title: An in vitro model for testing drugs to treat tinnitus.
abstract: Tinnitus affects approximately 50 million people in the USA alone, with 10 million being highly debilitated. Pharmacotherapy for tinnitus is still in emerging stages due to time consuming clinical trials and/or animal experiments. We tested a new cellular model where induced rapid neuronal firing or spiking was used as a mimic for the type of aberrant activity that may occur in tinnitus. Spontaneously active auditory cortical networks growing on microelectrode arrays were exposed to pentylenetetrazol (PTZ), a proconvulsant and an antagonist of GABA(A) receptor, which is implicated in tinnitus. Auditory cortical networks were then exposed to experimental tinnitus drugs linopirdine (Dup966, a potassium channel blocker), L-carnitine (an antioxidant), or selective Ca(2+) channel antagonists pregabalin (Lyrica), or gabapentin (Neurontin) at various concentrations. PTZ increased spike rate by 139.6±27% and burst rate by 129.7±28% in auditory cortical networks with a phenotypic high firing of excitable neurons. Reductions of increased activity were observed to varying degrees using the experimental tinnitus drugs. The potency of the drugs was linopirdine (EC(50): 176±7.0 μM)>L-carnitine (EC(50): 1569±41 μM)>pregabalin (EC(50): 8360±340 μM), >gabapentin, with 34.2±7.5% efficacy (EC(50): 2092±980 μM). These studies provide proof of principle for the use of auditory cortical networks on microelectrode array as a feasible platform for semi-high throughput application for screening of drugs that might be used for the treatment of tinnitus.
authors: Department of Biology, University of North Texas, Denton, TX 76203, USA.
authors: Calvin
authors: C
authors: Wu
authors: Kamakshi
authors: K
authors: Gopal
authors: Guenter W
authors: GW
authors: Gross
authors: Thomas J
authors: TJ
authors: Lukas
authors: Ernest J
authors: EJ
authors: Moore
mesh_terms: D000588:Amines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D002331:Carnitine / Q000494:pharmacology / Q000627:therapeutic use; D003292:Convulsants / Q000494:pharmacology / Q000627:therapeutic use; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000077206:Gabapentin; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010433:Pentylenetetrazole / Q000494:pharmacology / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000069583:Pregabalin; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D014012:Tinnitus / Q000188:drug therapy* / Q000473:pathology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000588:Amines; D000975:Antioxidants; D002121:Calcium Channel Blockers; D003292:Convulsants; D003509:Cyclohexanecarboxylic Acids; D007211:Indoles; D026902:Potassium Channel Blockers; D011725:Pyridines; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C061017:linopirdine; D002331:Carnitine; D010433:Pentylenetetrazole