Elsevier

Neuroscience Letters

Volume 516, Issue 1, 10 May 2012, Pages 57-61
Neuroscience Letters

Lithium and oxidative stress lessons from the MPTP model of Parkinson's disease

https://doi.org/10.1016/j.neulet.2012.03.055Get rights and content

Abstract

Lithium has been successfully employed therapeutically for treatment of bipolar depressive illness; however, its mechanism of action is poorly understood. Recently, it has been demonstrated by us that lithium can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) dopaminergic neurotoxicity in mice. From analyzing the pattern of protection in various parameters, we suggest that lithium protects against MPTP-induced depletion of striatal dopamine (DA) by preventing free radical-induced inactivation of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis. Possible neuroprotective effect of lithium against H2O2-induced cell death was assessed in human neuroblastoma; SH-SY5Y cell line. Pretreatment with LiCl (2 mM and 4 mM) for 7 days protected against H2O2 neurotoxicity in a dose-dependent manner. However, this protection could not be achieved through short-term incubation with LiCl. In agreement; we found that lithium lacks immediate antioxidant activity using the in vitro lipid peroxidation essay indicating that not acute but chronic treatment with lithium allows cells to deal better with oxidative stress.

Highlights

► Li+ protects against MPTP, in part by preventing inactivation of tyrosine hydroxylase. ► In cell culture, long and not short incubation with Li+ protects against H2O2. ► In agreement we found that lithium, in vitro; lacks immediate antioxidant activity. ► Lithium induced anti-oxidative state plays a major role in its neuro-protection.

Introduction

Research into the pathogenesis of Parkinson's disease (PD) has been rapidly advanced by the development of animal models for the disease. Initial models were developed by using toxins that specifically targeted DA neurons. Among these, the most successful is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model [4], a toxin that replicates in humans, nonhumans primates and rodents severe PD-like syndrome [32]. Lithium has been extensively used as a long-term mood stabilizer for the treatment of bipolar disorder and depressive disorders because of its ability to effectively control depression and suicidal thoughts, in some cases [28]. During the last decade new data have emerged applying for a role of neuroprotection in the mechanisms underlying the therapeutic efficacy of lithium [31]. Recently we have shown that lithium can prevent MPTP-induced neurotoxicity in mice [34]. The neuroprotective effect of lithium was determined by the following parameters: prevention of MPTP-induced fall in striatal TH protein levels and TH activity, as well as prevention of striatal depletion of DA and its metabolites, 3,4-dihydroxyphenylactetic acid (DOPAC) and homovanillic acid (HVA) and prevention of the increase in striatal DA turnover, (DOPAC + HVA):DA ratio, normally resulting from MPTP treatment. The neuroprotective action of lithium in this model of PD has been attributed to its anti-apoptotic activity, which among other factors includes induction of Bcl-2 and reduction of Bax and an opposing effect was seen with MPTP alone. In this model there is an increased free radical production [8]. Indeed, MPTP toxicity is significantly reduced in transgenic mice overexpressing the free radical scavenging enzymes Cu/Zn or Mn superoxide dismutase (SOD) [23], [27].

Conversely, MPTP toxicity is exacerbated in mice with deficiencies of glutathione peroxidase, Cu/Zn or Mn SOD [2]. However, the critical oxidant might be peroxynitrite, which is formed by the chemical reaction of a nitric oxide (NO) with an O2 radical. Knockout of neuronal nitric oxide synthase (nNOS) in mice or inhibitors of nNOS markedly attenuate MPTP neurotoxicity [18], [22], [25], [30].

Section snippets

Methods and materials

All procedures were in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Technion Animal Ethics committee (Haifa, Israel).

Results

In these studies we decided to choose the lowest (1.1 g/kg) and the highest (4.4 g/kg) lithium concentrations, since these concentrations were demonstrated in our previous studies to induce the lowest and the highest protection against MPTP-induced depletion of striatal DA [34]. The two dietary dosages, 1.1 and 4.4 g/kg diet of LiCl were fed to mice over a four week period and serum lithium was determined at the 1st, 2nd and 4th week and resulted in serum lithium concentrations at the last day of

Discussion

In order to further evaluate the neuroprotective effect of lithium in the MPTP mouse model of PD, we investigated the interrelationship between the levels of striatal TH, the rate limiting enzyme in DA synthesis, TH activity and DA in each individual treated mouse. First, in consistent with other studies [24], [33], MPTP administration regime of 4 × 24 mg/kg/day, induced ∼50% depletion of striatal TH level, and ∼75% depletion of striatal DA levels. The decrement in DA levels, which exceeded the

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