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

Brain Res. 2015 Oct 5;1622:127-36. doi: 10.1016/j.brainres.2015.06.018. Epub 2015 Jun 26.

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.

Keywords: AIM; Calpain 1; Combination therapy; MPTP; Neurodegenerative disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology*
  • Brain Stem / drug effects
  • Brain Stem / pathology
  • Brain Stem / physiopathology
  • Calpain / antagonists & inhibitors
  • Calpain / metabolism
  • Carbidopa / pharmacology*
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Line
  • Corpus Striatum / drug effects
  • Corpus Striatum / pathology
  • Corpus Striatum / physiopathology
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / pathology
  • Dopaminergic Neurons / physiology
  • Drug Therapy, Combination
  • Histone Acetyltransferases / metabolism
  • Levodopa / pharmacology*
  • Lithium Chloride / pharmacology*
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / pathology
  • MPTP Poisoning / physiopathology
  • Male
  • Mice, Inbred C57BL
  • Motor Activity / drug effects*
  • Motor Activity / physiology
  • Rats
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Antiparkinson Agents
  • Levodopa
  • Tyrosine 3-Monooxygenase
  • Histone Acetyltransferases
  • Calpain
  • Capn1 protein, rat
  • Capn1 protein, mouse
  • Capn2 protein, mouse
  • Lithium Chloride
  • Carbidopa