Creatine supplementation lowers brain glutamate levels in Huntington?s disease

Abstract

There is evidence from in vitro and animal experiments that oral creatine (Cr) supplementation might prevent or slow down neurodegeneration in Huntington's disease (HD). However, this neuroprotective effect could not be replicated in clinical trials, possibly owing to treatment periods being too short to impact on clinical endpoints. We used proton magnetic resonance spectroscopy ((1)H-MRS) as a surrogate marker to evaluate the effect of Cr supplementation on brain metabolite levels in HD.Twenty patients (age 46+/-7.3 years, mean duration of symptoms 4.0+/-2.1 years, number of CAG repeats 44.5+/-2.7) were included. The primary endpoint was metabolic alteration as measured by (1)H-MRS in the parieto-occipital cortex before (t1) and after 8-10 weeks (t2) of Cr administration. Secondary measures comprised the motor section of the Unified Huntington's Disease Rating Scale and the Mini Mental State Examination. (1)H-MRS showed a 15.6% decrease of unresolved glutamate (Glu)+glutamine (Gln; Glu+Gln=Glx; p<0.001) and a 7.8% decrease of Glu (p<0.027) after Cr treatment. N-acetylaspartate trended to fall (p=0.073) whereas total Cr, choline-containing compounds, glucose, and lactate remained unchanged. There was no effect on clinical rating scales. This cortical Glx and Glu decrease may be explained by Cr enhancing the energy-dependent conversion of Glu to Gln via the Glu-Gln cycle, a pathway known to be impaired in HD. Since Glu-mediated excitotoxicity is presumably pivotal in HD pathogenesis, these results indicate a therapeutic potential of Cr in HD. Thus, longterm clinical trials are warranted.

The application of NMR-based metabonomics in neurological disorders

“…Bender et al, 90 Verbessem et al, 142 Matthews et al, 150 Tabrizi et al, 146 Kasparova et al 39 Evaluation of striatal allografts in primate model of HD Palfi et al 114 Evaluation of ciliary neurotrophic factor in primate model of HD Mittoux et al 115 Metabolic profiling of blood sera from HD patients Underwood et al 122 Alzheimer's disease Metabolic characterization to improve the understanding and diagnosis of AD Fernandez et al, 40 Pfefferbaum et al, 41 Cheng et al, 48 Frederick et al 127 Schizophrenia Metabolic characterization of human brain tissues from schizophrenic patients Prabakaran et al 17 Bipolar disorder Biomarker evaluation Gallelli et al 33 …”

“…90,[142][143][144][145][146] Creatine has several potential neuroprotective effects, including buffering intracellular mitochondrial energy reserves, stabilizing intracellular calcium, and inhibiting activation of the mitochondrial permeability transition pore, which have all been linked to apoptotic and oxidative cell death. Initial pilot 1 H MRS studies have shown alterations in glutamate and glutamine ratios after creatine treatment that may be indicative of creatine enhancing the energy-dependent conversion of glutamate to glutamine, which has been shown to be perturbed in HD.…”

“…Both genetic and environmental factors have been implicated in the onset and development of PD. Twin studies, 87,88 case control studies, 89,90 and the identification of mutations in several genes in familial PD [91][92][93][94][95][96][97] point to there being a significant genetic contribution to the etiology of PD, in at least a proportion of patients. The association of environmental toxins with parkinsonism derives from studies implicating carbon monoxide, 98 manganese, 99 industrial herbicides, 100 and, most importantly, 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP).…”

Impaired Bioenergetics in Clinical Medicine: A Target to Tackle

“…Creatine also improved brain bioenergetics in a dose-ranging 31 P MRS study of adolescent females with drug-resistant depression (Kondo et al 2016). Yet, several clinical studies reported low-to-medium therapeutic potential of creatine to positively dysfunctional energy metabolism in Huntington's disease (Bender et al 2005) and Parkinson's disease (Bender et al 2006), also schizophrenia (Kaptsan et al 2007). Co-administration of creatine and ketogenic diet did not result in 31 P-MRS visible changes in muscle energy metabolism in patients with McArdle disease although the intervention showed some energy-independent beneficial effects (Vorgerd and Zange 2007).…”

Neuroprotective Agents in Glaucoma

“…Third, the administration of creatine could result in a decreased release of glutamate. This may be achieved either through increased glutamate uptake into synaptic vesicles, which is an energy-dependent process, ( Xu et al, 1996) or by an increased conversion of glutamate to glutamine (Bender et al, 2005). Finally, creatine supplementation may inhibit the opening of the PTP through the action of Mi-Ck (Beal, 2003;Kroemer et al, 2007).…”