Elsevier

Brain Research

Volume 1622, 5 October 2015, Pages 127-136
Brain Research

Research report
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

https://doi.org/10.1016/j.brainres.2015.06.018Get rights and content

Highlights

  • Lithium reduces MPTP-induced abnormal involuntary movements (AIMs) in a mouse model.

  • Lithium׳s effect is mediated by calpain 1 inhibition.

  • Lithium increases the HAT activity and tyrosine hydroxylase expression.

  • Combining lithium with l-Dopa/Carbidopa may be a viable option for PD.

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.

Introduction

Parkinson׳s disease (PD) is a progressive movement disorder with a prevalence of 1.8% in individuals of 65 years or older (de Rijk et al., 2000, Bogaerts et al., 2008); its etiology is largely unknown in most cases. Dopamine replacement therapy using levodopa (l-Dopa) has remained the most effective treatment to reduce motor symptoms in PD. Currently most patients taking l-Dopa also receive the DOPA decarboxylase inhibitor, Carbidopa, for higher efficacy and lower side-effects (Celesia and Wanamaker, 1976, Wajsbort et al., 1978). However, chronic l-Dopa treatment results in abnormal involuntary movements (AIMs) including dyskinesia, in approximately 30% patients after 4–6 years of treatment; almost 90% of patients suffer from this complication after 9 years of chronic use (Ahlskog and Muenter, 2001).

Lithium has been the most commonly-used mood-stabilizing drug for the treatment of bipolar disorder. However, its recently discovered neuroprotective and neurotrophic properties have suggested it as a potential repurposed therapeutic for several neurodegenerative conditions (Li et al., 2002, Pies, 2002). Chronic lithium treatment was found to significantly attenuate neurodegeneration in the trigeminal, facial, ambiguus, and hypoglossal nuclei associated with an animal model of amyotrophic lateral sclerosis (ALS) (Ferrucci et al., 2010). In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication PD mouse model, lithium was reported to prevent MPTP-induced neurotoxicity via regulation of Bcl-2 and Bax (Youdim and Arraf, 2004). Currently, lithium is in widespread “off label” usage for PD. It has been suggested that its co-administration could possibly provide some level of symptomatic relief against l-Dopa-induced dyskinesia (LID) and akinesia associated with “on–off” phenomenon complications following long-term l-Dopa treatment (Smith, 1976, Coffey et al., 1982). Lithium appears to be relatively safe at lower therapeutic dosages, readily penetrates the blood brain barrier, and low cost generic versions are available, making lithium an appealing drug for potential use in PD. Recently we demonstrated that chronic oral lithium administration was sufficient to prevent age-related, pesticide-induced alpha-synuclein aggregation and associated neuronal loss in multiple brain regions in a pan-neuronal human alpha-synuclein A53T mutant over-expressing transgenic line (Kim et al., 2011a).

The potential mechanisms by which lithium may modulate dopamine levels and reduce AIMs are largely unknown. Recent post-mortem studies, however, demonstrated that this could be via inhibition of a pathway involving calpain activation. Calpains have been shown to be elevated in human PD brains and calpain inhibition has been demonstrated to prevent reduction in the number of tyrosine hydroxylase (TH) positive cells in both MPTP and 6-hydroxydopamine (6-OHDA) treated rodent models of PD (Mouatt-Prigent et al., 1996, Crocker et al., 2003, Alvira et al., 2008). The calpain inhibitor MDL28170 was also shown to augment TH levels in the striatum of 6-OHDA lesioned rats, resulting in reductions in AIM frequencies (Chagniel et al., 2012). Here, we demonstrate that low-dose lithium with l-Dopa/Carbidopa reduces MPTP-induced AIMs in a mouse model coinciding with both calpain-1 inhibition and up-regulation of TH expression within both the striatum and the Substantia Nigra pars compacta (SNpc). These results suggest the potential use of lithium in combination with l-Dopa/Carbidopa (Sinemet®), not only as a neuroprotectant, but also for reducing AIMs and alleviating potential side-effects associated with currently available treatments for PD.

Section snippets

In the hindlimb clasping test, the combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs) in MPTP-lesioned mice

Using the hindlimb clasping test, we assessed AIMs after chronic MPTP treatment via analysis of hindlimb clasping severity and average instances of hindlimb clasping in the various experimental paradigms. In the comparison of pre-treatment (black filled bars) and post-treatment conditions (lined bars), we found that only the combination of lithium and l-Dopa/Carbidopa significantly reduced the severity of hindlimb clasping behavior (Fig. 1B, p<0.001), while we detected significant reductions in

Discussion

In this study, we demonstrated that combined lithium (0.127% LiCl in food) and l-Dopa/Carbidopa (IP injection: 100 mg/kg levodopa and 25 mg/kg Carbidopa) therapy significantly reduced MPTP-induced AIMs in mice as indicated by improvements in the hindlimb clasping test (Fig. 2, video data are Supplemented). The combination therapy not only reduces MPTP-induced AIMs but also increases TH expression in both the ST and the brainstem (Farah et al., 2013, Lieu et al., 2014). We found that lithium

MPTP treatment and lithium feeding

All animal protocols were conducted in accordance with the United States Public Health Service Guide for the Care and Use of Laboratory Animals; all procedures were approved by the Buck Institute Animal Care and Use Committee. All efforts were made to minimize animal numbers and distress. C57BL/6J male mice (8 months of age) were obtained from Charles River Laboratory (Wilmington, MA) and intraperitoneally injected with 25 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, Sigma, St.

Acknowledgments

We thank Dr. Alan Hubbard at the University of California, Berkeley for statistical discussion for this paper. This study was supported by NIH-5P20GM103653-02 (YHK) and NIH-RL1 NS062415 (JKA).

References (42)

  • S.H. Koh et al.

    Inhibition of glycogen synthase kinase-3 reduces l-dopa-induced neurotoxicity

    Toxicology

    (2008)
  • G. Kusakawa et al.

    Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25

    J. Biol. Chem.

    (2000)
  • C.A. Lieu et al.

    Lithium prevents parkinsonian behavioral and striatal phenotypes in an aged parkin mutant transgenic mouse model

    Brain Res.

    (2014)
  • G. McColl et al.

    Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans

    J. Biol. Chem.

    (2008)
  • A. Mouatt-Prigent et al.

    Increased M-calpain expression in the mesencephalon of patients with Parkinson׳s disease but not in other neurodegenerative disorders involving the mesencephalon: a role in nerve cell death?

    Neuroscience

    (1996)
  • A.M. Rice et al.

    Inhibition of 20S and 26S proteasome activity by lithium chloride: impact on the differentiation of leukemia cells by all-trans retinoic acid

    J. Biol. Chem.

    (2001)
  • M. Riverol et al.

    Levodopa induces long-lasting modification in the functional activity of the nigrostriatal pathway

    Neurobiol. Dis.

    (2014)
  • A. Siddiqui et al.

    Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: implications for Parkinson׳s disease

    Free Radic. Biol. Med.

    (2012)
  • D.F. Smith

    Antagonistic effect of lithium chloride on l-dopa-induced locomotor activity in rats

    Pharmacol. Res. Commun.

    (1976)
  • L. Yao et al.

    Activation of transcription factor MEF2D by bis(3)-cognitin protects dopaminergic neurons and ameliorates Parkinsonian motor defects

    J. Biol. Chem.

    (2012)
  • J.E. Ahlskog et al.

    Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature

    Mov. Disord.

    (2001)
  • Cited by (0)

    View full text