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Creatine Information Summary

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A number of compounds were identified as candidates for further study by the Committee to Identify Neuroprotective Agents in Parkinson's (CINAPS). Of these compounds, Minocycline, Creatine , CoQ10 and GPI 1485 have been selected for testing in the Neuroprotection Clinical Trial.

CREATINE

There is evidence of both oxidative stress and mitochondrial dysfunction in PD, which can be potentially be counteracted by creatine's protective effects. This drug has the ability to restore and maintain cellular energy reserves and is generally well tolerated, with the following occasional side effects: weight gain, edema, nausea, vomiting and diarrhea. In rare cases, muscle cramps, liver and kidney problems have been reported.

 

Scientific Rationale

C reatine is converted to phosphocreatine by creatine kinase in various tissues.1 Phosphocreatine functions as an energy buffer by transfer of a phosphoryl group to ADP and thereby maintaining ATP concentrations. In doing so, it ensures the function of active transport mechanisms (Na+-K+-ATPase, Ca+2-ATPase) that regulate cellular homeostasis.2,3 Creatine may also act as an indirect antioxidant by enhancing energy transduction. There is evidence of both oxidative stress and impaired mitochondrial function in PD. It was initially believed that creatine exerted protective effects by antagonizing the formation of the mitochondrial permeability transition pore (MPT). This has not been supported by preclinical studies, and recent emphasis has been on creatine's ability to restore/maintain cellular energy reserves following excitotoxic states.3
  1. Dev Neurosci. 1993;249-60.
  2. Brain Res. 2000;860:195-8.
  3. J Neurochem. 2001;76:425-34.
  4. Ann Neurology 2001; 49: 561-574.

Animal Model Data

RODENT: MPTP produces neurotoxic effects by disrupting mitochondrial energy production. Once MPTP is converted to MPP+, it blocks mitochondrial energy production through the inhibition of complex I of the electron transport chain, ultimately leading to neuronal injury.

Creatine has demonstrated efficacy for prevention of MPTP-induced neuronal injury in rats.1,2 Rats given a 1% creatine diet for 2 weeks experienced only a 10% loss of DA neurons after MPTP administration (not significantly different from non-MPTP treated animals) in contrast to a 70% neuronal loss among those not supplemented with creatine. Sparing of neurons in this model increased with higher levels of creatine supplementation, ranging from 0.25-1%; however diets >= 2% showed no additional benefit.

  1. Exp Neurol. 1999;157:142-9.
  2. Pharmacol Rev. 2000;53:161-71.

Pharmacokinetics (including blood brain barrier (BBB) penetration)

Following oral administration, creatine circulates to the brain and it is transported into cells by a high affinity transmembrane transport process.1 In animals, oral supplementation (human equivalent 400 mg/kg/day) significantly increases (30-54%) brain creatine (creatine/phosphcreatine) after 4 weeks (p<0.01).2 There is continued rise in brain creatine concentrations for up to 8 weeks. Interestingly, creatine tends to be transported to organs with low baseline concentrations, so if there is a prexisting local deficit, creatine is more likely to concentrate in the specific organ.2 There have been no well-performed pharmacokinetic studies examining creatine. Preliminary reports show that creatine (1-10 g) has a Tmax of < 2 hours; however with higher dosages, the Tmax is delayed > 3 hours.3 Delayed absorption related to increasing dosage may be due to the fact that creatine is primarily transported across the intestine by amino acid transporters. The extent of creatine's protein binding is not known.

Creatine is eliminated renally at a rate similar to xylose, suggesting that its renal elimination is comparable to GFR. However in unsupplemented patients, most creatine is reabsorbed after renal excretion.3 Many other variables are found to increase creatine uptake, including exercise, catecholamines, and IGF-1 and insulin.3

  1. J Neurochem. 199;52:544-50.
  2. Life Sci. 2001;69:1805-15.
  3. Pharmacol Rev. 2000;53:161-71.

Safety/Tolerability in Humans

Generally well tolerated, with occasional weight gain, edema, nausea, vomiting, diarrhea. Muscle cramps, hepatic, and renal dysfunction are rare.

Pharmacol Rev. 2000;53:161-71.

Drug Interaction Potential

Not studied

Clinical Trial/Epidemiological Evidence in Human PD

Several small, short-term, studies in neurological disorders with presumed bioenergetic defects, including mitochondrial disorders and myopathies, in which creatine monohydrate in dosages up to 10g/day was well tolerated.

A nn Neurology 2001; 49: 561-574

Last updated September 09, 2008