Creatine and Its Potential Therapeutic Value for Targeting Cellular Energy Impairment in Neurodegenerative Diseases

Abstract

Substantial evidence indicates bioenergetic dysfunction and mitochondrial impairment contribute either directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders. Treatment paradigms aimed at ameliorating this cellular energy deficit and/or improving mitochondrial function in these neurodegenerative disorders may prove to be useful as a therapeutic intervention. Creatine is a molecule that is produced both endogenously, and acquired exogenously through diet, and is an extremely important molecule that participates in buffering intracellular energy stores. Once creatine is transported into cells, creatine kinase catalyzes the reversible transphosphorylation of creatine via ATP to enhance the phosphocreatine energy pool. Creatine kinase enzymes are located at strategic intracellular sites to couple areas of high energy expenditure to the efficient regeneration of ATP. Thus, the creatinekinase/phosphocreatine system plays an integral role in energy buffering and overall cellular bioenergetics. Originally, exogenous creatine supplementation was widely used only as an ergogenic aid to increase the phosphocreatine pool within muscle to bolster athletic performance. However, the potential therapeutic value of creatine supplementation has recently been investigated with respect to various neurodegenerative disorders that have been associated with bioenergetic deficits as playing a role in disease etiology and/or progression which include; Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease. This review discusses the contribution of mitochondria and bioenergetics to the progression of these neurodegenerative diseases and investigates the potential neuroprotective value of creatine supplementation in each of these neurological diseases. In summary, current literature suggests that exogenous creatine supplementation is most efficacious as a treatment paradigm in Huntington's and Parkinson's disease but appears to be less effective for ALS and Alzheimer's disease.

Creatine as a booster for human brain function. How might it work?

“…These include the fact that the human trials did not use as much creatine as trials in mice and failure to fully understand the mechanisms of each disease [92]. The trials in Parkinson's disease which did show some promise were conducted in early stage Parkinson's disease, while the Phase III trial was in patients whose disease was further progressed.…”

Using direct infusion mass spectrometry for serum metabolomics in Alzheimer’s disease

“…On the other hand, decreases in creatine and carnitine were also found in relation to this situation of abnormal energetic metabolism. Creatine plays a fundamental role in energy buffering and overall cellular bioenergetics through the creatine kinase/phosphocreatine system, being responsible for the transfer of energy from mitochondria to cytosol [68]. In the case of carnitine, several physiological functions can be highlighted, such as transport of fatty acids into mitochondria for β-oxidation, oxidation of pyruvate, and others [69].…”

Expression and distribution of creatine transporter and creatine kinase (brain isoform) in developing and mature rat cochlear tissues

“…Creatine kinase (CK) catalyzes the reversible transfer of phosphate to creatine from ATP. Creatine has long been taken as a nutritional supplement for metabolic support by athletes, and in recent years, it has received considerable attention in clinical trials as a potential oral therapy for Parkinson's and Huntington's disease with its emerging role as a CNS protectant (Dedeoglu et al 2003;Lensman et al 2006;Ravina 2006;Ohtsuki and Terasaki 2007;Adhihetty and Beal 2008;Béard and Braissant 2010). Here, we present the Wrst detailed study characterizing expression levels, tissue and cellular distribution of CRT and CK brain cytosolic isoform (CKB) in the developing and mature rat cochlea.…”