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The combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs) via calpain-1 inhibition in a mouse model: Relevance for Parkinson׳s disease therapy.

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.
AuthorsCarol A Lazzara, Rebeccah R Riley, Anand Rane, Julie K Andersen, Yong-Hwan Kim
JournalBrain research (Brain Res) Vol. 1622 Pg. 127-36 (Oct 05 2015) ISSN: 1872-6240 [Electronic] Netherlands
PMID26119916 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 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
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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