Abstract |
Lithium has recently been suggested to have neuroprotective effects in several models of neurodegenerative disease including Parkinson׳s disease (PD). Levodopa ( l-Dopa) replacement therapy remains the most common and effective treatment for PD, although it induces the complication of l-Dopa induced dyskinesia after years of use. Here we examined the potential use of lithium in combination with l-Dopa/ Carbidopa for both reducing MPTP-induced abnormal involuntary movements (AIMs) as well as protecting against cell death in MPTP-lesioned mice. Chronic lithium administration (0.127% LiCl in the feed) in the presence of daily l-Dopa/ Carbidopa injection for a period of 2 months was sufficient to effectively reduce MPTP-induced AIMs in mice. Mechanistically, lithium was found to suppress MPTP-induced calpain activities in vivo coinciding with down-regulation of calpain-1 but not calpain-2 expression in both the striatum (ST) and the brain stem (BS). Calpain inhibition has previously been associated with increased levels of the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), which is probably mediated by the up-regulation of the transcription factors MEF-2A and 2D. Lithium was found to induce up-regulation of TH expression in the ST and the BS, as well as in N27 rat dopaminergic cells. Further, histone acetyltransferase (HAT) expression was substantially up-regulated by lithium treatment in vitro. These results suggest the potential use of lithium in combination with l-Dopa/ Carbidopa not only as a neuroprotectant, but also for reducing AIMs and possibly alleviating potential side-effects associated with the current treatment for PD.
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Authors | Carol A Lazzara, Rebeccah R Riley, Anand Rane, Julie K Andersen, Yong-Hwan Kim |
Journal | Brain research
(Brain Res)
Vol. 1622
Pg. 127-36
(Oct 05 2015)
ISSN: 1872-6240 [Electronic] Netherlands |
PMID | 26119916
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2015 Elsevier B.V. All rights reserved. |
Chemical References |
- Antiparkinson Agents
- Levodopa
- Tyrosine 3-Monooxygenase
- Histone Acetyltransferases
- Calpain
- Capn1 protein, rat
- Capn1 protein, mouse
- Capn2 protein, mouse
- Lithium Chloride
- Carbidopa
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Topics |
- Animals
- Antiparkinson Agents
(pharmacology)
- Brain Stem
(drug effects, pathology, physiopathology)
- Calpain
(antagonists & inhibitors, metabolism)
- Carbidopa
(pharmacology)
- Cell Death
(drug effects, physiology)
- Cell Line
- Corpus Striatum
(drug effects, pathology, physiopathology)
- Dopaminergic Neurons
(drug effects, pathology, physiology)
- Drug Therapy, Combination
- Histone Acetyltransferases
(metabolism)
- Levodopa
(pharmacology)
- Lithium Chloride
(pharmacology)
- MPTP Poisoning
(drug therapy, pathology, physiopathology)
- Male
- Mice, Inbred C57BL
- Motor Activity
(drug effects, physiology)
- Rats
- Tyrosine 3-Monooxygenase
(metabolism)
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