Riluzole|1744-22-5|安捷凯

Background

Riluzole, a novel glutamate-modulating agent, has neuroprotective effects [1] [2], via a complex mechanism involving inhibition of voltage-dependent Na channels, high-voltage activated Ca and K channels, and inhibition of protein kinase C. It was suggested that this mechanism was involved in antioxidative processes [3]. The IC50 to inhibit inward Na+ currents in primary cultures of rat cortical neurons is 51 μM [4].
Glutamate-mediated impairments were related to neurodegenerative diseases. Reduction of excess central nervous system (CNS) glutamate was the same aim of several treatment strategies [1] [5].
In HEKGLT1, HEKGLAST or HEKEAAC1 cells, riluzole increased Na+-dependent uptake in a dose-dependent manner, with significant effects at concentrations as low as 0.01–0.1 μM and the highest effect at 100 μM. The increase in glutamate uptake induced by 100 μM riluzole was similar in all cell lines (+27% in HEKGLAST, +38% in HEKGLT1, +39% in HEKEAAC1). Higher riluzole concentrations (300 and 1000 μM) were toxic, since at the end of experiments the majority of cells were floating, and specific and non-specific glutamate uptake were reduced by more than 50% [3].
In rat cortical synaptosomes, Na+-dependent L-[3H] glutamate uptake was increased by riluzole (0.1-100μM), a significant 16% increase was found with 100μM riluzole. With 300μM riluzole, no real effect was found on glutamate uptake. Possibly high concentration can lead to toxic effects. Both specific and non-specific glutamate uptakes were markedly reduced (about 50%) by 1 mM riluzole, at this concentration, synaptosomal integrity may be lost [3].
参考文献:
[1]. Christiane Malgouris, Florence Bardot, Marc Daniel, et al. Riluzole, a Novel Antiglutamate, Prevents Memory Loss Hippocampal Neuronal Damage in lschemic Gerbils. The Journal of Neuroscience, 1989, 9(11): 3720-3727.
[2]. Carlos A. Zarate, Jr., Jennifer L. Payne, Jorge Quiroz, et al. An Open-Label Trial of Riluzole in Patients With Treatment-Resistant Major Depression. Am J Psychiatry, 2004, 161:171-174.
[3]. Elena Fumagalli, Marcella Funicello, Thomas Rauen, et al. Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. European Journal of Pharmacology, 2008, 578: 171-176.
[4]. Masanori Ohashi, Akiyoshi Saitoh, Misa Yamada, et al. Riluzole in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice. Psychopharmacology, 2015, 232:391–398.
[5]. M. J. Hudspith. Glutamate: a role in normal brain function, anaesthesia, analgesia and CNS injury. British Journal of Anaesthesia, 1997, 78: 731-747.

Protocol

Cell experiment:

Two-electrode voltage clamp of Xenopus oocytes expressing exogenous GABAA receptors is performed with a CA-1B high performance oocyte clamp. The extracellular recording solution is ND-96 medium. Riluzole is applied from a common tip via a gravity-driven multibarrel drug-delivery system. Data acquisition and analysis are performed with pCLAMP 6 software[1].

Animal experiment:

Adult male Sprague-Dawley rats (180 to 350 g) are housed in a temperature-controlled room and maintained on a 12-h day/night cycle with unrestricted access to food and water. Pain behaviors are measured before and 5 h after induction of a mono-arthritis in the left knee joint. To test the effects of systemic (intraperitoneal, i.p.) application of Riluzole, pain behaviors are measured 1 h postinjection of Riluzole in normal and arthritic animals. To determine effects of Riluzole into the amygdala, pain behaviors are measured 15 min after starting Riluzole application through a stereotaxically implanted microdialysis probe. To investigate site of action in the amygdala of systemically applied Riluzole, potassium channel blockers are administered into the amygdala 45 min after systemic application of Riluzole and pain behaviors are measured 15 min later, i.e., 1 h postinjection of riluzole (i.p.)[2].

参考文献:

[1]. He Y, et al. Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function. Neuropharmacology. 2002 Feb;42(2):199-209.
[2]. Thompson JM, et al. Small-conductance calcium-activated potassium (SK) channels in the amygdala mediate pain-inhibiting effects of clinically available riluzole in a rat model of arthritis pain. Mol Pain. 2015 Aug 28;11:51.

安捷凯在线客服

扫一扫加微信

信号通路

生命科学

有机化学

无机化学

材料科学

Riluzole

Riluzole详情

Background

Protocol

安捷凯在线客服