title: 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.
authors.affiliation: Department of Biological Sciences, Delaware State University, Dover, DE 19901-2277, United States.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Lazzara
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, United States.
authors.forename: Rebeccah R
authors.initials: RR
authors.lastname: Riley
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, United States.
authors.forename: Anand
authors.initials: A
authors.lastname: Rane
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, United States. Electronic address: jandersen@buckinstitute.org.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Andersen
authors.affiliation: Department of Biological Sciences, Delaware State University, Dover, DE 19901-2277, United States. Electronic address: yhkim@desu.edu.
authors.forename: Yong-Hwan
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001933:Brain Stem / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D002230:Carbidopa / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004359:Drug Therapy, Combination; D051548:Histone Acetyltransferases / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology*; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D051548:Histone Acetyltransferases; D002154:Calpain; C000606071:Capn1 protein, rat; C112682:Capn1 protein, mouse; C570925:Capn2 protein, mouse; D018021:Lithium Chloride; D002230:Carbidopa
keywords: AIM; Calpain 1; Combination therapy; MPTP; Neurodegenerative disease