to MPP(+) in both types of cultures. These protective effects were accompanied by a dose-dependent decrease of intracellular ATP depletion caused by MPP(+) (30-300 microM:) in SH-SY5Y cells without affecting intracellular net NADH content, suggesting a reduction of cellular ATP consumption rather than normalization of mitochondrial ATP production. Riluzole (1-10 microM:) also attenuated oxidative injury in both cell types induced by exposure to L-DOPA and 6-hydroxydopamine, respectively. Consistent with its antioxidative effects, riluzole reduced lipid peroxidation induced by Fe(3+) and L-DOPA in primary mesencephalic cultures. Riluzole (10 microM) did not alter high-affinity uptake of either DA or MPP(+). However, in the same cell systems, riluzole induced neuronal and glial cell death with concentrations higher than those needed for maximal protective effects (> or =100 microM:). These data demonstrate that riluzole has protective effects on DA neurons in vitro against neuronal injuries induced by (a) impairment of cellular energy metabolism and/or (b) oxidative stress. These results provide further impetus to explore the neuroprotective potential of riluzole in Parkinson's disease.
7. Riluzole, a glutamate release inhibitor, and motor behavior.
Kretschmer BD, Kratzer U, Schmidt WJ
Naunyn-Schmiedeberg's Archives of Pharmacology 358(2), 181-190.Riluzole (2-amino-6-trigluoromethoxy benzothiazole) has neuroprotective, anticonvulsant, anxiolytic and anesthetic qualities. These effects are mediated by blockade of glutamate transmission, stabilizing of sodium channels and blockade of gamma-aminobutyric acid (GABA) reuptake. The action profile of riluzole is dominated by its effects on glutamate transmission which are predominately mediated by N-methyl-D-aspartate (NMDA) receptor-linked processes in vitro. In vivo studies show that blockade and stimulation of the different NMDA receptor complex binding sites or AMPA receptors modulate motor behavior in a characteristic manner. It was therefore interesting to examine if blockade of glutamatergic transmission by riluzole induced similar behavioral effects as direct NMDA/AMPA receptor antagonists and if these effects are mediated by a specific receptor. The effects of riluzole alone and in combination with several other neuroactive compounds on the central nervous system was assessed by behavioral paradigms to evaluate sniffing behavior, locomotion, ataxia and rigidity. Accompanying compounds included the NMDA receptor agonist NMDA, the partial glycine site agonist D-cycloserine (DCS), and the alpha-amino-3-hydroxy-5-phenyl-4-isoxazolepropionic acid (AMPA) receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo-diazepine HCl]. Riluzole influenced neither stereotyped sniffing behavior nor locomotion but impaired motor coordination and attenuated rigidity induced by blockade of dopamine D1 and D2 receptor antagonists when given alone. At higher doses spontaneous behavioral activity decreased and motor coordination was more impaired. Augmentation of the riluzole effects were observed when NMDA, but not GYKI 52466, was coadministered. The glycine site agonist DCS increased the anticataleptic properties of riluzole. The results indicate that when given alone, riluzole has a behavioral profile resembling that of competitive NMDA receptor antagonists. However, coadministration of riluzole with NMDA/AMPA receptor ligands suggests that this assumption is incorrect, and that riluzole affects glutamatergic transmission by a more indirect mechanism. Nevertheless, the profile of riluzole together with its pre- and postsynaptic blockade of glutamatergic transmission implies beneficial properties in diseases where an overactive glutamate system induces chronic neurotoxicity and/or acute behavioral effects.
8. Interaction of the neuroprotective drug riluzole with GABA(A) and glycine receptor channels.
Mohammadi B, Krampfl K, Moschref H, Dengler R, Bufler J.
Eur J Pharmacol 2001 Mar 16;415(2-3):135-40
Neurological Department, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
Riluzole is used as therapeutic agent in amyotrophic lateral slerosis. We investigated the interaction of riluzole with recombinant GABA (gamma-aminobutyric acid)(A) receptor channels (alpha(1)beta(2)gamma(2)-subunits) and glycine receptor channels (alpha(1)beta-subunits) transiently expressed in HEK293 cells. For electrophysiological experiments, the patch-clamp technique in combination with tools for ultrafast solution exchange was used. Saturating concentrations of GABA or glycine were applied with different concentrations of riluzole to outside-out patches containing alpha(1)beta(2)gamma(2) GABA(A) receptor channels or alpha(1)beta-glycine receptor channels on their surface, respectively. The current declined after application of GABA or glycine with three time constants of desensitization to a steady-state current amplitude. Application of riluzole resulted in a shift to fast desensitized states at both receptors. The proportion of the time constants of fast desensitization increased and the time constants of slow desensitization and the steady-state current decreased whereas the maximal current amplitudes were not affected by riluzole. The data of the study demonstrate for the first time interaction of GABAergic and glycinergic currents with riluzole under physiological conditions.
poster:Ame Sans Vie
thread:263518
URL: http://www.dr-bob.org/babble/20030928/msgs/264687.html