Functional screening of traditional antidepressants with primary cortical neuronal networks grown on multielectrode neurochips.
We optimized the novel technique of multielectrode neurochip recordings for the rapid and efficient screening of neuroactivity. Changes in the spontaneous activity of cultured networks of primary cortical neurons were quantified to evaluate the action of drugs on the firing dynamics of complex network activity. The multiparametric assessment of electrical activity changes caused by psychoactive herbal extracts from Hypericum, Passiflora and Valeriana, and various combinations thereof revealed a receptor-specific and concentration-dependent inhibition of the firing patterns. The spike and burst rates showed significant substance-dependent effects and significant differences in potency. The effects of specific receptor blockades on the inhibitory responses provided evidence that the herbal extracts act on gamma-amino butyric acid (GABA) and serotonin (5-HT) receptors, which are recognized targets of pharmacological antidepressant treatment. A biphasic effect, serotonergic stimulation of activity at low concentrations that is overridden by GABAergic inhibition at higher concentrations, is apparent with Hypericum alone and the triple combination of the extracts. The more potent neuroactivity of the triple combination compared to Hypericum alone and the additive effect of Passiflora and Valeriana suggest a synergy between constituent herbal extracts. The extracts and their combinations affected the set of derived activity parameters in a concomitant manner suggesting that all three constituent extracts and their combinations have largely similar modes of action. This study also demonstrates the sensitivity, selectivity and robustness of neurochip recordings for high content screening of complex mixtures of neuroactive substances and for providing multiparametric information on neuronal activity changes to assess the therapeutic potential of psychoactive substances.
Gramowski
Alexandra
A
Division of Cell Biology and Biosystems Technology, Institute of Biological Sciences, University of Rostock, Albert-Einstein-Strasse, 318059 Rostock, Germany. alexandra.gramowski@uni-rostock.de
Jügelt
Konstantin
K
Stüwe
Simone
S
Schulze
Roland
R
McGregor
Gerard P
GP
Wartenberg-Demand
Andrea
A
Loock
Jan
J
Schröder
Olaf
O
Weiss
Dieter G
DG
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D041743:Herb-Drug Interactions / Q000502:physiology; D020902:Hypericum / Q000737:chemistry; D051379:Mice; D046228:Microarray Analysis / Q000295:instrumentation* / Q000379:methods; D008839:Microelectrodes / Q000592:standards; D009415:Nerve Net / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D029598:Passiflora / Q000737:chemistry; D010936:Plant Extracts / Q000494:pharmacology*; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014632:Valerian / Q000737:chemistry; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000928:Antidepressive Agents; D010936:Plant Extracts; D018079:Receptors, GABA; D011985:Receptors, Serotonin; D012701:Serotonin; D005680:gamma-Aminobutyric Acid