Inhibition of PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson’s Disease Therapy
Abstract
:1. Introduction
2. Materials and Methods
2.1. Subjects
2.2. Compounds
2.3. Design of Experiments
2.4. In Vivo Tests
2.4.1. Locomotor Activity
2.4.2. Bar Test
2.5. Ex Vivo Bioanalytical Procedures
2.6. Statistical Analysis and Plots
3. Results
3.1. Treatment with L-DOPA + Carbidopa Restores Motor Functions and Brain DA Levels in DDD Rats
3.1.1. Motor Functions
3.1.2. DA Levels in the Striatum and the FC
3.2. Treatment with MP-10 Restores Motor Functions in DDD Rats without Affecting Brain DA Content
3.2.1. Motor Functions
3.2.2. DA Tissue Content in MP-10 Treated DDD Rats
4. Discussion
4.1. A Novel Model of Acute Severe DA Deficiency, DDD Rats
4.2. DA-Independent Restoring of DDD Rats’ Motor Functions by PDE10A Inhibition
4.3. Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Chemical Compounds Studied in this Article
References
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Name of Experiment and Subjects | Phase | Procedures Order |
---|---|---|
MOTOR EFFECTS OF L-DOPA + CARBIDOPA IN THE DDD RATS DAT-KO rats (females, n = 30) Group 1 (n = 7)—0 + 0 mg/kg Group 2 (n = 7)—10 + 10 mg/kg Group 3 (n = 7)—20 + 10 mg/kg Group 4 (n = 9)—40 + 10 mg/kg | I. Baseline | (1) Locomotor activity test (60 min) (2) Bar test |
II. αMPT | (1) αMPT administration. Doses: 250 mg/kg, i/p (2) Locomotor activity test (60 min) (3) Bar test | |
III. L-DOPA | (1) L-DOPA + carbidopa administration. Doses: 0 + 0, 10 + 10, 20 + 10, 40 + 10 mg/kg, i/p (2) Locomotor activity test (30 min) (3) Bar test (4) Locomotor activity test (30 min) | |
Euthanasia, brain sampling for neurochemical analysis | ||
MOTOR EFFECTS OF PDE10A INHIBITOR IN THE DDD RATS DAT-KO rats (females, n = 35) Group 1 (n = 9)—0 mg/kg Group 2 (n = 9)—1 mg/kg Group 3 (n = 9)—3 mg/kg Group 4 (n = 8)—5 mg/kg | I. Baseline | (1) Locomotor activity test (60 min) (2) Bar test |
II. αMPT | (1) αMPT administration. Doses: 250 mg/kg, i/p (2) Locomotor activity test (60 min) (3) Bar test | |
III. MP-10 (1) | (1) MP-10 administration. Doses: 0, 1, 3, 5 mg/kg, i/p (2) Locomotor activity test (60 min, postinjection time—30 min) (3) Bar test | |
IV. MP-10 (2) | (1) Locomotor activity test (60 min) (2) Bar test | |
V. MP-10 (3) | (1) Locomotor activity test (60 min) (2) Bar test | |
Euthanasia, brain sampling for neurochemical analysis |
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Sukhanov, I.; Dorotenko, A.; Fesenko, Z.; Savchenko, A.; Efimova, E.V.; Mor, M.S.; Belozertseva, I.V.; Sotnikova, T.D.; Gainetdinov, R.R. Inhibition of PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson’s Disease Therapy. Biomolecules 2023, 13, 9. https://doi.org/10.3390/biom13010009
Sukhanov I, Dorotenko A, Fesenko Z, Savchenko A, Efimova EV, Mor MS, Belozertseva IV, Sotnikova TD, Gainetdinov RR. Inhibition of PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson’s Disease Therapy. Biomolecules. 2023; 13(1):9. https://doi.org/10.3390/biom13010009
Chicago/Turabian StyleSukhanov, Ilya, Artem Dorotenko, Zoia Fesenko, Artem Savchenko, Evgeniya V. Efimova, Mikael S. Mor, Irina V. Belozertseva, Tatyana D. Sotnikova, and Raul R. Gainetdinov. 2023. "Inhibition of PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson’s Disease Therapy" Biomolecules 13, no. 1: 9. https://doi.org/10.3390/biom13010009