Simple determination of riluzole in rat brain by high-performance liquid chromatography and spectrophotometric detection

Maltese, Adriana; Maugeri, Francesco; Drago, Filippo; Bucolo, Claudio

doi:10.1016/j.jchromb.2004.11.053

Cited by 24 publications

(14 citation statements)

References 10 publications

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“…The dose of riluzole was established from data obtained from our earlier and other researchers' experiments (Lang-Lazdunski et al, 1999;Nó grádi and Vrbová, 2001;Fehlings, 2001, 2002;Wahl et al, 1993). It has also been reported that 5 mg/kg riluzole administered IP in rats produces a significant riluzole level in the brain (Maltese et al, 2005), suggesting that this dose is able to produce therapeutic effects.…”

Section: Riluzole Treatmentmentioning

confidence: 99%

Increased Survival and Reinnervation of Cervical Motoneurons by Riluzole after Avulsion of the C7 Ventral Root

Pintér

Gloviczki²,

Szabó

et al. 2010

Journal of Neurotrauma

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Although adult motoneurons do not die if their axons are injured at some distance from the cell body, they are unable to survive injury caused by ventral root avulsion. Some of the injured motoneurons can be rescued if the ventral root is re-inserted into the spinal cord. Brachial plexus injuries that involve the complete or partial avulsion of one or more cervical ventral roots can be treated successfully only if satisfactory numbers of motoneurons remain alive following such an injury at the time of reconstructive surgery. Here we investigated the various strategies that could be used to rescue injured rat cervical motoneurons. The seventh cervical ventral root (C7) was avulsed and various therapeutic approaches were applied to induce motoneuronal survival and regeneration. Avulsion of the root without reimplantation resulted in very low numbers of surviving motoneurons (65 AE 8 SEM), while treatment of the injured motoneurons with riluzole resulted in high numbers of surviving motoneurons (637 AE 26 SEM). When the C7 ventral root was reimplanted or a peripheral nerve implant was used to guide the regenerating axons to a muscle, considerable numbers of motoneurons regenerated their axons (211 AE 15 SEM and 274 AE 28 SEM, respectively). Much greater numbers of axons regenerated when reimplantation was followed by riluzole treatment (573 AE 9 SEM). These results show that injured adult motoneurons can be rescued by riluzole treatment, even if they cannot regenerate their axons. Reinnervation of the peripheral targets can also be further improved with riluzole treatment.

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Section: Riluzole Treatmentmentioning

confidence: 99%

Increased Survival and Reinnervation of Cervical Motoneurons by Riluzole after Avulsion of the C7 Ventral Root

Pintér

Gloviczki²,

Szabó

et al. 2010

Journal of Neurotrauma

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“…Riluzole was quantified in blood and brain using an HPLC/UV detection method already described in a previous study (18). Brain concentrations were corrected in order to consider vascular concentrations in the brain, as in previous study (15).…”

Section: High Performance Liquid Chromatographic Analysismentioning

confidence: 99%

Brain and Plasma Riluzole Pharmacokinetics: Effect of Minocycline Combination

et al. 2009

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-Purpose. Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the loss of motorneurons. The only drug approved is riluzole. Minocycline is an antibiotic with numerous neuroprotective properties. riluzole and minocycline were given to an animal model of ALS and had beneficial effect on the disease. The combination was then tested in humans in phase II and phase III studies with less beneficial effects and a faster decline of the disease in the group treated with minocycline. In a previous study, we showed that riluzole is transported out of the brain by the P-glycoprotein at the bloodbrain barrier level. In this work, we tested the hypothesis of a drug-drug interaction between riluzole and minocycline. Methods. We studied in CF1 mice, the plasma and brain pharmacokinetics of riluzole combined or not with minocycline. Results. Our results showed that riluzole pharmacokinetics are not linear with dose, but that brain AUC 0-t increase proportionally with plasma AUC 0-t . At the dose of 10 mg/kg, the brain AUC0-t /plasma AUC0-t ratio was 4.6 in mdr1a (-/-) mice and 2.4 in mdr1a (+/+) mice. The combination of minocycline (170 mg/kg) and riluzole (10 mg/kg) induced a 2 fold increase in the brain AUC0-t of riluzole and induced a neuromuscular toxicity in mice. This effect of minocycline was not found at low concentration (10 mg/kg of minocycline). Conclusions. If our results are confirmed in humans, riluzole brain concentrations could be predicted by plasma concentrations. Furthermore, the combination of high doses of minocycline with riluzole could induce neurological toxicity that lead to deceiving results in ALS clinical studies. Hence, a dose-range of minocycline combined with riluzole should be tested in further clinical studies.

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“…However, in humans, there is a large variability in pharmacokinetic clearance rate (Bruno et al 1997) and in individual peak serum concentration, which ranges up to 1,552 ng/ml, equivalent to 6.6 M (Groeneveld et al 2008); while individuals with high serum levels showed a lower level of muscle fasciculation and cramping, high serum levels do not correlate with slower disease progress or longer survival time (Groeneveld et al 2003(Groeneveld et al , 2008. In addition, levels of riluzole are four-to sixfold higher than plasma/serum levels after oral dosing in mice, rats, and monkeys, and high CNS levels persist for many hours after a single dose of riluzole (Colovic et al 2004;Maltese et al 2005;Martinet et al 1997;Milane et al 2009;Wu et al 2013). This high brain-to-blood concentration ratio is presumably due to the high lipid solubility of riluzole, although there is also evidence that riluzole is a substrate for blood-brain barrier transporters (Milane et al 2007(Milane et al , 2009.…”

mentioning

confidence: 99%

“…Furthermore, pharmacokinetic studies in mice, rats, and monkeys indicate that riluzole concentration in brain tissue is four to six times higher than peak plasma concentration after a single dose of riluzole (Colovic et al 2004;Maltese et al 2005;Martinet et al 1997;Milane et al 2009;Wu et al 2013). In these species, CNS levels of riluzole remain high with a half-life of Ͼ9 h, and repeated dosing causes accumulation of Fig.…”

mentioning

confidence: 99%

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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Simple determination of riluzole in rat brain by high-performance liquid chromatography and spectrophotometric detection

Cited by 24 publications

References 10 publications

Increased Survival and Reinnervation of Cervical Motoneurons by Riluzole after Avulsion of the C7 Ventral Root

Increased Survival and Reinnervation of Cervical Motoneurons by Riluzole after Avulsion of the C7 Ventral Root

Brain and Plasma Riluzole Pharmacokinetics: Effect of Minocycline Combination

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

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