Abstract
Quinine is an antimalarial drug that is toxic to the auditory system by commonly inducing hearing loss and tinnitus, presumably due to its ototoxic effects on disruption of cochlear hair cells and blockade of ion channels of neurons in the auditory system. To a lesser extent, quinine also causes ataxia, tremor, and dystonic reactions. As dopaminergic neurons are implicated to play a role in all of these diseases, we tested the toxicity of quinine on induced dopaminergic (iDA) neurons derived from human pluripotent stem cells (iPSCs) and primary dopaminergic (DA) neurons of substantia nigra from mice brain slices. Patch clamp recordings and combined drug treatments were performed to examine key physiological properties of the DA neurons. We found that quinine (12.5–200 μM) depolarized the resting membrane potential and attenuated the amplitudes of rebound spikes induced by hyperpolarization. Action potentials were also broadened in spontaneously spiking neurons. In addition to quinine attenuating hyperpolarization-dependent conductance, the tail currents following withdrawal of hyperpolarizing currents were also attenuated. Taken together, we found that iPSC-derived DA neurons recapitulated all the tested physiological properties of human DA neurons, and quinine had distinct effects on the physiology of both iDA and primary DA neurons. This toxicity of quinine may be the underlying mechanism for the movement disorders of cinchonism or quinism and may play a role in tinnitus modulation.
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Abbreviations
- ACSF:
-
Artificial cerebrospinal fluid
- 4-AP:
-
4-Aminopyridine
- DA neuron:
-
Dopaminergic neuron
- Ih :
-
Hyperpolarization-dependent inward current
- iDA neuron:
-
Induced dopaminergic neuron
- iPSCs:
-
Induced pluripotent stem cells
- ITail :
-
Tail currents
- TEA:
-
Tetraethylammonium
- TH:
-
Tyrosine hydroxylase
- TTX:
-
Tetrodotoxin
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Acknowledgements
This work was supported by the Howard University BFPSAP grant (X.Z.), the Hearing Heath Foundation (X.Z.), Maryland Stem Cell Research Fund (M.Y.), and Latham Trust Fund (T.H.). ML252 were kindly provided by Dr. Craig W. Lindsley (Vanderbilt University).
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The experimental protocols involving human iPSCs were approved by Howard University Institutional Biosafety Committee and Johns Hopkins Medicine Institutional Review Boards. Animal use and experimental protocols were approved by the Institutional Animal Care and Use Committee of the Howard University College of Medicine.
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Zou, L., Xue, Y., Jones, M. et al. The Effects of Quinine on Neurophysiological Properties of Dopaminergic Neurons. Neurotox Res 34, 62–73 (2018). https://doi.org/10.1007/s12640-017-9855-1
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DOI: https://doi.org/10.1007/s12640-017-9855-1