There is a substantial body of literature, which has demonstrated that
creatine has
neuroprotective effects both in vitro and in vivo.
Creatine can protect against excitotoxicity as well as against β-
amyloid toxicity in vitro. We carried out studies examining the efficacy of
creatine as a
neuroprotective agent in vivo. We demonstrated that
creatine can protect against excitotoxic lesions produced by
N-methyl-D: -aspartate. We also showed that
creatine is neuroprotective against lesions produced by the toxins
malonate and
3-nitropropionic acid (3-NP) which are reversible and irreversible inhibitors of
succinate dehydrogenase, respectively.
Creatine produced dose-dependent
neuroprotective effects against
MPTP toxicity reducing the loss of
dopamine within the striatum and the loss of dopaminergic neurons in the substantia nigra. We carried out a number of studies of the
neuroprotective effects of
creatine in transgenic mouse models of
neurodegenerative diseases. We demonstrated that
creatine produced an extension of survival, improved motor performance, and a reduction in loss of motor neurons in a transgenic mouse model of
amyotrophic lateral sclerosis (ALS).
Creatine produced an extension of survival, as well as improved motor function, and a reduction in striatal
atrophy in the R6/2 and the N-171-82Q transgenic mouse models of
Huntington's disease (HD), even when its administration was delayed until the onset of disease symptoms. We recently examined the
neuroprotective effects of a combination of
coenzyme Q10 (
CoQ10) with
creatine against both
MPTP and 3-NP toxicity. We found that the combination of CoQ and
creatine together produced additive
neuroprotective effects in a chronic
MPTP model, and it blocked the development of
alpha-synuclein aggregates. In the 3-NP model of HD, CoQ and
creatine produced additive
neuroprotective effects against the size of the striatal lesions. In the R6/2 transgenic mouse model of HD, the combination of CoQ and
creatine produced additive effects on improving survival.
Creatine may stabilize
mitochondrial creatine kinase, and prevent activation of the mitochondrial permeability transition.
Creatine, however, was still neuroprotective in mice, which were deficient in
mitochondrial creatine kinase. Administration of
creatine increases the brain levels of
creatine and
phosphocreatine. Due to its
neuroprotective effects,
creatine is now in clinical trials for the treatment of
Parkinson's disease (PD) and HD. A phase 2 futility trial in PD showed approximately a 50% improvement in Unified Parkinson's Disease Rating Scale at one year, and the compound was judged to be non futile.
Creatine is now in a phase III clinical trial being carried out by the NET PD consortium.
Creatine reduced plasma levels of 8-hydroxy-2-deoxyguanosine in HD patients phase II trial and was well-tolerated.
Creatine is now being studied in a phase III clinical trial in HD, the CREST trial.
Creatine, therefore, shows great promise in the treatment of a variety of
neurodegenerative diseases.