This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A major goal of the neuroscience community is to develop neuroprotective treatment strategies that will slow or forestall the progression of chronic neurodegenerative disease. Parkinson's disease ((PD) is one of the most common adult-onset neurodegenerative disorders, affecting approximately 1 million people in North America that is characterized chronically by tremor, rigidity, bradykinesia and postural instability. The clinical features of PD usually emerge in mid to late adulthood with tremor and bradykinesia being the most obvious initial manifestations. Illness and disability progressively advance despite treatments that temporarily ameliorate the signs and symptoms of PD. Many patients have deterioration in cognitive performance and disorders mood and behavior in addition to the progressive impairment of motor function. Eventually PD leads to profound functional disability in the areas of employability, ambulation and self-care. Although the advent of levodpa therapy has been associated with a prolongation of survival in RD, there is still substantial functional disability associated with advancing PD {Hoehn et al. 1976; Uitti, et al. 1993; Diamond, et al., 1987; Rajput, et al., 1984; Clarke, et al., 1995}. No treatment has been definitively identified to slow the progression of PD. Current dopaminergic therapies in PD are symptomatic (relieve signs and symptoms), but there are both short-term (motor fluctuations) and long-term (possible hastening of disease progression) concerns about these medications that warrant a reassessment of therapeutic strategies. The pathology of PD is characterized by the loss of pigmented neurons in the brainstem, particularly dopaminergic neurons in the substantia nigra pars compacta and neuroadenergic neurons in the locus ceruleus. The loss of nigral neurons is associated with the presence of intracytoplasimic eosinophilic inclusions (Lewy bodies). The cause of neuronal dysfunction and death, and the nature of intracytoplasmic inclusions remain largely obscure, although the latter are consistently immunostained with antibodies to alpha-synuclein and ubiquitin.These neuropathologic changes are associated with neurochemical abnormalities including diminished striatal levels of dopamine and its metabolites. Although the pathogenesis of PD has not been fully elucidated, there are important clues as to potential mechanisms. The identification of a large familial cluster of PF with a mutation in the alpha synuclein and ubiquitin. These neuropathologic changes are associated with neuropathologic changes are associated with neurochemical abnormalities including diminished striatal levels of dopamine and its metabolites. Although the pathogenesis of PD has not been fully elucidated, there are important clues as to potential mechanisms. The identification of a large familial cluster of PD with a mutation in the alpha-synuclein gene [Polymeropoulos, et al., 1997], the identification of mutations in the parkingene [Kitada, et al., 2998] and evidence for familiar aggregation of PD in Iceland are epidemiologic studies [Gorell, et al., 2998; Seidler, et al., 1996] suggesting that environmental factors may contribute to the development of PD. Currently the relative contribution and importance of these factors are unknown. Based on accumulated observations in animal models, there appear to be several classes of agents that may be useful as neuroprotective strategies. These classes include NOS inhibitors, anti-apoptotic agents such as JNK inhibitors and potentially MAP-B inhibitors (via the mechanism of bcl-2 upregulation), neuroimmunophilin compounds, glutamate antagonists (including amantadine and riluzole), D2 receptor agonists including pramipexole antioxidant agents including Coenzyme Q10 and acetyl-levo-carnitine, and anti-inflammatory agents including sodium salicylate, acetylsalicylic acid and cyclo-oxygenase 2 inhibitors. In addition to having demonstrated efficacy in preclinical models of PD, several of these compounds have been tested in humans, including dosage ranging tolerability studies. The impact of inhibitors on disease progression has also been reported. Minocycline is a semisynthetic second-generation tetracycline antibiotic that has neuroprotective properties that are distinct from its anti-microbial action. Minocycline is FDA approved for the treatment of a variety of infections including brain and meningeal infections and has been well tolerated when used chronically for diverse conditions such as acne and rheumatoid arthritis. Minocycline is highly lipid soluble and has been shown to have good brain penetration and bioavailability (Saivin 1988). The toxicities of Minocycline are similar to other tetracyclines and it is contraindicated in pregnancy and during childhood. Minocycline is protective in a broad range of models of CNS injury and degeneration including MPTP and 6 hydroxydopamine models of PD (Wu, et al., 2002) and excitotoxicity (Tikka, et al., 2001). With respect to PD, the main actions of Minocycline are twofold: its ability to inhibit microglial activation and microglial derived mediators of cytotoxic damage such as interleukin-1beta, NADPH-oxidase, and inducible nitric oxide synthase (iNOS) and interrupt apoptosis via inhibition of caspase 1 and 3 (Du, et al., 2001; Chen, et al., 2000). Creatine is a natural derivative of the amino acids arginine and glycine. In humans it is synthesized primarily in the liver, kidney and pancreas and can be supplied endogenously through the diet. The primary food sources are animal protein including meat and fish. Cells primarily use creatine in the intermediate form of phosphocreatine that serves as as a phosphate donor to generate AT from ADP. Creatine supplementation by humans has generally been used for improving performance in athletes. Oral supplementation of creatine leads to increased plasma free creatine, increased muscle and brain creatine and phosphocreatine and can lead to enhanced athletic performance (Williams, et al., 1998; Gordon, et al., 1995; and Earnest, et al., 1995). There have been no major safety or tolerability problems with oral supplementation of creatine in dosages as high as 20 grams per day for short periods in normal healthy individuals. The main reasons for using creatine in PD is its potential to support and stabilize mitochondrial function by serving as an energy buffer. Evidence of mitochondrial dysfunction and oxidative stress has been shown in experimental models of PD and in tissue from PD patients. Creatine could support or augment mitochondrial function by acting as an energy buffer, by acting indirectly as an antioxidant, and by antagonizing mitochondrial permeability (Tarnopolsky et al., 1999). Creatine is protective in animal models of PD (Mathews, et al., 1999) and other neurodegenerative disorders including HD (Andreassen, et al., 2001), and ALS (Klivenyi, et al., 1999).
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