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