**6. Conclusion**

In conclusion, L-dopa metabolism after administration in PD patients is an important component for Hcy elevation and for increase toxicity in peripheral blood lymphocytes. Therapy of L-dopa leads to increases of the level factors inducing in oxidative stress and apoptosis as well as changes concentrations of risk factors of vascular diseases such as: Hcy, Cys and ADMA especially after long-term therapy. Analysis of the level of 8-oxo2dG, Hcy, Cys and ADMA may be a new biomarkers of severity and progression of PD.

It seems that for elevated levels of biothiols in PD, is not only important genotype *MTHFR,*  TT (C677T) but also CC (A1298C), AA (G1793A), and *MTHFD1,* AA (G1958A) and *MTR,* GG (A2756G), which have a tendency for increased frequency in PD patients. In PD, there are more significant differences of the levels of biothiols in patients with one of genotype: Hcy [*MTHFR*: CT (C677T) and GG (G1793A); *MTR*, AG (A2756G)], Met [*MTR*, AA (A2756G)], Cys [*MTR*, AG (A2756G)], and Met/Hcy [*MTHFR*: CC, CT (C677T) and AA (A1298C), and GG (G1793A); *MTHFD1* AA (G1958A); *MTR* AA (A2756G)]. Moreover only polymorphisms of folate-dependent enzyme *MTHFD1* have pointed to significant differences in intensity of turnover of circulating biothiols between both neurodegenerative diseases: AD, and PD, which differ in the localization of neurotoxic lesions in the CNS.

Therefore in PD, monitoring of thiols compound levels in particular Hcy, is recommended. In the patients with PD administration of vitamins B6, B12, folates may cause a decrease in Hcy level, due to increased efficiency of remethylation and transsulfuration processes.

### **7. References**

Accinni, R., Bartesaghi, S., De Leo, G., Cursano, C.F., Achilli, G., Loaldi, A., Cellerino, C., & Parodi, O. (2000). Screening of homocysteine from newborn blood spots by high-performance liquid chromatography with coulometric array detection. *Journal of Chromatography A*, Vol.896, No.1-2, (Obctober 2000), pp. 183-189, ISSN 0021-9673

preparations have reflected duration of administration of the drug. Patients have seemed most exposed to oxidative stress, resulting from L-dopa administration, during the first 5 years of treatment with the preparation and following long-term (over 10 years) its administration. According to Spencer et al. (1995), the augmented oxidative stress in patients treated with L-dopa might have resulted from lowered levels of antioxidants (GSH), disturbed mitochondrial transport and from excessive oxidation of dopamine. Reports of the literature (Miller et al., 2003) and present results indicate that plasma Hcy levels in PD have been affected also by pharmacotherapy with L-dopa. In present study levels of the sulfuric amino acid were also affected by duration of the 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, it seems that all time are disturbed metabolism of Hcy to Met and Cys.

Cys and ADMA may be a new biomarkers of severity and progression of PD.

which differ in the localization of neurotoxic lesions in the CNS.

dementia in the patients.

**6. Conclusion** 

**7. References** 

0021-9673

Treatment with L-dopa preparations seems to be a potential risk factor for vascular diseases in PD patients. According to Lamberti et al. (2005), administration of vitamin B12 and of folates decreases plasma level of Hcy particularly in patients with PD during treatment with L-dopa preparations and in this way prevents against intensification of vascular lesions and

In conclusion, L-dopa metabolism after administration in PD patients is an important component for Hcy elevation and for increase toxicity in peripheral blood lymphocytes. Therapy of L-dopa leads to increases of the level factors inducing in oxidative stress and apoptosis as well as changes concentrations of risk factors of vascular diseases such as: Hcy, Cys and ADMA especially after long-term therapy. Analysis of the level of 8-oxo2dG, Hcy,

It seems that for elevated levels of biothiols in PD, is not only important genotype *MTHFR,*  TT (C677T) but also CC (A1298C), AA (G1793A), and *MTHFD1,* AA (G1958A) and *MTR,* GG (A2756G), which have a tendency for increased frequency in PD patients. In PD, there are more significant differences of the levels of biothiols in patients with one of genotype: Hcy [*MTHFR*: CT (C677T) and GG (G1793A); *MTR*, AG (A2756G)], Met [*MTR*, AA (A2756G)], Cys [*MTR*, AG (A2756G)], and Met/Hcy [*MTHFR*: CC, CT (C677T) and AA (A1298C), and GG (G1793A); *MTHFD1* AA (G1958A); *MTR* AA (A2756G)]. Moreover only polymorphisms of folate-dependent enzyme *MTHFD1* have pointed to significant differences in intensity of turnover of circulating biothiols between both neurodegenerative diseases: AD, and PD,

Therefore in PD, monitoring of thiols compound levels in particular Hcy, is recommended. In the patients with PD administration of vitamins B6, B12, folates may cause a decrease in Hcy level, due to increased efficiency of remethylation and transsulfuration processes.

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**17** 

*U.S.A.* 

**Inflammatory Responses and Regulation** 

Parkinson's disease (PD) is a slow, progressive neurodegenerative disorder affecting an estimated 6 million people worldwide (Litteljohn, Mangano et al. 2011). The etiology of the disease is characterized by increasing loss over time of dopaminergic neurons (DA-neurons) in the substantia nigra (SN) as well as the depletion of dopamine in the striatum, which eventually leads to pathological and clinical symptoms (Jenner and Olanow 2006). PET imaging and post-mortem analyses of the brains of PD patients indicate that the appearance of symptoms, including tremor, bradykinesia, rigidity, slowness of movement, and postural instability (Jellinger 2001), generally are manifest once 60% of DA-neurons have died and a 70% threshold decrease in normal DA activity has been reached (Klockgether 2004; Litteljohn, Mangano et al. 2011). Epidemiological studies indicate that only about 10% of PD cases are early onset , i.e. prior to the age of 50 and occur mainly in familial clusters (Mizuno, Hattori et al. 2001). These cases have established genetic bases due to mutations in several recently identified genes, including parkin, leucine-rich repeat kinase 2 (LRRK2), α-synuclein, PINK-1, or DJ-1 (Polymeropoulos, Lavedan et al. 1997; Lucking, Durr et al. 2000; Abou-Sleiman, Healy et al. 2003; Farrer, Haugarvoll et al. 2006; Sun, Latourelle et al. 2006; Jiang, Wu et al. 2007; Weng, Chou et al. 2007; Bonifati, Wu-Chou et al. 2008). The majority of PD cases (approximately 90%) are late onset and idiopathic (Tanner 2003). Although the etiology of idiopathic PD is uncertain, this form of PD particularly affects the elderly, with average onset of clinical symptoms between 60 and 65 years of age (Litteljohn, Mangano et al. 2011). Idiopathic PD is thus age-associated, with approximately 1% of the population being affected by 65-70 year of age, increasing to 4-5% at 85 years (Fahn 2003; Tansey, McCoy et al. 2007). However, the causes of idiopathic non-familial PD are probably multifactorial, with some form of genetic predisposition, environmental insults and/or aging all likely to be important factors in disease initiation and progression (Nagatsu and

Sawada 2006; Dickson 2007; Vilar, Coelho et al. 2007; Singh, Singh et al. 2008).

While the exact cause of chronic neurodegeneration of PD is not known, increasing evidence suggests that chronic inflammation is the fundamental process mediating the progressive nature of the neurodegeneration characteristic of PD (McGeer, Yasojima et al. 2001; Hirsch and Hunot 2009). In animal PD models, long-term inflammation induces progressive loss of DA neurons within the SN brain region (Gao, Jiang et al. 2002; Dauer and Przedborski 2003; Bartels and Leenders 2007). Neuroinflammation, which is characterized by activation of

**1. Introduction** 

**in Parkinson's Disease** 

Lynda J. Peterson and Patrick M. Flood *The University of North Carolina at Chapel Hill,* 

