Direct Effects of Riluzole on 5-Hydroxytryptamine (5-HT)3 Receptor–Activated Ion Currents in NCB-20 Neuroblastoma Cells

Abstract

Abstract. The pharmacological action of riluzole, a drug that has been approved as a neuroprotective agent for the treatment of amyotrophic lateral sclerosis, has not yet been established. We examined the effects of riluzole on 5-hydroxytryptamine (5-HT) 3 receptors in NCB-20 neuroblastoma cells using the whole-cell voltage clamp technique combined with a fast drug application method. Co-application of riluzole (1 -300 μM, 5 s) produced a dose-dependent reduction in peak amplitudes and in the rise slope of the currents induced by 2 μM 5-HT. In addition, 5-HT 3 -mediated currents evoked by dopamine, a partial 5-HT 3 -receptor agonist, were inhibited by riluzole co-application. These inhibitory effects were clearly shown at low concentrations of 5-HT. The decay time constants of the receptor desensitization and deactivation were also significantly attenuated by riluzole. G-protein inhibitors (pertussis toxin and guanosine 5'-[β-thio] diphosphate) did not completely block these inhibitory actions of riluzole. These results indicate that riluzole inhibits 5-HT 3 -induced ion currents directly by slowing channel activation in NCB-20 neuroblastoma cells.

Beyond weakness: Characterization of pain, sensory profile and conditioned pain modulation in patients with motor neuron disease: A controlled study

“…In our study, most patients (78.8%) were taking riluzole, a drug thought to act on the excitotoxicity induced by excessive glutamate release and known to increase survival for a few months in ALS patients (Bensimon et al., ). Riluzole also has a putative effect of inhibiting 5′HT‐3 receptors (Kim et al., ). In experimental models of nerve lesions, decreased 5′HT‐3 effects tend to increase DNIC effects, which was not seen here.…”

A Review of the Neural Mechanisms of Action and Clinical Efficiency of Riluzole in Treating Amyotrophic Lateral Sclerosis: What have we Learned in the Last Decade?

“…Rapid application of either agonist to NCB‐20 neuroblastoma cells elicited rapid inward currents which were reduced in amplitude and rise slope by riluzole. The IC 50 for reducing the rise slope of serotonin‐elicited currents was 3.6 μM, and 4.8 μM for dopamine‐elicited currents [106], suggesting that riluzole directly slowed 5HT‐3 channel activation, as blockade of G protein modulation did not alter responses to riluzole. As serotonin acting on 5HT‐3 receptors is thought to promote gut motility [107], functional antagonism of 5HT‐3 receptor responses by riluzole should inhibit gut motility.…”

potencial uso do riluzole no tratamento do câncer

“…As pesquisas in vitro sobre o tratamento de câncer com riluzole foram mais frequentes entre células cancerígenas humanas, em especial: neuroblastoma 5,25,27,62 , melanoma 28,35,39,42,80 e células cancerígenas mamárias 7,33,43,52,61,82,85 .…”

“…O riluzole (6-(trifluoromethoxy)-1,3-benzothiazol-2-amine; C8H5F3N2OS) está entre as novas drogas estudadas para o tratamento de alguns tipos de câncer, sendo classificado como uma droga antiexcitatória neuroprotetora que bloqueia a liberação de glutamato e os efeitos glutamatérgicos nos neurônios do Sistema Nervoso Central (SNC) [5][6][7] .…”

“…Estas evidências demonstram que o riluzole reduz a liberação de glutamato dos terminais nervosos glutamatérgicos, sendo que sua aplicação prolongada no núcleo caudado em SNC aumenta o tamanho da quantidade de glutamato liberado sob a despolarização de potássio através de um processo cálcio dependente, diminuindo a ativação de receptores AMPAR que desencadeam um dano neuronal excitotóxico e, consequentemente, o câncer. [5][6][7][9][10][11]14 Há vários estudos sobre câncer utilizando linhagens celulares, humanas e modelos animais, demonstrando o efeito antitumoral diverso do riluzole 13,17,18 . Contudo, os resultados destas pesquisas estão dispersos em inúmeras publicações dificultando uma identificação completa e abrangente dos avanços do tratamento com riluzole nos inúmeros tipos de cânceres.…”