2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission—II Biochemical properties

Mizoule, J.; Bs, Meldrum; Mazadier, Martine; Croucher, Martin J.; Ollat, Catherine; Uzan, A.; Legrand, Jean-Christophe; Guérémy, C.; Fur, G. Le

doi:10.1016/0028-3908(85)90196-0

Cited by 157 publications

(77 citation statements)

References 52 publications

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“…The positive results of recent, preliminary clinical trials with riluzole (37), a drug that alters glutamatergic neurotransmission (34,38,39), appear to validate this therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.

Rothstein

Bristol

Hosler

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

259

110

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Mutations in the gene for Cu/Zn superoxide dismutase (SOD1) have been detected in some families with an autosomal dominant form ofamyotrophic lateral sclerosis; these mutations appear to reduce the activity of this enzyme. To determine whether decreased SOD activity could contribute to motor neuron loss, SODi was inhibited chronically with either antisense oligodeoxynucleotides or diethyldithiocarbamate in spinal cord organotypic cultures. Chronic inhibition of SOD resulted in the apoptotic degeneration of spinal neurons, including motor neurons, over several weeks. Motor neuron loss was markedly potentiated by the inhibition of glutamate transport.In this paradigm, motor neuron toxicity could be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by the non-N-methyl-D-aspartate glutamate receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-SH-2,3-benzodiazepine hydrochloride. These data support the hypothesis that the loss ofmotor neurons in familial amyotrophic lateral sclerosis could be due to a reduction in SODi activity, possibly potentiated by inefficient glutamate transport.Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized clinically by progressive weakness, wasting of muscles, and spasticity due to the slow loss of lower motor neurons in the spinal cord and in the neocortex. Familial ALS represents 5-10o of all cases and is virtually indistinguishable clinically from the more common sporadic form. Mutations in the Cu/Zn superoxide dismutase (SOD1) gene on chromosome 21 have been detected in some families with the autosomal dominant form of familial AML (1, 2). Initial studies indicate that these mutations reduce the activity of SODi (2,3). This protein is a homodimeric metalloenzyme that catalyzes the dismutation of the superoxide anion to oxygen and hydrogen peroxide (4). Excessive levels of oxygen radicals, such as superoxide anion, have been implicated in neuronal injury, either directly or through the formation of more reactive oxygen species such as hydroxyl radicals (5-7). However, it has not been established that a chronic reduction in SODi activity diminishes the viability of spinal motor neurons. To investigate this, we have developed a model of slow toxicity in cultured organotypic spinal cord slices which combines the advantages of long-term survival with partially preserved synaptic connections (8). In this model, SOD activity was inhibited by the use of either antisense oligodeoxynucleotides (ODNs) or metal-chelating agents such as diethyldithiocarbamate (DDC), which has been shown to potentiate oxygen radical-induced toxicity in acute preparations (5). METHODSOrganotypic Spinal Cord Cultures. Eight-day-old neonatal rat pups were decapitated, and the spinal cords were rapidly harvested and cultured (8). Culture medium, including any added pharmacological agent, was changed twice weekly. With this technique, >95% of the explants can be maintained in culture for >3 months with excellent organotypic cellular organization...

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Section: Discussionmentioning

confidence: 99%

Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.

Rothstein

Bristol

Hosler

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

259

110

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“…Riluzole was originally suggested as a treatment for ALS because of its ability to reduce glutamatergic synaptic transmission (Benavides et al 1985) and hence reduction of excitotoxic insult to motor neurons (Rothstein et al 1993). In six HMs voltage-clamped at Ϫ65 mV, paired glutamatergic EPSCs (Fig.…”

Section: Riluzole Hyperpolarizes Hypoglossal Motor Neurons By De-mentioning

confidence: 99%

“…The neuroprotective properties of riluzole in ALS were originally hypothesized to be due to its ability to reduce glutamatergic synaptic transmission (Benavides et al 1985;Centonze et al 1998;He et al 2002;Lamanauskas and Nistri 2008;Prakriya and Mennerick 2000). However, other neuronal responses also occur at similar or lower concentrations of riluzole, including inhibition of the persistent Na ϩ current (Lamanauskas and Nistri 2008; Urbani and Belluzzi 2000;van Zundert et al 2008), reduced action potential firing (Kuo et al 2006;Urbani and Belluzzi 2000;van Zundert et al 2008), potentiation of the Ca 2ϩ -dependent K ϩ current (Cao et al 2002), and inhibition of voltage-gated Ca 2ϩ channels (Huang et al 1997;Hubert et al 1998;Lamanauskas and Nistri 2008).…”

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confidence: 99%

“…It is worth noting that miniature EPSC amplitude reduction by riluzole, although statistically significant, was small, suggesting that direct modulation of synaptically activated glutamate receptors by riluzole may be a minor contributor to reduction of synaptic transmission; in contrast, while the reduction of glutamate receptor currents by riluzole was greater, the method of application used here is more likely to activate predominantly extrasynaptic glutamate receptors (Townsend et al 2003). In addition, although some studies have reported that electrophysiological responses to glutamate receptor ligands were inhibited by riluzole (Centonze et al 1998;Debono et al 1993;Zona et al 2002), this inhibition may be via indirect modulation of receptor function, as a number of radioligand binding studies have consistently failed to find any interaction of riluzole with the NMDA, glycine, or phencyclidine binding sites of NMDA glutamate receptors or the ligand binding site of non-NMDA glutamate receptors (Benavides et al 1985;Debono et al 1993;He et al 2002).…”

mentioning

confidence: 99%

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Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole

Bellingham

2013

Journal of Neurophysiology

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Bellingham MC. Pre-and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole. J Neurophysiol 110: 1047-1061, 2013. First published June 5, 2013 doi:10.1152/jn.00587.2012.-Riluzole is the sole treatment for amyotrophic lateral sclerosis (ALS), but its therapeutically relevant actions on motor neurons are not well defined. Whole cell patch-clamp recordings were made from hypoglossal motor neurons (HMs, n ϭ 25) in brain stem slices from 10-to 23-day-old rats anesthetized with pentobarbital sodium to investigate the hypothesis that riluzole inhibits HMs by multiple mechanisms. Riluzole (20 M) hyperpolarized HMs by decreasing an inward current, inhibited voltage-gated persistent Na ϩ and Ca 2ϩ currents activated by slow voltage ramps, and negatively shifted activation of the hyperpolarization-activated cationic current (I H ). Repetitive firing of HMs was strongly inhibited by riluzole, which also increased action potential threshold voltage and rheobase and decreased amplitude and maximum rise slope but did not alter the maximal afterhyperpolarization amplitude or decay time constant. HM rheobase was inversely correlated with persistent Na ϩ current density. Glutamatergic synaptic transmission was inhibited by riluzole by both pre-and postsynaptic effects. Riluzole decreased activity-dependent glutamate release, as shown by decreased amplitude of evoked and spontaneous excitatory postsynaptic currents (EPSCs), decreased paired-pulse ratio, and decreased spontaneous, but not miniature, EPSC frequency. However, riluzole also decreased miniature EPSC amplitude and the inward current evoked by local application of glutamate onto HMs, suggesting a reduction of postsynaptic glutamate receptor sensitivity. Riluzole thus has a marked inhibitory effect on HM activity by membrane hyperpolarization, decreasing firing and inhibiting glutamatergic excitation by both preand postsynaptic mechanisms. These results broaden the range of mechanisms controlling motor neuron inhibition by riluzole and are relevant to researchers and clinicians interested in understanding ALS pathogenesis and treatment.

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“…Chemically, riluzole is 2-amino-6-(trifluoromethoxy) benzothiazole, and can easily cross the blood-brain barrier. 110 Riluzole is the only drug currently approved (by the FDA in US, CPMP in Figure 2 The glutamatergic system as a target of novel medications. Glutamate is synthesized in neuron from a-ketoglutarate through the tricarboxylic acid (TCA) cycle.…”

Section: Riluzolementioning

confidence: 99%

Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology

et al. 2004

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Bipolar affective disorder (manic-depressive illness) is a common, severe, chronic, and often life-threatening illness, associated with significant comorbidity. The recognition of the significant morbidity and mortality of patients with bipolar disorder, as well as the growing appreciation that a high percentage of patients respond poorly to existing treatments, has made the task of discovering new therapeutic agents, that are both efficacious and have few side effects increasingly more important. Most recent agents introduced into the pharmacopeia for the treatment of bipolar disorder have been anticonvulsants and atypical antipsychotics. We propose that novel treatments developed specifically for bipolar disorder will arise from (1) understanding more precisely the molecular mechanisms of treatments that are clearly efficacious or (2) developing medications based on the knowledge obtained of the underlying pathophysiology of bipolar disorder. Knowledge with regard to the underlying pathophysiology of bipolar disorder is increasing at a rapid pace, including alterations in intracellular signaling cascades as well as impairments of cellular plasticity and resilience in critical neuronal circuits. We propose that therapeutics designed to enhance cellular plasticity and resilience and that counter maladaptive stress-responsive systems may have considerable utility for the treatment of bipolar disorder. Therapeutic strategies designed to address cellular resilience and plasticity include the regulation of neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and glutamatergic throughput and mitochondrial function. While the task of developing novel medications for bipolar disorder is truly daunting, these and similar approaches will ultimately lead to better medications for the millions who suffer from this devastating illness.

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2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission—II Biochemical properties

Cited by 157 publications

References 52 publications

Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.

Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.

Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole

Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology

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