**3. Homocysteine and asymmetric dimethylarginine and L-dopa treatment in Parkinson's disease**

Elevated Hcy level is a risk factor for vascular diseases, cognitive impairment and dementia, and neurodegenerative diseases (e.g. PD). It is also known that vascular dementia and cognitive impairment worsen the prognosis of PD patients, and it is important to minimize

Oxidative DNA Damage and the Level of Biothiols, and L-Dopa Therapy in Parkinson's Disease 357

Under normal conditions, in the presence of a positive Met balance, most of Hcy undergoes transsulfuration catalyzed by cystathionine β-synthetase (CBS), which requires derivative of

Homocysteine or it oxidative product, homocysteine acid are thought to exhibit its prooxidative activity most probably through its direct interaction with NMDA receptors (it represents an agonist of NMDA receptor). Agnati et al. (2005) have shown that Hcy may pass the blood/brain barrier and that level of plasma Hcy corresponds to Hcy concentration

**3.2 Influence of L-dopa treatment on the plasma level of biothiols in Parkinson's** 

In PD, the high Hcy concentration may augment risk of the disease through its direct toxic effect on dopaminergic neurons. Studies *in vitro* on human dopaminergic neurons have documented a significant increase in neurotoxicity accompanying high Hcy levels (Duan et al., 2002). In parallel, elevated Hcy levels in PD have been shown to carry potential for deterioration of cognitive and motoric functions, for depression and elevated risk to develop

Reports of the literature (Florczak et al., 2008; Miller et al., 2003) indicate that plasma Hcy levels in PD have been affected also by pharmacotherapy with L-dopa. It is indicated that in PD patients who are initiating L-dopa therapy, Hcy elevates within six weeks to a few months after L-dopa initiation (O'Suilleabhain et al., 2004a). Study Florczak et al., 2008 indicated that the sulfuric amino acids were also affected by duration of the L-dopa pharmacotherapy. The most exposed to neurotoxic effects of Hcy have seemed to be the patients during the first 5 years L-dopa treatment while its continued administration has resulted in stably elevated Hcy level. The study of Miller et al. (1997) indicates that L-dopa may induce elevated levels of Hcy during its methylation to 3-O-methyldopa (3-OMD) with involvement of COMT (catechol Omethyltransferase) both in peripheral blood leukocytes and in nigrostriatal neurons. In the course of the reaction, COMT in presence of magnesium ions induces in parallel transition of

Elevated level of Hcy in *substantia nigra* of PD patients has been demonstrated already after 3 months of L-dopa treatment (Yasui et al., 2003). Long-term administration of L-dopa is thought to promote benign vascular lesions in patients with PD and may result in the patients in cognitive disturbances or dementia, particular at late stages of treatment with the preparation (Muller et al., 1999). On the other hand, COMT has a broad detoxification potential in human. Two compounds are currently available, entacapone peripheral and tolcapone central blocking of COMT. COMT inhibition is also under suspicion to prevent motor complications and seems that has beneficial effect on the L-dopa-related hyper-Hcy as well (Muller, 2009a; Nevrly et al., 2010). Some animal studies shown that COMT inhibition can eliminate L-dopa-induced hyper-Hcy but not all previous studies confirm it. Study Dorszewska et al. (2007) have shown that augmented plasma levels of Hcy in PD possibly could have developed due to altered processes of Hcy remethylation to Met and transsulfuration to Cys. Simultaneuosly, in the PD patients a decreased concentration of Met has been observed, paralleled by elevated levels of Cys and lowered ratio of Met and Cys to Hcy. The demonstrated at present decrease in Met to Hcy ratio may be linked to transformation of Hcy to thiolactone in endothelial cells. According to one of more recent hypothesis, sulfonic sulfur of thiol compounds may be involved in development of Hcyinduced arteriosclerotic lesions (Toohey, 2001). At the same time, the demonstrated at

vitamin B6, pyridoxal phosphate.

vascular diseases (Kuhn et al., 1998).

SAM to SAH and further hydrolysis of SAH to Hcy (Fig. 2).

in the brain.

**disease** 

the risk of their occurrence as much as possible. Gorell et al. (1994) indicated that patients with PD have shown an increased risk for cardiovascular disease and stroke. In PD not only Hcy, but also cysteine (Cys), product of Hcy metabolism may promote pathological alterations such as: atherosclerosis and thrombogenesis (Muller, 2008).
