Effects Of Riluzole Research Articles

Riluzole and amyotrophic lateral sclerosis survival: a population‐based study in southern Italy

Riluzole is to date the only treatment that prolongs amyotrophic lateral sclerosis (ALS) survival. However, results on the efficacy of riluzole in observational population-based studies with a longer follow-up are conflicting and it is still unclear if the effect of the drug is limited to an early stage of the disease and to some specific subgroups of patients. The objective is: (i) to evaluate the effect of riluzole on ALS survival in a cohort of incident cases; (ii) to examine whether bulbar-ALS benefits from the medication to a greater extent and (iii) to assess the efficacy of the drug in elderly patients. Source of the study was a prospective population-based registry of ALS established in Puglia, Southern Italy. We examined survival of 126/130 incident ALS cases diagnosed during the period 1998-1999. Seventy-three patients were prescribed riluzole and the remaining 53 were not. Riluzole therapy increased survival rates at 12 months by approximately 10% and prolonged survival by 6 months (18.2 months vs. 12.4; peto-test: 2.78; P = 0.09). This beneficial effect was present amongst bulbar-onset ALS (peto-test: 4.11; P = 0.042), but not in subjects with limb-onset (peto-test: 0.48; P = 0.4). In patients aged >70 years riluzole treatment was associated with an 8 months longer median survival time [15.4 months vs. 7.1] and a reduction in mortality rate at 12 months by 27%, regardless of site of symptoms onset. In multivariate analysis, riluzole use was an independent predictor of survival at 12 months from the diagnosis with borderline significance (P = 0.06). Riluzole was effective amongst cases with bulbar-onset ALS (P = 0.04), whereas in subjects with limb-onset there was no effect on survival at 12 months (P = 0.5). In each model riluzole did not influence survival at 24 months. Conversely, riluzole use was associated with an improvement in survival amongst elderly patients both at 12 (P = 0.07), at 24 months (P = 0.03) and in the entire follow-up period (P < 0.04). In this population-based series, we found that riluzole therapy improves ALS survival. The efficacy of the drug was present amongst bulbar-onset ALS and older patients, but not in subjects with limb-onset. The favourable effect of the drug was transient, as it was lost in prolonged follow-up. Our observations support the use of riluzole at an early stage of ALS in bulbar and elderly patients. However, the appropriate duration of riluzole treatment remains to be established.

Effects of riluzole and flufenamic acid on eupnea and gasping of neonatal mice in vivo

The pre-Bötzinger complex (PBC), part of the ventral respiratory group that is responsible for inspiratory rhythm generation, contains at least two types of pacemaker neurons. In vitro studies have shown that bursting properties of one type of pacemaker relies on a riluzole-sensitive persistent sodium current, whereas bursting of a second type is sensitive to flufenamic acid (FFA), a calcium-dependent nonspecific cationic current blocker. In vitro, under control conditions, the PBC generates fictive eupneic activity that depends on both riluzole-sensitive and FFA-sensitive pacemaker neurons. During hypoxia the PBC generates fictive gasping activity and only riluzole-sensitive pacemaker neurons appear to be necessary for this rhythm. We carried out pharmacological experiments to test the role of respiratory pacemaker neurons in vivo by performing plethysmographic recordings on neonate mice. As reported in vitro, eupnea activity in vivo is abolished only if both FFA and riluzole are coadministered intracisternally, but not when either of them is administered independently. On the other hand riluzole, but not FFA, drastically reduced gasping generation and compromised the ability of mice to autoresucitate. Neither substance P nor forskolin was able to reestablish respiratory activity after riluzole and FFA coapplication. Our results confirm in vitro reports and suggest that eupnea generation in neonates requires a complex neuronal network that includes riluzole- and FFA-sensitive elements and that gasping activity depends mostly on a riluzole-sensitive mechanism.

The Whisking Rhythm Generator: A Novel Mammalian Network for the Generation of Movement

Using the rat vibrissa system, we provide evidence for a novel mechanism for the generation of movement. Like other central pattern generators (CPGs) that underlie many movements, the rhythm generator for whisking can operate without cortical inputs or sensory feedback. However, unlike conventional mammalian CPGs, vibrissa motoneurons (vMNs) actively participate in the rhythmogenesis by converting tonic serotonergic inputs into the patterned motor output responsible for movement of the vibrissae. We find that, in vitro, a serotonin receptor agonist, alpha-Me-5HT, facilitates a persistent inward current (PIC) and evokes rhythmic firing in vMNs. Within each motoneuron, increasing the concentration of alpha-Me-5HT significantly increases the both the magnitude of the PIC and the motoneuron's firing rate. Riluzole, which selectively suppresses the Na(+) component of PICs at low concentrations, causes a reduction in both of these phenomena. The magnitude of this reduction is directly correlated with the concentration of riluzole. The joint effects of riluzole on PIC magnitude and firing rate in vMNs suggest that the two are causally related. In vivo we find that the tonic activity of putative serotonergic premotoneurons is positively correlated with the frequency of whisking evoked by cortical stimulation. Taken together, these results support the hypothesized novel mammalian mechanism for movement generation in the vibrissa motor system where vMNs actively participate in the rhythmogenesis in response to tonic drive from serotonergic premotoneurons.

Comparison of the Anti-Arrhythmic Effects of Lidocaine and Riluzole Immediately Post-Coronary Artery Occlusion in Pigs

Comparison of the Anti-Arrhythmic Effects of Lidocaine and Riluzole Immediately Post-Coronary Artery Occlusion in Pigs

Preliminary Evidence of Riluzole Efficacy in Antidepressant-Treated Patients with Residual Depressive Symptoms

Excessive glutamatergic neurotransmission may contribute to the pathophysiology of major depressive disorder (MDD). Recent evidence suggests that riluzole and other agents that target glutamate neurotransmission may show antidepressant activity. Ten patients with treatment-resistant depression had riluzole added to their ongoing medication regimen for 6 weeks, followed by an optional 6-week continuation phase. Depression and anxiety severity were assessed using the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). Linear mixed models were used to test for a linear trend in HDRS and HARS scores across time with treatment. Subjects' HDRS and HARS scores declined significantly following the initiation of riluzole augmentation therapy. The effect of riluzole was significant at the end of the first week of treatment and persisted for the 12-week duration of the study. These data suggest that riluzole augmentation produces antidepressant and anxiolytic effects in patients with treatment-resistant depression.

A comparison of the glutamate release inhibition and anti‐allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain

The effects of treatment with the anti-convulsant agents, lamotrigine and riluzole were compared with gabapentin in a rat experimental model of neuropathic pain. Rats were treated intraperitoneally, with gabapentin (30, 100 and 300 mg/kg), lamotrigine (2, 10 and 50 mg/kg) or riluzole (6 and 12 mg/kg) prior to, and every 12 h for 4 days following chronic constriction injury (CCI) of the sciatic nerve. Mechanical and cold sensitivity were assessed prior to surgery (baseline) and then at 4, 8 and 12 days following CCI. The four-day treatment with each of the agents was effective at producing reductions in the development of mechanical and cold hypersensitivity for periods ranging from the fourth to 12th day. The highest doses of each of the agents were also assessed on formalin-induced nociceptive behaviors and on formalin-induced increases in extracellular glutamate (Glu) and aspartate (Asp) in the spinal cord dorsal horn (SCDH) of awake behaving rats using in vivo microdialysis. Nociceptive scores in formalin test were significantly decreased by gabapentin (300 mg/kg i.p.) and riluzole (12 mg/kg i.p.), but not by lamotrigine (50 mg/kg i.p.). Formalin-induced increases in glutamate levels in SCDH were lowered significantly, as compared with the controls, with all drugs both in the first phase and second phases, with the greatest effects for riluzole and gabapentin. Similar suppressive effects of the drugs were observed on formalin-induced increases in spinal aspartate, except that gabapentin and lamotrigine produced effects only during the second phase. Riluzole produced profound and prolonged reductions in the spinal levels of glutamate and aspartate both for basal and formalin-stimulated release. In conclusion, the results suggest that the anti-convulsant agents gabapentin, lamotrigine and riluzole may reduce the development of hyperalgesia in a rat model of neuropathic pain by reducing the spinal release of glutamate. Riluzole's pronounced suppressive effects on spinal EAA levels is attributed to its established role as a glutamate release inhibitor and an enhancer of glutamate transporter activity.

Placebo‐controlled trial of riluzole in multiple system atrophy

We performed a placebo-controlled cross-over trial of riluzole (100 mg b.i.d.) in 10 patients with probable multiple system atrophy (MSA) administering riluzole and placebo for 4 weeks each with a 4-week washout period. Outcome measures evaluated short-term anti-Parkinsonian effects using the Unified Parkinson's Disease Rating Scale (UPDRS) subscales (UPDRS-II, activities of daily living; UPDRS-III, motor examination; sum of UPDRS-II and -III) before and at the end of each treatment phase. Delta values were calculated by subtracting the UPDRS scores measured at the end of each treatment arm from those before onset of each medication phase. Riluzole was generally well tolerated. There were no significant anti-Parkinsonian effects of riluzole comparing the UPDRS delta values for both treatment arms using the Wilcoxon signed-rank test. It is unlikely that riluzole treatment could have clinically meaningful anti-Parkinsonian effects in MSA. A trial assessing the disease-modifying potential of riluzole in MSA is underway.

Effect of Riluzole on Ca2+ Movement and Cytotoxicity in Madin-Darby Canine Kidney Cells

Riluzole is a drug used in the treatment of amyotrophic lateral sclerosis; however, its in vitro action is unclear. In this study, the effect of riluzole on intracellular Ca2+ concentration ([Ca2+]i) in Madin-Darby canine kidney (MDCK) cells was investigated using the Ca2+ -sensitive fluorescent dye, fura-2. Riluzole (100-500 microM) caused a rapid and sustained increase of [Ca2+]i in a concentration-dependent manner (EC50 = 150 microM). Some 40 and 50% of this [Ca2+]i increase was prevented by the removal of extracellular Ca2+ and the addition of La3+, respectively, but was unchanged by dihydropyridines, verapamil and diltiazem. In Ca2+ -free medium, thapsigargin - an inhibitor of the endoplasmic reticulum (ER) Caz+ -ATPase--caused a monophasic [Ca2+]i increase, after which the increasing effect of riluzole on [Ca2+]i was attenuated by 70%; in addition, pre-treatment with riluzole abolished thapsigargin-induced [Ca2+]i increases. U73122, an inhibitor of phospholipase C (PLC), abolished ATP (but not riluzole)-induced [Ca2+]i increases. At concentrations of 250 and 500 microM, riluzole killed 40 and 95% cells, respectively. The cytotoxic effect of riluzole (250 microM) was unaltered by pre-chelating cytosolic Ca2+ with BAPTA. Collectively, in MDCK cells, riluzole rapidly increased [Ca2+]i by stimulating extracellular Ca2+ influx via an La3+ -sensitive pathway and intracellular Ca2+ release from the ER via, as yet, unidentified mechanisms. Furthermore, riluzole caused Ca2+ -unrelated cytotoxicity in a concentration-dependent manner.

Essential role of the persistent sodium current in spike initiation during slowly rising inputs in mouse spinal neurones

Spinal motoneurons, like many neurons, respond with repetitive spiking to sustained inputs. The afterhyperpolarization (AHP) that follows each spike, however, decays relatively slowly in motoneurons. The slow depolarization during this decay should allow sodium (Na+) channel inactivation to keep up with its activation and thus should prevent initiation of the next spike. We hypothesized that the persistent component of the total Na+ current provides the mechanism that generates a rate of rise sufficiently rapid to generate a spike. In large cultured spinal neurons, presumed to be primarily motoneurons, inhibition of persistent sodium current (NaP) by the drug riluzole at low concentrations resulted in a loss of repetitive firing. However, cells remained fully capable of producing spikes to transient inputs. These effects of riluzole were not due to insufficient depolarization, enhancement of the AHP, or sustained Na+ channel inactivation. To further test this hypothesis, computer simulations were performed with a kinetic Na+ channel model that provided greater independent control of NaP relative to transient Na+ current (NaT) than that provided by riluzole administration. The model was tuned to generate substantial NaP and exhibited good repetitive firing to slowly rising inputs. When NaP was sharply reduced without significantly altering NaT, the model reproduced the effects of riluzole administration, inducing failure of repetitive firing but allowing single spikes in response to sharp transients. These results strongly support the essential role of NaP in spike initiation to slow inputs in spinal neurons. NaP may play a fundamental role in determining how a neuron responds to sustained inputs.

Interaction of Riluzole with the Closed Inactivated State of Kv4.3 Channels

The effect of riluzole on Kv4.3 was examined using the whole-cell patch-clamp technique. Riluzole inhibited the peak amplitude of Kv4.3 in a reversible, concentration-dependent manner with an IC(50) of 115.6 microM. Under control conditions, a good fit for the inactivation of Kv4.3 currents to a double exponential function, with the time constants of the fast component (tau(f)) and the slow component (tau(s)), was obtained. tau(f) was not altered by riluzole at concentrations up to 100 microM, but tau(s) became slower with increasing riluzole concentration, resulting in the crossover of the currents. The inhibition increased steeply with increasing channel activation at more positive potentials. In the full activation voltage range positive to (+)30 mV, however, no voltage-dependent inhibition was found. Riluzole shifted the voltage dependence of the steady-state inactivation of Kv4.3 in the hyperpolarizing direction in a concentration-dependent manner. However, the slope factor was not affected by riluzole. The K(i) for riluzole for interacting with the inactivated state of Kv4.3 was estimated from the concentration-dependent shift in the steady-state inactivation curve and was determined to be 1.2 muM. Under control conditions, closed state inactivation was fitted to a single exponential function. Riluzole caused a substantial acceleration in the closed state inactivation. In the presence of riluzole, the recovery from inactivation was slower than under control conditions. Riluzole induced a significant use-dependent inhibition of Kv4.3. These results suggest that riluzole inhibits Kv4.3 by binding to the closed inactivated state of the channels and that the unbinding of riluzole occurs from the closed state during depolarization.

Neuroprotective agents: is effective on toxicity in glial cells?

1. Glial cells are the most abundant cell population in the central nervous system. The aim of this study was to examine the effects of melatonin, 7-nitroindazole, and riluzole on glutamate toxicity in primary glial cell culture. 2. Glutamate toxicity was induced by addition of 100 microM glutamate to the cultures, and then 100 microM melatonin, 500 microM 7-nitroindazole, and 10 (M riluzole were administered in different groups. Lactate Dehydrogenase activity and nitrite levels were determined at the 1st, 6th, and 24th h. 3. Melatonin, 7-nitroindazole, and riluzole decrease Lactate Dehydrogenase activity at the 1st, 6th, and 24th h (at all hours, p<0.05). Nitrite levels were decreased by melatonin and riluzole at the 1st, 6th, and 24th h. 4. In this study, we observed that melatonin, 7-nitroindazole, and riluzole are effective as protective agents on glutamate toxicity in mixed glial cells.

Delayed amnesic syndrome after riluzole autointoxication in Huntington disease

No treatment has been shown effective in slowing Huntington disease (HD). However, the anti-glutamatergic agent riluzole has been shown to reduce chorea.1,2 Therefore, trials have been performed to study the effect of riluzole on progression of HD. In the European Huntington’s Disease Initiative (EHDI) trial, patients were treated with 50 mg of riluzole (or placebo) BID. Side effects included general asthenia, nausea, and elevated serum transaminase levels. Less frequently, abdominal discomfort, dizziness, headaches, acute hepatitis, and neutropenia were noted.1,3 Little is known about the effects of riluzole overdose; both methemoglobinemia and an amnesic syndrome have been reported only once each.4,5 We present a woman who developed an amnesic syndrome 4 days after ingestion of 3 g of riluzole. A 44-year-old woman who had been diagnosed with HD in 2000 presented at the emergency room in March 2003 after ingestion of 60 tablets of study medication (riluzole, after …

Specific regulation of rat glial cell line‐derived neurotrophic factor gene expression by riluzole in C6 glioma cells

Contrasting with its robust expression during embryogenesis, the glial cell line-derived neurotrophic factor (GDNF) is repressed in the adult organism. However, rapid induction of this neuronal growth factor is observed following diverse neuronal insults and it is now widely accepted that the control of its expression could constitute a powerful target in neuropharmacology. We investigated the effects of the neuroprotective drug, riluzole, on the GDNF gene expression in glial cells. Exposure of C6 glioma cells to riluzole (1 microM) significantly increased GDNF protein and mRNA levels. Using luciferase reporter gene constructs encoding fragments of the 5' untranslated region of the rat GDNF gene, we demonstrated that riluzole mediates its effect at the transcription level. Furthermore, luciferase assays revealed the presence of a negative regulatory region within the +343/+587 region of exon 1. This region was shown to contribute to the high sensitivity and specificity of the induction mediated by riluzole in the C6 glioma cell line at pharmacologically relevant concentrations. The effects of riluzole were inhibited by the mitogen-activated protein kinase extracellular signal-related kinase (MEK) inhibitor PD 98059. Together, these results indicated that the induction of GDNF release by riluzole in the C6 glioma cells results from the activation of its corresponding gene promoter through a signalling pathway involving MEK activity. This study suggests that the regulation of GDNF gene transcription in glial cells could contribute to the pharmacological properties of riluzole and possibly other neuroprotective drugs.

Riluzole, unlike the AMPA antagonist RPR119990, reduces motor impairment and partially prevents motoneuron death in the wobbler mouse, a model of neurodegenerative disease

The wobbler mouse is one of the most useful models of motoneuron degeneration, characterized by selective motoneuronal death in the cervical spinal cord. We carried out two parallel studies in wobbler mice, comparing the anti-glutamatergic drug riluzole and the AMPA receptor antagonist RPR119990. Mice were treated with 40 mg/kg/day of riluzole or with 3 mg/kg/day of RPR119990 from the 4th to the 12th week of age. Here, we show that chronic treatment with riluzole improves motor behavior, prevents biceps muscle atrophy and decreases the amount of motoneuron loss in treated wobbler mice. Chronic treatment with the AMPA antagonist RPR119990 is ineffective in improving motor impairment, in reducing motoneuronal loss and muscular atrophy in treated mice. These results, together with the unchanged immunostaining for the AMPA receptor subunit GluR2 in wobbler mice, suggest that AMPA receptor-mediated injury is unlikely to be involved in neurodegeneration in wobbler disease, and that the protective effect of riluzole in wobbler mice seems to be independent of its anti-glutamatergic activity, as suggested in other models of neurodegeneration. Immunostaining of cervical spinal cord sections shows that in riluzole-treated wobbler mice BDNF expression is significantly increased in motoneurons with no changes in the high-affinity receptor Trk-B. Our data confirm that riluzole has beneficial effects in wobbler mice, and suggest that these effects could be associated to the increased levels of the neurotrophic and neuroprotective factor BDNF.

The glutamate release inhibitor riluzole attenuates the formation of conditioned place aversion induced by naloxone in rats undergoing a single morphine exposure

Acute morphine exposure has been hypothesized to produce long-lasting central changes that contribute to the withdrawal aversion. We have most recently demonstrated that those changes may involve the glutamatergic system, including multiple classes of receptors. The present study was undertaken to further determine the involvement of the glutamatergic system by examining the effect of riluzole, a glutamate release inhibitor, on the motivational component of withdrawal from acute morphine dependence. The role of the amygdala in the action of riluzole was also assessed. We investigated the effects of riluzole on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal from a single morphine exposure 24 h before, and on c-Fos expression within the amygdala during the withdrawal period in rats. Riluzole (2, 4, 8 mg/kg) dose-dependently attenuated the CPA without producing place conditioning itself. This result provided further evidence that glutamatergic mechanisms may be recruited in adaptational changes following acute morphine exposure and play a role in withdrawal aversion. In addition, riluzole appeared to produce nonspecific effects on c-Fos expression by itself, without specifically modifying c-Fos expression following naloxone-precipitated withdrawal in any region of the amygdala examined, suggesting that the amygdala may not serve as a specific site of action for riluzole.

Riluzole Inhibits VEGF-Induced Endothelial Cell Proliferation In Vitro and Hyperoxia-Induced Abnormal Vessel Formation In Vivo

The present study examined the effects of riluzole, a Food and Drug Administration-approved drug for amyotrophic lateral sclerosis, on VEGF-stimulated endothelial cell proliferation in culture, and on neovascularization in a rat model of retinopathy of prematurity (ROP). Human umbilical vein endothelial cell and bovine retinal endothelial cell cultures were treated with VEGF to induce endothelial cell proliferation in the presence or absence of riluzole. Activation of PKC betaII was examined by quantifying its phosphorylated form on immunoblots. ROP was induced in 5-day-old rat pups by raising them in hyperoxic conditions for 7 days and in normoxic conditions for the next 5 days. Dextran fluorescence retinal angiography was used to quantitatively assess ROP. Riluzole inhibited VEGF-stimulated PKC betaII activation and cell proliferation in bovine retinal endothelial cell and human umbilical vein endothelial cell cultures. In addition, systemic administration of riluzole substantially ameliorated abnormal new vessel formation in the rat ROP model. The present results suggest that riluzole is a potent inhibitor of VEGF-induced endothelial cell proliferation both in vivo and in vitro. Since long-term use of riluzole has already been proven safe in humans, the present data indicate that clinical trials of riluzole for proliferative retinopathies should be implemented expeditiously.

Alpha-Linolenic acid and riluzole treatment confer cerebral protection and improve survival after focal brain ischemia

We investigated here the effects of alpha-linolenic acid and riluzole, both activators of the 2P-domain K+ channel family TREK/TRAAK, in a model of focal ischemia clinically relevant to stroke, not only assessing neuronal protection, but also long term survival. Moreover, all the drug treatments were initiated post-ischemia.Mice were subjected to transient middle cerebral artery occlusion (1 h) and reperfusion according to the intraluminal filament model. Drugs were injected into the jugular vein according to three protocols: (i) a single dose of 4mg/kg riluzole or 500nmol/kg alpha-linolenic acid at different reperfusion time; (ii) a three-day therapy (a single dose of 2mg/kg riluzole and 250nmol/kg alpha-linolenic acid given 1–2, 48 and 72 h after reperfusion); (iii) a three-week therapy (a single dose of 2mg/kg riluzole and 250nmol/kg alpha-linolenic acid given once a week during three weeks after reperfusion. A combined treatment with 2mg/kg riluzole+250nmol/kg alpha-linolenic acid injected 2 h after reperfusion was also tested.A single dose of riluzole (4mg/kg) or alpha-linolenic acid (500nmol/kg) injected up to 3 h after reperfusion reduced drastically the stroke volume by 75% and 86%, respectively. Neurological deficits 24 h after ischemia were significantly improved by alpha-linolenic acid500 or riluzole4 with a neurological score of 1.8 as compared with 2.5 observed in vehicle-treated mice. Alpha-linolenic acid- and riluzole treatment were associated with a reduction in cytopathological features of cell injury, including DNA fragmentation and Bax expression in the cortex and the caudate putamen. With regard to the survival rate at 30 days, the best protections were obtained with the alpha-linolenic acid-injection in the three-week therapy as well as with a single dose of the combined treatment (2mg/kg riluzole+250nmol/kg alpha-linolenic acid). Palmitic acid, a saturated fatty acid that does not activate the 2P-domain K-channel TREK/TRAAK family, did not provide any neuroprotection.Taken together, these data suggest that the TREK/TRAAK K-channel family may be a promising target for neuroprotection, and that riluzole and alpha-linolenic acid could be of therapeutic value against focal ischemia/reperfusion injury to the brain.

European-Huntington-Disease-Initiative (EHDI)-Study: Effect of riluzole on disease progression

Riluzole has been shown to modify disease progression in amyotrophic lateral sclerosis (ALS) resulting in improved survival rates compared to controls.

Suppression of abnormally increased excitability of monosynaptic spinal reflex arcs by riluzole

We studied the effects of a neuroprotector, riluzole, on the evoked mass activity of spinal neuronal mechanisms and on action potentials (APs) recorded from the sciatic nerve in intact rats and rats with the manifestations of postdenervational and 4-aminopyridine (4-AP)-induced hyperreflexia, as well as in animals in the superreflexia state (induced by combined action of denervation and 4-AP). We measured the parameters of monosynaptic reflex discharges (monosynaptic reflexes, MRs) recorded from the ventral root (VR), of the spinal dorsal surface potential (DSPs), and of mass APs evoked in afferent and efferent fibers of the SN before and 10, 30, 60, and 120 min after injection of riluzole. It was found that in intact animals riluzole significantly (by 60–70%) decreased the amplitude of VR MRs and those of the afferent peak and N1 component of DSPs. Riluzole exerted smaller suppressive effects on mass APs in the afferent fibers of the SN; the effect on APs in the SN efferent fibers was the minimum (a 4 to 5% decrease). Under conditions of increased sensitivity of the motoneuronal postsynaptic membrane to the transmitter (postdenervational hyperreflexia) and an increased release of glutamate from presynaptic elements (4-AP-induced hyperreflexia), as well as under superreflexia conditions, the dynamics of suppression of the evoked spinal activity by riluzole showed relatively moderate differences from those in intact animals. Under the above conditions, riluzole in the same manner decreased the amplitude of VR MRs. In the superreflexia state, the agent blocked the development of additional components of these dramatically increased potentials (in the above state, their amplitude increased by nearly nine times, on average, and this resulted in the generation of such components). We believe that the inhibitory effect of riluzole on glutamatergic neurotransmission in the spinal cord is based, first of all, on blocking of excitation in afferent presynaptic terminals. The possibility to use riluzole for correction of abnormally increased hyperexcitability of the spinal neuronal systems is discussed.

Neuroprotective effect of riluzole in acute noise-induced hearing loss

Riluzole has been reported to protect against the deleterious effect of cerebral ischemia by blocking glutamatergic neurotransmission. Here, we investigated whether acoustic trauma-induced cochlear excitotoxicity could be attenuated by riluzole. Cumulative intracochlear perfusion of riluzole completely abolished single-nerve fiber activity in the guinea pig cochlea and the compound action potential of the auditory nerve. Guinea pigs treated with riluzole (100 microM) showed significantly less hearing threshold shift than untreated guinea pigs, and presented no sign of dendritic damage in the cochlea observable by electron microscopy. When coapplied with glutamate, riluzole did not prevent glutamate-induced swelling of auditory nerve dendrites, suggesting that the protective effect of riluzole was mediated principally by inhibition of glutamate release from sensory inner hair cells.