Lack of Antiparkinsonian Effects of Systemic Injections of the Specific T-Type Calcium Channel Blocker ML218 in MPTP-Treated Monkeys

• Type of Material: Article
• Authors: Adriana Galvan, Emory University; Annaelle Devergnas, Emory University; Damien Pittard, Emory University; Gunasingh Masilamoni, Emory University; Jocelyn Vuong, Emory University; J. Scott Daniels, Vanderbilt University; Craig W. Lindsley, Vanderbilt University; Ryan D. Morrison, Vanderbilt University; Thomas Wichmann, Emory University
• Language: English
• Date: 2016-11-01
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 American Chemical Society.
• Final Published Version (URL): http://dx.doi.org/10.1021/acschemneuro.6b00186
• Title of Journal or Parent Work: ACS Chemical Neuroscience
• ISSN: 1948-7193
• Volume: 7
• Issue: 11
• Start Page: 1543
• End Page: 1551
• Grant/Funding Information: This project was supported through grants from NIH/NINDS (R01-NS054976 [TW] and P50-NS071669 [Udall Center grant, TW]), a grant from the Michael J. Fox foundation, and a grant from the NIH/ORIP to the Yerkes Center (P51 OD011132).
• Keywords: SUBTHALAMIC NUCLEUS; MOTOR THALAMUS; Neurosciences; NIGROSTRIATAL PATHWAY; PALLIDAL SEGMENT; Life Sciences & Biomedicine; Neurosciences & Neurology; MPTP; CA2+ CHANNELS; Pharmacology & Pharmacy; NIGRA PARS RETICULATA; BASAL GANGLIA; pharmacokinetic; behavior; DRUG ETHOSUXIMIDE; T-type calcium channel; parkinsonism; ML218; Biochemistry & Molecular Biology; PARKINSONS-DISEASE; NEURONAL-ACTIVITY; Nonhuman primates; Science & Technology; Chemistry, Medicinal
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Neuroscience

Abstract

Dopaminergic medications ameliorate many of the motor impairments of Parkinson's disease (PD). However, parkinsonism is often only partially reversed by these drugs, and they can have significant side effects. Therefore, a need remains for novel treatments of parkinsonism. Studies in rodents and preliminary clinical evidence have shown that T-type calcium channel (TTCC) antagonists have antiparkinsonian effects. However, most of the available studies utilized nonselective agents. We now evaluated whether systemic injections of the specific TTCC blocker ML218 have antiparkinsonian effects in MPTP-treated parkinsonian Rhesus monkeys. The animals were treated chronically with MPTP until they reached stable parkinsonism. In pharmacokinetic studies, we found that ML218 reaches a peak CSF concentration 1-2 h after s.c. administration. In electrocardiographic studies, we found no effects of ML218 on cardiac rhythmicity. As expected, systemic injections of the dopamine precursor L-DOPA dose-dependently increased the movements in our parkinsonian animals. We then tested the behavioral effects of systemic injections of ML218 (1, 10, or 30 mg/kg) or its vehicle, but did not detect specific antiparkinsonian effects. ML218 (3 or 10 mg/kg) was also not synergistic with L-DOPA. Using recordings of electrocorticogram signals (in one animal), we found that ML218 increased sleep. We conclude that ML218 does not have antiparkinsonian effects in MPTP-treated parkinsonian monkeys, due at least in part, to the agent's sedative effects.