Investigating the potential neuroprotective effects of statins on DNA damage in mice striatum / Tjaart Nicolaas Coetsee
Coetsee, Tjaart Nicolaas
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Parkinson's disease occurs after loss of the nigrostriatal neurons responsible for regulating normal motor function (Chase, et al., 1998). Oxidative damage to DNA is caused by endogenous cellular sources (Marnett, 2000) such as hydrogen peroxide, which is extremely reactive and can add bases to or abstract hydrogen atoms from DNA (Cooke, et al., 2006). There therefore exists a baseline level of DNA damage (Marnett, 2000) which is continually being repaired. This process is critical to the survival of all cells and a failure to protect the genome would result in the induction of mutations leading to cell death (Cooke, et al., 2006). Current treatment of Parkinson's disease focuses on symptomatic management with dopaminergic drugs such as L-DOPA. This approach is only highly effective in the early stages of the disorder and long-term treatment often loses its efficacy (Jenner, 2003) and leads to the occurrence of side-effects. The challenge is to find methods to conserve and protect the nigrostriatal neurons, thereby preventing the onset of Parkinson's disease. The widening role of the statin drugs, used in the treatment of dyslipidaemias (Hamelin and Turgeon, 1998), has been the subject of recent studies and they have as such been shown to reduce LDL oxidation, preserve endogenous superoxide dismutase, increase a-tocopherol (an antioxidant), reduce lipoprotein oxidation in a number of oxidative systems, protect against DNA damage caused by antineoplastic agents, and to reduce DNA damage in hypercholesterolemic patients (Shin, et al., 2005). We therefore investigated the potential neuroprotective effect of selected statins drugs (pravastatin, simvastatin and atorvastatin) on the striatum. MPTP (1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) treated C57BI/J6 mice were used as an animal model to replicate Parkinson's disease. MPTP is a neurotoxin which causes selective neuronal death in the striatum through the inhibition of mitochondria1 complex I. Groups of ten mice were treated with 70 mg / kg of pravastatin, simvastatin, atorvastatin or no drug (control group) for five consecutive days. Five mice from each group received an "immediate onset PD model for rapid degeneration with necrotic cell death" dose of MPTP (50 mg / kg) intraperitonially. After decapitation the striatum was isolated and analysed. The immediate state of DNA damage in the tissue (baseline damage) was determined using the microgel electrophoresis (comet) assay. Further DNA damage was induced by treating the sample with H2O2 for thirty minutes after which the process was stopped and the DNA damage determined. Two more comet assays were performed at twenty minute intervals to determine the amount of repair that took place. MPTP treatment increased the level of DNA damage in the striatum. Treatment with statins also increased levels of DNA damage, but left the repair processes intact, increasing the amount of repair that took place as well. The DNA repair of mice treated with MPTP and statins, however was decreased. The results obtained do not substantiate the hypothesis that the beneficial effects of statins in PD patients could be ascribed to their capacity to reduce DNA damage. The protective mechanism of the statins in PD patients may be attributed to mechanisms other than protection against DNA damage, such as its antioxidative or anti-inflammatory properties.
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