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

Abstract

Lithium has long been used as a treatment for the psychiatric disease bipolar disorder. However, previous studies suggest that lithium provides neuroprotective effects in neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease. The exact mechanism by which lithium exerts these effects still remains unclear. In the present study, we evaluated the effects of low-dose lithium treatment in an aged mouse model expressing a parkin mutation within dopaminergic neurons. We found that low-dose lithium treatment prevented motor impairment as demonstrated by the open field test, pole test, and rearing behavior. Furthermore, lithium prevented dopaminergic striatal degeneration in parkin animals. We also found that parkin-induced striatal astrogliosis and microglial activation were prevented by lithium treatment. Our results further corroborate the use of this parkin mutant transgenic mouse line as a model for PD for testing novel therapeutics. The findings of the present study also provide further validation that lithium could be re-purposed as a therapy for PD and suggest that anti-inflammatory effects may contribute to its neuroprotective mechanisms.

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

“…We consistently found that lithium induced a concomitant increase in TH expression (Fig. 6E) (Lieu et al, 2014). …”

“…These data show that lithium up-regulates TH expression, while L-Dopa/Carbidopa may either not affect TH expression or provide partial negative feedback to the lithium-induced TH up-regulation (Fig. 3A) (Blunt et al, 1991; Riverol et al, 2014; Lieu et al, 2014). Therefore, we found statistically significant increases only in lithium-fed mice compared with saline controls following MPTP exposure (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 treatment protects dopaminergic neurons in both the ST and the SNpc against MPTP-induced neurotoxicity, based on TH-labeled cell count.…”

“…In this study, we further investigated the mechanism of lithium in inducing neuroprotective effects in PD models (Kim et al, 2011a; Lieu et al, 2014). Lithium-mediated increases in TH protein levels and reductions in MPTP-induced AIMs were found to occur in conjunction with suppression of calpain 1 expression in the ST and the SN of MPTP-lesioned mice (Farah et al, 2013).…”

“…The up-regulation of TH may be mediated via calpain 1 inhibition, but reduced 20S proteasomal activity or enhanced neurogenesis may also play a role in reducing AIMs (data not shown) (Rice and Sartorelli, 2001; Alvira et al, 2008; Crespo-Biel et al, 2009). In addition, we recently reported that lithium inhibits glial activation, increased by chronic insults in striatum (Lieu et al, 2014). …”