**9. Acknowledgement**

This work was supported by the Department of Veterans Affairs Research and Development Services Northwest Network Mental Illness Research, Education and Clinical Center at the Seattle Puget Sound Health Care Center. The authors thank Dr. Charles Wilkinson and Carl Sikkema for CSF catecholamine analysis.

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**12** 

*France* 

**A Therapeutic Target** 

Max de Reggi and Bouchra Gharib

**The Energy Crisis in Parkinson's Disease:** 

Mhamad Abou-Hamdan, Emilie Cornille, Michel Khrestchatisky,

The energy demand of the brain is very large: it accounts for 20% of the body's energy consumption, even though its weight is less than 2% of the total body mass. In the adult, brain energy comes primarily from glucose through oxidative glycolysis. The end product is acetyl-coenzyme A (acetyl-CoA), which enters the mitochondria and feeds into the tricarboxylic acid (TCA) cycle to produce energy in the form of reductants, such as NADH. The chemical energy of NADH is then used by the respiratory chain, or electron transport chain, to synthesize ATP (Fig. 1). Energy depletion is a major factor in the cascade of events culminating in dopaminergic neuronal death in Parkinson's disease (PD). There are two reasons for that. First, a frequent feature of the disease, as well as of other neurodegenerative diseases, is an alteration of glucose metabolism. Second, there is a decrease of mitochondrial respiratory chain activity due to, in particular, inhibition of the

Complex I activity is redox-dependent and thiol-regulated; therefore its inhibition is associated with oxidative stress. Depletion of GSH, a major antioxidant and redox modulator, is observed in the substantia nigra of parkinsonian patients, as well as in the mouse MPTP model of the disease. Conversely, the restoration of GSH levels preserves complex I activity. Accordingly, the maintenance of cellular redox homeostasis by thiol

In the case of the alteration of glucose metabolism, the brain has the ability to adapt its metabolism and to increase its reliance on lipids for energy production, through fatty acid βoxidation. The process involves a mitochondrial oxido-reductase superfamily with broad substrate specificity. The penultimate step of the process is catalyzed by L-3-hydroxyacyl-CoA dehydrogenase (HADH II) (EC 1.1.1.35). HADH II overexpression protects against acute brain injury and chronic neurodegeneration. By-products of fatty acid β−oxidation are the ketone bodies β-hydroxybutyrate and acetoacetate. When injected into mice or rats, or administered in the form of a ketogenic diet, ketone bodies have a protective role in a broad

In the present report, we examine the brain energy metabolism, its alterations associated with PD and how fatty acid β-oxidation can compensate such impairment. Energy store boosting agents have potential therapeutic properties. Pantethine, the precursor of vitamin

electron transport system complex I (NADH-ubiquinone oxidoreductase).

agents protects against nigrostriatal toxicity.

spectrum of cerebral injuries and diseases.

**1. Introduction** 

*NICN, UMR6184, CNRS, Aix-Marseille University, Marseille* 

fibers in the striatum and the substantia nigra pars reticulata in Parkinsonian model rats. *Neurosci. Res*. 59:1-7.

