Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes

Abstract

We have recently demonstrated that the glutamate transporter activator riluzole paradoxically enhanced glutamate-induced glutamate release from cultured astrocytes. We further showed that both riluzole and the α2δ subunit ligand gabapentin activated descending inhibition in rats by increasing glutamate receptor signaling in the locus coeruleus and hypothesized that these drugs share common mechanisms to enhance glutamate release from astrocytes. In the present study, we examined the effects of riluzole and gabapentin on glutamate uptake and release and glutamate-induced Ca2+ responses in primary cultures of astrocytes. Riluzole and gabapentin facilitated glutamate-induced glutamate release from astrocytes and significantly increased glutamate uptake, the latter being completely blocked by the non-selective glutamate transporter blocker DL-threo-β-benzyloxyaspartic acid (DL-TBOA). Riluzole and gabapentin also enhanced the glutamate-induced increase in intracellular Ca2+ concentrations. Some α2δ subunit ligands, pregabalin and L-isoleucine, enhanced the glutamate-induced Ca2+ response, whereas another, 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA), did not. The enhancement of glutamate-induced intracellular Ca2+ response by riluzole and gabapentin was blocked by the DL-TBOA and an inhibitor of Na+/Ca2+ exchange, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiurea (KB-R7943). Gabapentin’s enhancement of Ca2+ increase was specific to glutamate stimulation, as it was not mimicked with stimulation by ATP. These results suggest that riluzole and gabapentin enhance Na+-glutamate co-transport through glutamate transporters, induce subsequent Ca2+ influx via the reverse mode of Na+/Ca2+ exchange, and thereby facilitate Ca2+-dependent glutamate release by glutamate in astrocytes. The present study also demonstrates a novel target of gabapentinoid action in astrocytes other than α2δ subunits in neurons.

Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms

“…We previously demonstrated that gabapentin increases co-transport of Na + ions and glutamate via glutamate transporters, enhances the glutamate-induced intracellular Ca 2+ response via the reverse mode of Na + -Ca 2+ exchange, and by this mechanism facilitates glutamate release in cultured astrocytes (Yoshizumi et al, 2012a). Although GLT-1 may express in glutamatergic terminals in the LC (Medrano et al, 2013), the current study shows the in vivo relevance of this gabapentin’s action in astrocytes by demonstrating the role of GLT-1 in the gabapentin-induced glutamate increase in the LC.…”

“…We previously demonstrated in cultured astrocytes that gabapentin enhances Na + -glutamate co-transport through glutamate transporters, induces subsequent Ca 2+ influx via the reverse mode of Na + /Ca 2+ exchange, and thereby facilitates Ca 2+ -dependent glutamate release by glutamate (Yoshizumi et al, 2012a). However, the in vivo relevance of this action of gabapentin on astroglial glutamate regulation has not yet been tested in the LC.…”

Riluzole Partially Rescues Age-Associated, but not LPS-Induced, Loss of Glutamate Transporters and Spatial Memory

“…Riluzole (Ril), currently used to treat amyotrophic lateral sclerosis, can significantly enhance glutamate clearance via an increase GLT1 expression and reduction in pre-synaptic release (Yoshizumi et al, 2012). The current study investigated whether Ril could prevent cognitive deficits associated with aging or experimentally-induced chronic neuroinflammation produced by infusion of LPS into the IV th ventricle and also restore the balance of pro- and anti-inflammatory genes and proteins.…”

Using Our Understanding of Stress-Related Effects on Glutamate Neurotransmission to Guide the Development of Novel Treatment Strategies

“…More recent studies suggest much of riluzoles neuroprotective effects could be mediated through the effects on GLT1 expression (Fumagalli et al 2008;Yoshizumi et al 2012). As also described earlier, multiple open label (nonplacebo controlled) clinical studies have found riluzole to be effective in the treatment of MDD, bipolar disorder (BPD), anxiety and obsessive-compulsive disorder (OCD) (Coric et al 2005;Pittenger et al 2008;Sanacora et al 2004).…”