Organotypic Cultures as Tools for Testing Neuroactive Drugs - Link Between In-Vitro and In-Vivo Experiments
Abstract:The development of neuroactive drugs is a time consuming procedure. Candidate drugs must be run through a battery of tests, including receptor studies and behavioural tests on animals. As a rule, numerous substances with promising properties as assessed in receptor studies must be eliminated from the development pipeline in advanced test phases because of unforeseen problems like intolerable side-effects or unsatisfactory performance in the whole organism. Clearly, test systems of intermediate complexity would alleviate this inefficiency. In this review, we propose cultured organotypic brain slices as model systems that could bridge the ‘interpolation gap’ between receptors and the brain, with a focus on the development of new general anaesthetics with lesser side effects.
General anaesthesia is based on the modulation of neurotransmitter receptors and other conductances located on neurons in diverse brain regions, including cerebral cortex and spinal cord. It is well known that different components of general anaesthesia, e.g. hypnosis and immobility, are produced by the depression of neuronal activity in distinct brain regions. The ventral horn of the spinal cord is an important structure for the induction of immobility. Thus, the potentially immobilizing effects of a newly designed drug can be estimated from its depressant effect on neuronal network activity in cultured spinal slices. A drug's sedative and hypnotic potential can be examined in cortical cultures. Combined with genetically engineered mice, this approach can point to receptor subtypes most relevant to the drug's intended net effect and in return can help in the design of more selective drugs. In conclusion, the use of organotypic cultures permits predictions of neuroactive properties of newly designed drugs on an intermediate level, and should therefore open up avenues for a more creative and economic drug development process.
Keywords: GABA(A) receptor; GABAergic interneurons; Metabotropic GABAB receptors; Organotypic cultures; Pyramidal neurons; allosteric binding site; amnestic; amygdala; anaesthetics; antiepileptic; benzodiazepines; bicuculline; brain stem; cerebellum; cholinergic neurons; cortex; dopaminergic cells; electroencenphalogram (EEG); extrasynaptic sites; hippocampus; human embryo kidney (HEK); immobilizing effects; inhibitory postsynaptic currents; ionotropic GABAA receptors; local field potential (LFP); mivacurium; neocortex; neurotransmitters; phosphorylation; potassium channels; propofol; rocuronium; spinal cord; synchronizing; thalamic axon
Document Type: Research Article
Publication date: December 1, 2010
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