|M.Sc Student||Arraf Zaher|
|Subject||Neuroprotective Properties of Lithium in the 1-methyl-4-|
Model of Parkinson's Disease
|Department||Department of Medicine||Supervisor||Professor Emeritus Moussa Youdim|
|Full Thesis text|
Lithium has been reported to exert neuroprotective activity in several neuronal cell cultures and in vivo models against glutamate toxicity. Since this action was reported to be associated with alterations in the anti-apoptotic Bcl-2 family proteins, the effect of chronic lithium diet on the ability of the parkinsonism neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to deplete striatal dopamine (DA) in mice was determined. Mice were fed with a diet containing 1.1, 2.2, 3.3, and 4.4 g/kg lithium chloride (LiCl) for 4 weeks, during which time serum levels of lithium were monitored. At the end of lithium treatment the mice received 24 mg/kg MPTP i.p., once daily for 4 days. A direct relation was established with increased serum lithium and its ability to prevent MPTP-induced depletion of striatal DA and its metabolites 3,4-dihydroxyphenylactetic acid (DOPAC) and homovanillic acid (HVA). With the diet containing the highest lithium concentration, there was an almost complete prevention of: striatal DA depletion, reduction in tyrosine hydroxylase (TH) activity and protein level and increase in DA turnover (DOPAC + HVA)/DA, normally observed following MPTP treatment. Lithium did not interfere with the metabolism of MPTP, or with its brain uptake, since the level of its monoamine oxidase B (MAO-B) derived active metabolite, 1-methyl-4-phenyl-pyridinium (MPP+) in the striata of lithium and non-lithium treated mice were almost identical. From analyzing the pattern of protection in various parameters, we suggest that lithium protected against free radical-induced inactivation of TH. 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; lithium could not reverse Fe2+-induced formation of lipid peroxides, at any LiCl concentration examined in the in vitro lipid peroxidation essay. Evaluation of the levels of Bcl-2 and Bax, revealed that striatal Bcl-2 was significantly decreased, while Bax was increased in MPTP-treated mice. The neuroprotective action of lithium in this model of Parkinson’s disease has been attributed to its anti-apoptotic activity which among other factors includes induction of Bcl-2 and reduction of Bax. Today, 60 years after its introduction to psychiatry and almost a decade of new emerging data indicating for neuroprotective effects of lithium, there is absolutely a need for an epidemiologic study evaluating the efficacy of lithium in preventing neurodegenerative diseases.