Neuroprotective effects of riluzole: An electrophysiological and histological analysis in an in vitro model of ischemia

Siniscalchi, Antonio; Zona, Cristina; Sancesario, Giuseppe; D'Angelo, Enza; Zeng, Yong Chun; Mercuri, Nicola Biagio; Bernardi, Giorgio

doi:10.1002/(sici)1098-2396(19990601)32:3<147::aid-syn1>3.0.co;2-p

Cited by 22 publications

(6 citation statements)

References 35 publications

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“…Following 3-5 min incubation with trypan blue, the cells in the culture plates are fixed with 4% buffered formaldehyde and counted under a normal light microscope. In each field, the dead and total number of cells is counted and their ratio provides an estimate of percentage cell death [129]. …”

Section: Introductionmentioning

confidence: 99%

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

Woodruff

Thundyil

Tang

et al. 2011

Mol Neurodegeneration

509

367

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Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions.

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Section: Introductionmentioning

confidence: 99%

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

Woodruff

Thundyil

Tang

et al. 2011

Mol Neurodegeneration

509

367

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“…In addition, we have observed that a more evident protection is obtained perfusing the slices with the strictly-related local anesthetic lidocaine. Several studies have suggested that sodium channel blockers have a neuroprotective role in ischemic brain conditions (Obrenovitch, 1998;Probert et al, 1997;Siniscalchi et al, 1998Siniscalchi et al, , 1999Smith and Meldrum, 1995;Taylor and Meldrum, 1995;Weber and Taylor, 1994;Wiard et al, 1995). It is believed that this protection mainly depends on the inhibition of voltage-sensitive sodium channels (Calabresi et al, 2003a,c;Meldrum, 1996;Siniscalchi et al, 1998Siniscalchi et al, , 1999.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, an aggravating cellular damage is also produced by the increased energy demand in the absence of fuelling substrates necessary to eliminate the excess of sodium by the Na + /K + pump. As a matter of fact, many blockers of voltage-sensitive sodium channels have demonstrated neuroprotective properties in situations of energy deprivation (Calabresi et al, 1996;Cheung et al, 1992;Crumrine et al, 1997;Siniscalchi et al, 1998Siniscalchi et al, , 1999. For instance, it has been demonstrated that the sodium channel blocker and local anesthetic lidocaine exhibits neuroprotection in animal models of stroke (Butterworth and Hammon, 2002;Evans et al, 1984Evans et al, , 1989Lei et al, 2001Lei et al, , 2002Lei et al, , 2004Mitchell et al, 1999;Wang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

N‐ethyl lidocaine (QX‐314) protects striatal neurons against ischemia: An in vitro electrophysiological study

Armogida¹,

Giustizieri²,

Zona³

et al. 2009

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In this study, we have investigated the neuroprotective actions of the membrane impermeable, lidocaine analog, N-ethyl lidocaine (QX-314) in the striatum. The effects of this drug were compared with those caused by the strictly-related-compound and sodium channel blocker lidocaine. To address this issue, electrophysiological recordings were performed in striatal slices, in control condition (normoxia) and during combined oxygen and glucose deprivation (in vitro ischemia). Either QX-314 or lidocaine induced, to some extent, a protection of the permanent electrophysiological alteration (field potential loss) caused by a period (12 min) of ischemia. Thus, both compounds permitted a partial recovery of the ischemic depression of the corticostriatal transmission and reduced the amplitude of the ischemic depolarization in medium spiny neurons. However, while QX-314, at the effective concentration of 100 microM, slightly reduced the amplitude of the excitatory field potential and did not affect the current-evoked spikes discharge of medium spiny striatal neurons, equimolar lidocaine depressed the field potential and eliminated repetitive spikes on a depolarizing step. On the basis of these observations, our results suggest the use of QX-314 as a neuroprotective agent in ischemic brain disorders.

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“…Riluzole is also able to stimulate the large-conductance calcium-activated potassium channels in rat pituitary GH3 cells, to block in vitro the effects of NMDA and kainate in the rat striatum (Keita et al, 1997), and to exert neuroprotective properties in a model of ischemia (Siniscalchi et al, 1999). It has been also demonstrated that glutamatergic transmission pre-and postsynaptically is altered by riluzole (Cheramy et al, 1992;Hubert and Doble, 1989), although radioligand binding studies have not demonstrated that riluzole interacts directly with the glutamate receptors (Benavides et al, 1985;Debono et al, 1993;Koek and Woods, 1988).…”

Section: Discussionmentioning

confidence: 99%

Kainate‐induced currents in rat cortical neurons in culture are modulated by riluzole

Zona

Cavalcanti

Sarro

et al. 2002

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The action of the neuroprotective and anticonvulsant agent riluzole on kainate-induced currents was studied in rat cortical neurons in primary culture by using the whole-cell configuration of the patch-clamp technique. Kainate elicited macroscopic, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive inward currents in all the patched cells and the amplitude of the current was concentration-dependent (EC50= 106 microM). Riluzole decreased the inward currents induced by 100 microM kainate at all holding potentials and the reduction was dose-dependent (IC50= 101 microM). The maximal response to kainate decreased in the presence of 50 microM riluzole, without changing its EC50, indicating a noncompetitive mechanism of inhibition. The amplitude of the responses induced by kainate under control conditions and during riluzole was a linear function of the membrane potential and the reversal potential of the currents was not significantly different in the two experimental conditions. Instead, the total conductance of the cell membrane for the currents induced by 100 microM kainate was significantly reduced in the presence of 50 microM riluzole (P < 0.05). The analysis of the kainate membrane current noise performed under control conditions and during perfusion of 100 microM riluzole revealed that riluzole reduced the probability of kainate-activated ionic channels to be in the open state. Conversely, the unitary conductance of channels, as well as their characteristic time constant, seemed to be unchanged. These results reveal an additional mechanism by which riluzole can interact with glutamatergic neurotransmission and provides further support for the idea that riluzole may prove beneficial in the treatment of central nervous system injuries involving the excitotoxic actions of glutamate.

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Neuroprotective effects of riluzole: An electrophysiological and histological analysis in an in vitro model of ischemia

Cited by 22 publications

References 35 publications

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

N‐ethyl lidocaine (QX‐314) protects striatal neurons against ischemia: An in vitro electrophysiological study

Kainate‐induced currents in rat cortical neurons in culture are modulated by riluzole

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