Acute neuropharmacologic action of chloroquine on cortical neurons in vitro

Chloroquine, a common quinolone derivative used in the treatment of malaria, has been associated with neurologic side-effects including depression, psychosis and delirium. The neuropharmacologic effects of chloroquine were examined on cultured cortical neurons using microelectrode array (MEA) recording and the whole-cell patch clamp technique. Whole-cell patch clamp records under current-clamp mode also showed a chloroquine-induced depression of the firing rate of spontaneous action potentials by approximately 40%, consistent with the observations with the MEA recording, although no changes in either the baseline membrane potential or input resistance were observed. Voltage clamp recordings of spontaneous post-synaptic currents, recorded in the presence of tetrodotoxin, revealed no obvious changes in either the amplitude or rate of occurrence of inward currents with application of chloroquine at 10 microM, suggesting that the fundamental molecular mechanisms underlying spontaneous synaptic transmission may not be affected by acute application of the drug. In contrast, a concentration-dependent inhibition of whole-cell calcium current was observed in the presence of chloroquine. These acute neuropharmacologic changes were not accompanied by cytotoxic actions of the compound, even after exposure of up to 500 microM chloroquine for 7 h. These data suggest that chloroquine can depress in vitro neuronal activity, perhaps through inhibition of membrane calcium channels.

[1]  I. Gluzman,et al.  Antimalarials increase vesicle pH in Plasmodium falciparum , 1985, The Journal of cell biology.

[2]  H. Baba,et al.  Muscarinic facilitation of GABA release in substantia gelatinosa of the rat spinal dorsal horn , 1998, The Journal of physiology.

[3]  M. Milone,et al.  Effects of the quinoline derivatives quinine, quinidine, and chloroquine on neuromuscular transmission , 1996, Brain Research.

[4]  F. Riesen,et al.  Neurotoxic effects of chloroquine in vitro , 2005, Archives of Toxicology.

[5]  D. Stenger,et al.  Development and Application of Cell-Based Biosensors , 1999, Annals of Biomedical Engineering.

[6]  R. Wightman,et al.  Amine Weak Bases Disrupt Vesicular Storage and Promote Exocytosis in Chromaffin Cells , 1999, Journal of neurochemistry.

[7]  R. Shader,et al.  Lethality and Behavioral Side Effects of Chloroquine , 1982, Journal of clinical psychopharmacology.

[8]  P. Bernard.  Alterations of auditory evoked potentials during the course of chloroquine treatment. , 1985, Acta oto-laryngologica.

[9]  D A Stenger,et al.  Inhibition of spontaneous GABAergic transmission by trimethylolpropane phosphate. , 1999, Neurotoxicology.

[10]  D. Stenger,et al.  Identification of differential gene expression profiles in rat cortical cells exposed to the neuroactive agents trimethylolpropane phosphate and bicuculline. , 2001, Biosensors & bioelectronics.

[11]  P. Olliaro,et al.  Mode of action and mechanisms of resistance for antimalarial drugs. , 2001, Pharmacology & therapeutics.

[12]  G. Gross,et al.  Transparent indium-tin oxide electrode patterns for extracellular, multisite recording in neuronal cultures , 1985, Journal of Neuroscience Methods.

[13]  J. Noebels,et al.  Presynaptic Ca2+ Channels and Neurotransmitter Release at the Terminal of a Mouse Cortical Neuron , 2001, The Journal of Neuroscience.

[14]  Thomas M. McKenna,et al.  Enabling Technologies for Cultured Neural Networks , 1994 .

[15]  Effects of quinine on three different types of potassium currents in bullfrog sympathetic neurons , 1999, Neuroscience Letters.

[16]  G. Gross,et al.  Neurophysiologic effects of chemical agent hydrolysis products on cortical neurons in vitro. , 2001, Neurotoxicology.

[17]  Guenter W. Gross,et al.  Neuronal networks for biochemical sensing , 1992 .

[18]  A. Schousboe,et al.  Localization and pharmacological characterization of voltage dependent calcium channels in cultured neocortical neurons , 2001, International Journal of Developmental Neuroscience.

[19]  F. Deák,et al.  Inhibition of voltage-gated calcium channels by fluoxetine in rat hippocampal pyramidal cells , 2000, Neuropharmacology.

[20]  A. Bacci,et al.  A TTX-sensitive conductance underlying burst firing in isolated pyramidal neurons from rat neocortex , 1996, Brain Research.

[21]  J. Bernal,et al.  Antimalarial drugs inhibit calcium-dependent backward swimming and calcium currents in Paramecium calkinsi , 1993, Journal of Comparative Physiology A.

[22]  G. Gross,et al.  Characterization of acute neurotoxic effects of trimethylolpropane phosphate via neuronal network biosensors. , 2001, Biosensors & bioelectronics.

[23]  E. Kravitz,et al.  Presynaptic action of the neurosteroid pregnenolone sulfate on inhibitory transmitter release in cultured hippocampal neurons , 1997, Brain Research.

[24]  B. Sakmann,et al.  Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches , 1981, Pflügers Archiv.

[25]  J. Sánchez-Chapula,et al.  Chloroquine blocks the background potassium current in guinea pig atrial myocytes , 2000, Naunyn-Schmiedeberg's Archives of Pharmacology.

[26]  G. Gross.  Simultaneous Single Unit Recording in vitro with a Photoetched Laser Deinsulated Gold Multimicroelectrode Surface , 1979, IEEE Transactions on Biomedical Engineering.

[27]  K. Miller,et al.  Chloroquine treatment of severe malaria in children. Pharmacokinetics, toxicity, and new dosage recommendations. , 1988, The New England journal of medicine.

[28]  P. Phillips-Howard,et al.  CNS Adverse Events Associated With Antimalarial Agents , 1995, Drug safety.

[29]  D. Warhurst,et al.  Lysosomes, pH and the Anti-malarial Action of Chloroquine , 1972, Nature.

[30]  G. Gross,et al.  The use of neuronal networks on multielectrode arrays as biosensors. , 1995, Biosensors & bioelectronics.

[31]  D. Sulzer,et al.  Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: A mechanism of action , 1990, Neuron.

[32]  I. Gluzman,et al.  Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. , 1994, The Journal of clinical investigation.

[33]  A. Harsch,et al.  Odor, drug and toxin analysis with neuronal networks in vitro: extracellular array recording of network responses. , 1997, Biosensors & bioelectronics.

[34]  G. Pasternak,et al.  Interactions of chloroquine with benzodiazepine, γ-aminobutyric acid and opiate receptors , 1991 .

[35]  D. Warrell,et al.  Divided dose intramuscular regimen and single dose subcutaneous regimen for chloroquine: plasma concentrations and toxicity in patients with malaria. , 1986, British medical journal.

[36]  U. Misgeld,et al.  GABAB receptor‐mediated inhibition of spontaneous inhibitory synaptic currents in rat midbrain culture. , 1997, The Journal of physiology.

[37]  Coatney Gr.  Pitfalls in a Discovery: The Chronicle of Chloroquine , 1963 .

[38]  X. Lin,et al.  Effects of quinine on the excitability and voltage-dependent currents of isolated spiral ganglion neurons in culture. , 1998, Journal of neurophysiology.

[39]  R. Day,et al.  Antimalarials in rheumatic diseases. , 1990, Bailliere's clinical rheumatology.