Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice

Abstract

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10 (CoQ10). We have reported that CoQ10 is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ10 slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ10 from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ10 significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ10 resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ10 and CoQ9 were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ10 elevated CoQ10 plasma levels and significantly increased brain levels of CoQ9, CoQ10, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ10 exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ10 in HD patients are warranted.

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Recently, Smith et al (2006) have performed a dose ranging study administering co-enzyme Q 10 (an essential cofactor of the mitochondrial electron transport chain that can act as a potent antioxidant) in R6/2 mice. The treatment was initiated at postnatal day 28 and high doses of co-enzyme Q 10 significantly extended survival in R6/2 mice up to 25.3%.…”

“…In one of these studies, R6/2 mice were treated either with remacemide (a low affinity NMDA receptor channel blocker), co-enzyme Q 10 (a lower dose than the one used in the study by Smith et al, 2006, Section 2.7), or a combination of both compounds . Oral administration of remacemide and co-enzyme Q 10 alone (starting at the early age of 21 days) improved the survival of R6/2 mice, by 15.5% and 14.5%, respectively.…”

A small-molecule therapeutic lead for Huntington's disease: Preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse

“…Although most evidence suggests that huntingtin's toxicity resides in its soluble protein-protein interactions, huntingtin aggregates mark the presence of misfolded mutant huntingtin in vulnerable cell populations and are a hallmark of HD in humans (7) and in genetic in vivo (6,8,9) and in vitro (10) models of HD. Antioxidant and energy buffering compounds, such as coenzyme Q10 (11,12), creatine (13)(14)(15), and cystamine (16,17), which are neuroprotective in HD transgenic mice, significantly reduce huntingtin aggregates. Aggregation occurs in vivo in the presence of expressed polyglutamine-containing proteins, such as huntingtin or huntingtin fragments and adaptation to high-throughput screening has enabled the identification of selective inhibitors (18,19).…”

Relative Bioavailability of Coenzyme Q10 in Emulsion and Liposome Formulations

“…The dosage under clinical trials is currently up to 3,000 mg/day for human use (Ferrante et al, 2005;Levy et al, 2006). For animal study, the dosage was up to 20,000 mg/kg/day as reported by previous researchers (Yang et al, 2005;Smith et al, 2006).…”