Progress and Prospects in Parkinson's Research/Therapy/Neuroprotection/Creatine
There is a consistent history of research indicating a neuroprotective role for creatine in the treatment of PD. It is sold widely as a nutritional supplement.
Creatine is a nitrogenous organic acid that is produced from amino acids in the kidneys and liver. It is taken up by skeletal muscles, where it boosts the production of ATP. Creatine is not synthesized in the brain, but is made in glial cells. Neurons receive creatine slowly from nearby glia and from the blood via the creatine transporter. The function of a creatine transporter in mitochondrial membranes has not been well characterized. Its potential for use as a therapy for any disease which engenders muscular degeneration has been recognised for some time.
Matthews et al  reasoned that creatine and its derivatives might buffer against ATP depletion and thereby exert neuroprotective effects. They administered creatine to mice, which had been rendered Parkinsonian by the application of MPTP.
We found that oral supplementation with either creatine or cyclocreatine produced significant protection against MPTP-induced dopamine depletions in mice. Creatine protected against MPTP-induced loss of Nissl and tyrosine hydroxylase immunostained neurons in the substantia nigra.
NINDS NET-PD Investigators  This trial was to test whether creatine and minocycline alter the course of early PD relative to a predetermined futility threshold for progression of PD in a randomized, double-blind, Phase II futility clinical trial.
200 subjects were tested and the conclusions stated:-
Both creatine and minocycline should be considered for definitive Phase III trials to determine if they alter the long term progression of Parkinson disease (PD).
The National Institute of Neurological Disorders and Stroke (NINDS)  announced a double-blind, placebo-controlled, phase III study of the therapeutic effects of creatine. It invlves 1720 people with early-stage PD at 51 medical centres in the United States and Canada. The study is scheduled to last from 5 to 7 years.
Adhihetty and Flint-Beal  made a detailed case for consideration of creatine as a neuroprotective agent.
NINDS NET-PD Investigators carried out an 18-month follow-up on a creatine and minocycline futility study.This comprised a cohort of rently diagnosed PD patients not yet prescribed dopamine replacement therapy.
By 18 months, symptomatic treatment of PD symptoms was required in 61% of creatine, 62% of minocycline, and 60% of placebo-treated subjects.
Yang et al  examined whether a combination of CoQ(10) with creatine can exert additive neuroprotective effects in an MPTP mouse model of Parkinson's disease.
The combination of the two agents produced additive neuroprotective effects against dopamine depletion in the striatum and loss of tyrosine hydroxylase neurons in the substantia nigra pars compacta (SNpc) following chronic subcutaneous administration of MPTP.
The combination treatment resulted in significant reduction in lipid peroxidation and pathologic alpha-synuclein accumulation in the SNpc neurons of the MPTP-treated mice.
We also observed additive neuroprotective effects in reducing striatal lesion volumes produced by chronic subcutaneous administration of 3-NP to rats.
The combination treatment showed significant effects on blocking 3-NP-induced impairment of glutathione homeostasis and reducing lipid peroxidation and DNA oxidative damage in the striatum.
Lastly, the combination of CoQ(10) and creatine produced additive neuroprotective effects on improving motor performance and extending survival in the transgenic R6/2 HD mice
Kones  carried out a comprehensive review of the potential of vreatine in neurotherapy.
Jäger. Ralf; Puroura, Martin: Shao, Andrew; Inoune, Toshitada and Kreider, Richard B. Full Text Amino Acids. 40 (5): 1369–1383.
Analysis of the efficacy, safety, and regulatory status of novel forms of creatine.
Use the following links to query the PubMed, PubMed Central and Google Scholar databases using the Search terms:- Parkinson's_Disease Creatine.
This will list the latest papers on this topic. You are invited to update this page to reflect such recent results, pointing out their significance.
- Substances with possible neuroprotective properties:
- Caffeine,--Celastrol,--Co-Enzyme Q10,--Creatine,--DHA,--Exendin-4 (EX-4),--GDNF,--Glutathione (GSH),--GM1,--Isradipine,--Melatonin,--Minocycline,--Nicotine,--NSAIDs,--Phenylbutyrate,--Phytic Acid,--Probucol,--Quinoxaline,--Rasagiline,--Riboflavin,--Statins,--Tolcapone,--Urate & Uric Acid,--Vitamin D,--Vitamin E,--
- Matthews, R. T.;Ferrante, R. J.; Klivenyi, P.; Yang, L.; Klein, A. M.; Mueller, G.; Kaddurah-Daouk, R. and Beal, M. F. (1999) Abstract Exp. Neurol. 157 (1):142 - 149. Creatine and cyclocreatine attenuate MPTP neurotoxicity. http://www.ncbi.nlm.nih.gov/pubmed/10222117
- NINDS NET-PD Investigators (2006) Abstract Neurology. 66 (5):664 - 671. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. http://www.ncbi.nlm.nih.gov/pubmed/16481597
- NINDS (22/3/2007) Press Release NIH Announces Phase III Clinical Trial of Creatine for Parkinson's Disease http://www.ninds.nih.gov/news_and_events/news_articles/pressrelease_creatine_03222007.htm
- Adhihetty Peter J. and Flint Beal, M. (2008) Full Text Neuromolecular Med. 10 (4): 275–290. Creatine and Its Potential Therapeutic Value for Targeting Cellular Energy Impairment in Neurodegenerative Diseases. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886719/?tool=pmcentrez
- NINDS NET-PD Investigators. (2008) Abstract Clin. Neuropharmacol. 31 (3):141 - 150. A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results. http://www.ncbi.nlm.nih.gov/pubmed/18520981
- Yang,Lichuan; Calingasan, Noel Y.; Wille, Elizabeth J.; Cormier, Kerry; Smith, Karen; Ferrante, Robert J. and Flint Beal, M. (2009) Full Text J. Neurochem. 109 (5): 1427–1439. Combination Therapy with Coenzyme Q10 and Creatine Produces Additive Neuroprotective Effects in Models of Parkinson’s and Huntington’s Diseases. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866530/?tool=pmcentrez
- Kones, Richard (2010) Full Text Clin. Pharmacol. 2: 185–198. Mitochondrial therapy for Parkinson’s disease: Neuroprotective pharmaconutrition may be disease-modifying http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262379/?tool=pmcentrez