**7. Concluding remarks and future perspectives**

Deficits in mitochondrial activity in combination with increased oxidative stress, and agingassociated damage to mitochondrial DNA are key biochemical abnormalities associated with the pathogenesis of not only in sporadic PD but also in familial forms of the disease. Factors that trigger these mitochondrial abnormalities are still elusive, however one may speculate that strategies aimed at correcting these biochemical abnormalities might be useful in halting or slowing down the progression of PD. In this regard some of the candidate drugs which showed great efficacy in experimental models of PD have already made it to clinical trials. Preliminary clinical trial data on Coenzyme Q10 and creatine have shown some promise. There is also a great deal of enthusiasm following the recent identification of

development of PD-like motor abnormalities in mice (Tieu et al., 2003). Tieu's studies provide *in vivo* and *in vitro* evidence that DβHB protects not by alleviating MPTP-related complex I inhibition, but by enhancing oxidative phosphorylation via a mechanism

Therefore, modulation of DβHB levels may be a neuroprotective strategy for the treatment of neurodegenerative diseases such as PD. However, the long-term effects of the chronic use of DβHB on the cellular metabolism, and especially on mitochondrial function, are not known. DβHB has been administered orally for several months to two 6-months-old infants with hyperinsulinemic hypoglycemia (Plecko et al., 2002). The high dosage (up to 32 g/d) seemed to be tolerated by these patients. In addition, ketogenic diets have been used in humans as a treatment for refractory epilepsy. In general, patients tolerate the ketogenic diet well with mild side effects (Freeman et al., 2006). However, long-term ketone therapy will

A promising emerging therapeutic strategy involves fatty acids combined with pantethine. CoA is central in these fields, as illustrated by pantothenate kinase-associated neurodegeneration (PKAN). Pantothenate kinase catalyzes pantetheine phosphorylation to 4'-phosphopantetheine, the first step of CoA synthesis (Fig. 2). PKAN, due to insufficient kinase activity, occurs in early adulthood and its symptoms, such as dystonia, rigidity and tremor, recall PD and it may lead to PD in late adulthood. PKAN results in a decrease of CoA levels associated with mitochondrial dysfunction. These defects can be reversed by pantethine, the oxidized form of pantetheine. Dietary pantethine increased CoA synthesis, improved mitochondrial function, rescued brain degeneration, enhanced locomotor abilities, and increased lifespan in a Drosophila model of PKAN (Rana et al., 2010). Moreover, pantethine circumvented the impairment of fatty acid β-oxidation in rat liver mitochondria and microvessels of the brain (Morisaki et al., 1983). It has been shown recently that pantethine mitigated MPTP neurotoxicity in the mouse via the enhancement of fatty acid β−oxidation, leading to increased levels of circulating ketone bodies and improved mitochondrial function (Cornille et al., 2010). In addition, pantethine attenuates MPTPinduced neuroinflammation, as shown by reduced expression of macrophage antigen-1 (MAC-1), a critical trigger of microglial activation associated with neurodegeneration (Pei et al., 2007) (Fig. 3). Ultimately, pantethine protects from MPTP-induced blood-brain barrier

(BBB) leakage (Fig. 4) and significantly attenuates the clinical scores (Fig. 5).

Deficits in mitochondrial activity in combination with increased oxidative stress, and agingassociated damage to mitochondrial DNA are key biochemical abnormalities associated with the pathogenesis of not only in sporadic PD but also in familial forms of the disease. Factors that trigger these mitochondrial abnormalities are still elusive, however one may speculate that strategies aimed at correcting these biochemical abnormalities might be useful in halting or slowing down the progression of PD. In this regard some of the candidate drugs which showed great efficacy in experimental models of PD have already made it to clinical trials. Preliminary clinical trial data on Coenzyme Q10 and creatine have shown some promise. There is also a great deal of enthusiasm following the recent identification of

**7. Concluding remarks and future perspectives** 

dependent on mitochondrial complex II (succinate-ubiquinone oxidoreductase).

have to take into consideration possible adverse effects.

**6.3 Pantethine** 

novel mitochondrial targets such as PGC-1α and the sirtuin family of enzymes that are known to modulate aging, mitochondrial biogenesis, metabolic homeostasis and mitochondria-dependent cell death. These observations hold promise for future development of neuroprotective strategies in PD by targeting mitochondrial dysfunction. However it is important to remember that PD is a multi-factorial disease and mitochondrial dysfunction may only be a part of this complex process. Future research should thus focus on developing neuroprotective strategies by targeting multiple pathways involved in the disease process. Therapeutic approaches targeting both mitochondrial dysfunction and oxidative damage in neurodegenerative diseases and aging have great promise (Beal, 2005). Pantethine provides an example of molecule able to restore mitochondrial function while displaying antioxidant and anti-inflammatory properties. Perhaps, this safe and effective compound of natural origin merits consideration for broader use against pathologies such as PD.

The figure shows macrophage antigen-1 (Mac-1) immunostaining in SNpc, two days after MPTP injection. Microglial reaction was drastically reduced in pantethine-treated mice as compared to saline ones. No immunostaining was observed in control animals.

Evans blue was administered intravenously on day 16 after MPTP injection. The figure shows brains of saline mice with a diffuse dye leakage, and some intensively stained areas. In contrast, brains of pantethine-treated mice looked normal, with limited stained areas.

The Energy Crisis in Parkinson's Disease: A Therapeutic Target 285

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#### **8. Acknowledgements**

The authors thank Howard Rickenberg for the critical reading of the manuscript.

#### **9. References**


Fig. 5. Attenuation of the clinical scores by pantethine treatment in MPTP-injected mice.

The authors thank Howard Rickenberg for the critical reading of the manuscript.

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**13** 

**Analysis of Transcriptome Alterations in** 

*Institute of Molecular Genetics Russian Academy of Sciences,* 

Elena Filatova, Maria Shadrina, Petr Slominsky and Svetlana Limborska

The information that stems from the primary structure of DNA lies within the basis of every sign formation, although the regulation of any process occurs in different levels of cellular processes including transcription. In this context analysis of gene transcription is of great importance to improve our understanding of the pathogenesis of diverse disorders, and Parkinson's disease (PD) is not an exception. However, each disease has its own unique etiopathogenesis within organs and tissues, which is caused by disease-specific processes in cells, as well as at the genetic level. Knowledge of the etiology and pathogenesis of diseases at a cellular level opens wide prospects for diagnosis and treatment, even for complex and incurable disorders such as PD. Therefore, it is necessary to study the pathogenesis of specific disease at the cellular and genetic levels. Accordingly, the expression profiles of large numbers of genes are being studied in different neurodegenerative disorders, including PD. Although the mechanisms that initiate neuronal pathology in sporadic PD remain largely obscure, in this chapter we have tried to summarize all current knowledge in

The general approach in studying gene expression in PD is the analysis of transcript levels in tissues of the brain (the main organ that is affected in PD), which exhibit lesions that result in symptoms of PD. Unfortunately, only post-mortem tissues can be used in such studies. In addition, DNA microarrays are actively used in this type of study and there is a tendency to combine these data with the results of genome-wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) and point mutations in PD (Elstner, 2009). Combined analysis allows the identification of a number of candidate genes for further study; therefore, residual genes are more likely involved in the pathogenesis of PD

Thus, several tens of genes implicated in different metabolic pathways that are disturbed in PD have been identified during the analysis of transcription profiles in the substantia nigra of patients with PD. Mitochondrial dysfunction, oxidative stress, ubiquitin-proteasomal degradation of proteins, differentiation and functioning of dopaminergic (DA) neurons, DA

**1. Introduction** 

the field of the PD transcriptomics.

(Horan, 2009, Noureddine, 2005).

**2. Analysis of gene expression in PD** 

**2.1 Analysis of gene expression in brain tissues** 

**Parkinson's Disease** 

*Russian Federation* 

