title: Riluzole is a promising pharmacological inhibitor of bilirubin-induced excitotoxicity in the ventral cochlear nucleus.
abstract: OBJECTIVE
  Bilirubin encephalopathy as a result of hyperbilirubinemia is a devastating neurological disorder that occurs mostly in the neonatal period. To date, no effective drug treatment is available. Glutamate-mediated excitotoxicity is likely an important factor causing bilirubin encephalopathy. Thus, drugs suppressing the overrelease of glutamate may protect the brain against bilirubin excitotoxicity. Riluzole is a prescription drug known for its antiglutamatergic function. This study was conducted in the rat's ventral cochlear nucleus, a structure highly sensitive to bilirubin toxicity, to find whether riluzole can be used to inhibit bilirubin toxicity.
  
  
  METHODS
  Electrophysiology changes were detected by perforated patch clamp technique. Calcium imaging using Rhod-2-AM as an indicator was used to study the intracellular calcium. Cell apoptosis and necrosis were measured by PI/Hoechst staining.
  
  
  RESULTS
  In the absence of bilirubin, riluzole effectively decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and suppressed neuronal firing but did not change the amplitude of sEPSC and glutamate-activated currents (I(Glu)). Moreover, riluzole inhibited bilirubin-induced increases in the frequency of sEPSC and neuronal firing. Riluzole could prevent the bilirubin-induced increase in intracellular calcium, mediated by AMPA and NMDA receptors. Furthermore, riluzole significantly reduced bilirubin-induced cell death.
  
  
  CONCLUSIONS
  These data suggest that riluzole can protect neurons in the ventral cochlear nucleus from bilirubin-induced hyperexcitation and excitotoxicity through reducing presynaptic glutamate release.
authors.affiliation: Department of Otorhinolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Han
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Li
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Shi
authors.forename: Ji-Ping
authors.initials: JP
authors.lastname: Wang
authors.forename: Kai-Ming
authors.initials: KM
authors.lastname: Su
authors.forename: Xin-Lu
authors.initials: XL
authors.lastname: Yin
authors.forename: Shan-Kai
authors.initials: SK
authors.lastname: Yin
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001663:Bilirubin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017626:Cochlear Nucleus / Q000187:drug effects* / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D019782:Riluzole / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D019782:Riluzole; D001663:Bilirubin; D002118:Calcium
keywords: Bilirubin; Bilirubin encephalopathy; Excitatory postsynaptic current (EPSC); Excitotoxicity; Riluzole; Spontaneous action potential