TY - JOUR
T1 - Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress
AU - Guzman, Jaime N.
AU - Ilijic, Ema
AU - Yang, Ben
AU - Sanchez-Padilla, Javier
AU - Wokosin, David
AU - Galtieri, Dan
AU - Kondapalli, Jyothisri
AU - Schumacker, Paul T.
AU - Surmeier, D. James
N1 - Funding Information:
This work was supported by awards to DJS by the JPB Foundation, the IDP Foundation, and the NIH (NS NS047085). We wish to thank Toren Finkel for providing the mito-Keima plasmid, Savio Chan and Harry Xenias for guidance and technical assistance with the Coherent laser spinning-disk unit, and Craig Weiss, Mary Kan-do, and the Northwestern University Behavioral Phenotyping Core for help with open-field tests and data analysis.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson's disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. This treatment diminished cytosolic Ca2+ oscillations in SNc DA neurons without altering autonomous spiking or expression of Ca2+ channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass - demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well.
AB - The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson's disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. This treatment diminished cytosolic Ca2+ oscillations in SNc DA neurons without altering autonomous spiking or expression of Ca2+ channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass - demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well.
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U2 - 10.1172/JCI95898
DO - 10.1172/JCI95898
M3 - Article
C2 - 29708514
AN - SCOPUS:85048254469
VL - 128
SP - 2266
EP - 2280
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -