TY - JOUR
T1 - D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa
AU - Mailman, Richard B.
AU - Yang, Yang
AU - Huang, Xuemei
N1 - Funding Information:
This work was supported, in part, by Public Health Service research grants MH040537 (RBM), NS105471 (RBM), and NS105471 (XH). The authors thank the Axion Research Foundation for the technical support critical for these experiments.
Funding Information:
Dr. Mailman is an inventor of D 1 agonist technology, the conflicts-of-interest of which are managed by the Pennsylvania State University College of Medicine. He is the past recipient of research funds and consulting compensation from Pfizer, Inc. Dr. Huang is an inventor of D 1 agonist-related technology whose interests were assigned to the University of North Carolina. Dr. Huang has also received nominal transportation and per diem expenses from Acadia, Medtronics, and Cerevel Therapeutics, and research support from Pfizer, Biogen, and Biohaven. Drs. Mailman and Huang have no other conflicting interests. Dr. Yang has no conflicting interests. The opinions in this review are those of the authors alone and do not reflect those of the university or any other party.
PY - 2021/2/5
Y1 - 2021/2/5
N2 - Levodopa is the standard-of-care for Parkinson's disease, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral “dopamine agonist” matches the efficacy of levodopa. There are consistent data in both primate models and in Parkinson's disease showing that selective high intrinsic activity D1 agonists can equal levodopa in efficacy. There are, however, no data on whether such compounds would be effective in severe disease when levodopa efficacy is low or absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernible improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2 antagonist remoxipride. These data provide evidence that selective D1 agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson's patients.
AB - Levodopa is the standard-of-care for Parkinson's disease, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral “dopamine agonist” matches the efficacy of levodopa. There are consistent data in both primate models and in Parkinson's disease showing that selective high intrinsic activity D1 agonists can equal levodopa in efficacy. There are, however, no data on whether such compounds would be effective in severe disease when levodopa efficacy is low or absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernible improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2 antagonist remoxipride. These data provide evidence that selective D1 agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson's patients.
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U2 - 10.1016/j.ejphar.2020.173760
DO - 10.1016/j.ejphar.2020.173760
M3 - Article
C2 - 33279520
AN - SCOPUS:85097915282
VL - 892
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
M1 - 173760
ER -