264 Mitochondrial nutrition in PD clinical trials and clinical pharmacology (4). If promising results for potential neuroprotective agents are found in these pilot studies, the agents will be evaluated in larger, more definitive Phase III trials. The preliminary study in NET-PD shows that creatine and minocycline may warrant further study in PD (5). On the other hand, Olanow and colleagues recently reported the results of a clinical trial of the propargylamine TCH 346 (N-methyl-N-propargyl-10-aminomethyl-dibenzo[b,f]oxepin) as a neuroprotective drug in early PD (6). TCH346 provides neuroprotection in animal models of PD through interaction with a glycolytic enzyme GAPDH (7,8). GAPDH protein expression is substantially increased after exposure to various toxins long before the appearance of the classic markers of apoptosis (9) and blocking expression of GAPDH is anti-apoptotic (10). In the clinical trial, there were no significant differences between the drug-treated group and placebo with respect to the primary outcome measure of time to require dopaminergic treatment or the secondary out- come measures, including changes in clinical scores or quality-of-life measures (6). Mitochondrial Function as a Therapeutic Target in PD The cause of PD remains unknown, but our under- standing of mechanisms of nigral dopaminergic neuronal death was advanced by the discovery of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that selectively damages the nigrostriatal dopaminergic system and cause a parkinsonian syndrome in humans, monkeys and mice (11–14). The discovery that MPTP acts through inhibition of complex I of the electron transport chain stimulated study of mitochondrial func- tion in the brains from patients with PD. Schapira et al. (15) reported that complex I activity was selectively reduced in the substantia nigra of patients with PD. Parker et al. (16) reported a significant reduction in complex I activity in platelets from patients with relatively advanced PD. Platelets mirror certain biochem- ical processes that occur in the brain. For example, platelets have been shown to take up dopamine, and they contain monoamine oxidase B and a-synuclein. Mizuno et al. (17) proposed that energy crisis is the most important mechanism of nigral cell death in PD. In addition, oxidative stress has also been implicated as an important contributor to nigral cell death in PD, but it’s a secondary phenomenon on respiratory failure, because respiratory failure will increase oxygen-free radical and consume glutathione. On the other hand, exposure of nigral neurons to a high risk for oxidative damage because of its high dopamine content may be the reason for more pronounced nigral complex I deficiency compared with systemic organs. Oxidative stress and mitochondrial failure produce a vicious cycle in nigral neurons. The processes leading to death of dopaminergic neurons in PD are not fully understood. Current evidence suggests that cell death in PD occurs by either apoptosis or necrosis or both (18). Whether mitochondrial dysfunction contributes to necrosis in chronic forms of the neurodegeneration is less clear. However, it is at least theoretically possible that defects in mitochondrial electron transport could be severe enough to compromise total cellular ATP production and thereby result in necrosis. Therefore, mitochondria could be an important target for neuroprotection even if the destruction of neuron appears to be apoptotic, necrotic or intermediate between the two extremes (19,20). Mitochondrial Nutrition for the Treatment of PD Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport chain where it accepts electrons from complexes I and II. Coenzyme Q also serves as an important antioxidant in both mitochondria and lipid membranes. It is particularly effective within mitochon- dria. Substantial data have implicated mitochondrial dysfunction and excessive production of reactive oxygen species in the pathogenesis of PD. Furthermore, a significant reduction (33%) in the level of CoQ10 in mitochondria has been reported in PD patients compared with that in age/gender matched control subjects (21). The central role of CoQ10 in two areas implicated in the pathogenesis of PD, mitochondrial dysfunction and oxidative damages, suggest that it may be useful in slowing the progression of PD. Parkinson Study Group conducted a phase II study of CoQ10 in patients with early untreated PD in North America and found that, particularly at the highest dosage studied, 1200 mg/day, it appeared to reduce the functional decline in the patient, as measured by the change in the total score on the Unified Parkinson Disease Rating Scale (UPDRS) (22). Although the benefit was found in all three parts of the UPDRS [part 1 (mention, behavior and mood), part 2 (activities of daily living) and part 3 (motor examina- tion)], these results should be considered preliminary until confirmed by a larger phase III study. It is important to clarify how the exogenous CoQ10 works in the brain to reduce the dopaminergic neurode- generation. Previous in vitro studies have demonstrated that CoQ10 can reduce the death of dopaminergic cells induced by rotenone (23) and H2O2 (24). These studies indicate that CoQ10 offers neuroprotection at the mitochondrial level in the apoptotic pathway against mitochondrial dysfunction and oxidative stress. Although CoQ10 attenuated the toxin-induced reduction of dopa- mine content and tyrosine hydroxylase-immunoreactive