Lack of Antiparkinsonian Effects of Systemic Injections of the Specific T-Type Calcium Channel Blocker ML218 in MPTP-Treated Monkeys.
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.
Adriana
A
Galvan
Annaelle
A
Devergnas
Damien
D
Pittard
Gunasingh
G
Masilamoni
Jocelyn
J
Vuong
Department of Pharmacology and Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
J Scott
JS
Daniels
Department of Pharmacology and Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Ryan D
RD
Morrison
Department of Pharmacology and Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Craig W
CW
Lindsley
Thomas
T
Wichmann
D000818:Animals; D000978:Antiparkinson Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D001143:Arousal / Q000187:drug effects; D053961:Azabicyclo Compounds / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D001549:Benzamides / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D000069280:Electrocorticography; D005260:Female; D006321:Heart / Q000187:drug effects; D007980:Levodopa / Q000494:pharmacology; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D009043:Motor Activity / Q000187:drug effects; D017211:Treatment Failure
D000978:Antiparkinson Agents; D053961:Azabicyclo Compounds; D001549:Benzamides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; C000611565:ML218 compound; D007980:Levodopa
ML218; MPTP; Nonhuman primates; T-type calcium channel; behavior; parkinsonism; pharmacokinetic