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."

Background
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.

Research
1999

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."

2006

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)."

2007

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.

2008

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.

2009

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"

2010

Kones carried out a comprehensive review of the potential of vreatine in neurotherapy.