**2.1.1 Patients**

350 Etiology and Pathophysiology of Parkinson's Disease

Oxidative stress and excitotoxicity seems to play a pivotal role in pathogenesis of few major neurodegenerative diseases e.g. Alzheimer's disease (AD) and PD. The study of Jenner (2003) indicates that oxidative stress in the brain of PD patients may leads to formed reactive forms of oxygen (RFO). In the course of PD, RFO activate processes leading to the damage of DNA, proteins and lipids, and to a low level of antioxidants (Blake et al., 1997; Kikuchi et al., 2002). Moreover, in the patients suffering from PD, dopamine level-controlled deposition of ubiquitin- and α-synuclein-positive inclusion bodies (Lewy's bodies) takes place in the cytoplasm of dopaminergic neurons (Spillantini et al., 1997). Deposition of pathological proteins in brains of patients affected by the neurodegenerative diseases, result in pronounced neurotoxic effects on the central nervous system (CNS). In PD, augmented expression of α-synuclein may intensify oxidative stress (Hsu et al., 2000). Bergman et al. (1998) demonstrated that in the PD patients, dopaminergic neurons undergo oxidative damage of the compact portion of *substantia nigra* and dopamine levels decrease in putamen, a region of caudate nucleus. Moreover, ferrous ions released from damaged *substantia nigra* may provide an important substrate for oxidative reactions and for production of RFO

In PD, oxidative stress follows accumulation of the degradation products in the gray matter compact part of mesencephalon*,* and is accompanied not only by a high level of ferrous ions, and by decreased level of glutathione, malfunction of the respiratory chain complex I (Jenner, 2003; Schapira et al., 1990; Sian et al., 1994), and excessive oxidation processes,

L-Dopa after oral intake undergoes metabolism, including oxidative metabolism of dopamine, and auto-oxidation, and is transported across the blood-brain barrier. Only less than 5% of an oral dose of L-dopa after took delivered to the brain. Remain plasmatic levels of L-dopa undergoes peripheral oxidative metabolism and may generate ROS. Likely peripheral oxidation status in PD might be affected by L-dopa therapy (Cornetta et al.,

Some studies (e.g. Cornetta et al., 2009) suggest a toxic effect of L-dopa on neuronal cell *in vitro*, while *in vivo* studies in animal models are contradictory. However, in patients with PD some authors indicated on positive correlation between oxidative stress and L-dopa therapy (Florczak et al., 2008; Migliore at al., 2002), but there are also negative correlation between oxidative stress and L-dopa dosage in peripheral blood lymphocytes (in nine patients with

As indicated by literature reports, interaction of reactive oxygen with nucleic acids leads to oxidation of guanine and formation of 8-oxo-2'-deoxyguanosine (8-oxo2dG). Oxidative modification of guanine at C8 position may take place either in nucleic acids or free cellular nucleosides and nucleotides, ready to be incorporated to newly synthesized DNA chains. Incorporation of the modified nucleotide to DNA may results in mutations due to pairing of 8-oxoguanosine with cytosine and adenosine. In the course of pairing with adenosine, 8 oxoguanosine induces GC→AT transversions (Hirano, 2008). 8-Oxoguanina or its nucleoside, 8-oxo2dG there are though to represent markers of oxidative DNA damage. Augmented levels of 8-oxo2dG were demonstrated in brain and in lymphocytes of patients with PD (Alam et al., 1997; Dorszewska et al., 2007; Florczak et al., 2008; Kikuchi et al., 2002; Zhang et al., 1999). This indicates a gradual increase of nucleic acid damage during development of this disease, and high level of oxidized guanine in DNA is considered a risk

especially in patients treated with L-dopa (Spencer et al., 1994).

PD et paper of Cornetta et al., 2009; Prigione et al., 2006).

factor for senescence and neurodegenerative diseases (e.g. PD).

**2. 8-Oxo-2'-deoxyguanosine and L-dopa treatment in Parkinson's disease** 

(Jenner, 2003).

2009).

The studies were conducted on 98 patients with PD, including 37 women and 61 men aging 34-81 years (mean age: 60.8±10.7 years). Among the patients with PD, 27 patients (9 women and 18 men) awaited L-dopa treatment (patients' age: 34-79 years) and the remaining 71 individuals, 28 women and 43 men (patients' age: 35-81 years) were treated with L-dopa preparations in daily doses (up to 5 years treatment to 500 mg/day, 5-10 year treatment 500- 800 mg/day, and over 10 year treatment 800-1500 mg/day).

Control group included 50 individuals, 34 women and 16 men, 22-76 years of age (mean age: 44.6±16.2 years).

Patients with PD were diagnosed using the criteria of UK Parkinson's Disease Society Brain Bank (Litvan et al., 2003), however stage of disease according to the scale of Hoehn and Yahr.

None of the control subjects had verifiable symptoms of dementia or any other neurological disorders and smoking, and drinking habits.

A Local Ethical Committee approved the study and the written consent of all patients or their caregivers was obtained.
