Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease

Abstract

There is substantial evidence that bioenergetic defects and excitotoxicity may play a role in the pathogenesis of Huntington's disease (HD). Potential therapeutic strategies for neurodegenerative diseases in which there is reduced energy metabolism and NMDA-mediated excitotoxicity are the administration of the mitochondrial cofactor coenzyme Q10 and the NMDA antagonist remacemide. We found that oral administration of either coenzyme Q10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intranuclear inclusions in the R6/2 transgenic mouse model of HD. The combined treatment, using coenzyme Q10 and remacemide together, was more efficacious than either compound alone, resulting in an approximately 32 and 17% increase in survival in the R6/2 and N171-82Q mice, respectively. Magnetic resonance imaging showed that combined treatment significantly attenuated ventricular enlargement in vivo. These studies further implicate defective energy metabolism and excitotoxicity in the R6/2 and N171-82Q transgenic mouse models of HD and are of interest in comparison with the outcome of a recent clinical trial examining coenzyme Q10 and remacemide in HD patients.

Fig. 1.

Kaplan–Meier survival curves showing the effects of coenzyme Q_10, remacemide, and the combination of coenzyme Q₁₀ and remacemide on cumulative survival in R6/2 transgenic mice (A) and the combined therapy in N171–82Q transgenic mice. Although both coenzyme Q₁₀ and remacemide equally improved survival in the R6/2 mice (p < 0.001), the combination treatment was more than twice that of either compound alone (p < 0.0001). Although the combined therapy significantly extended survival in the N171–82Q mice (p < 0.05), the significance value was much lower because of marked variability in this murine model of Huntington's disease. CoQ, Coenzyme Q₁₀.

Fig. 2.

Effects of coenzyme Q_10, remacemide, and the combination of coenzyme Q₁₀ and remacemide on rotarod performance in R6/2 transgenic mice (A). All three treatments significantly improved motor performance throughout the extent of the lifespan of the mice. The combined treatment was more efficacious than either treatment alone. Effects of coenzyme Q_10,remacemide, and the combination of coenzyme Q₁₀ and remacemide resulted in significant attenuation of body weight loss in comparison with the unsupplemented R6/2 mice (B). The combined oral supplement resulted in less weight loss than either compound separately in the R6/2 transgenic mice. There was a significant reduction in weight loss from 9 and 7 weeks in the separate compound trials and combined treatment, respectively (p < 0.05; p < 0.01). The combined oral supplement resulted in a significant attenuation of weight loss in the N171–82Q mice at ∼15 weeks and continued throughout the remaining lifespan (C).CoQ, Coenzyme Q₁₀.

Fig. 3.

Effects of the combined treatment of coenzyme Q₁₀ and remacemide on gross atrophy and ventricular enlargement in R6/2 mice at 13 weeks. In comparison with a littermate nonmutant transgene mouse (A), marked gross atrophy and enlarged lateral ventricles are evident in the unsupplemented R6/2 mouse (B) in coronal sections at the rostral level of the anterior commissure. Less atrophy and ventricular enlargement are seen in the supplemented mouse (C). Scale bar (shown in A): 2 mm.

Fig. 4.

A, Selected T2-weighted images from four consecutive 1 mm slices in both a coenzyme Q₁₀/remacemide-treated and an untreated animal. Note the much larger ventricles in the untreated animals. B,Bar graph of the effect of coenzyme Q₁₀/remacemide treatment on ventricular size in the HD mice. CoQ, Coenzyme Q₁₀;Rem, remacemide; Untreat, untreated.

Fig. 5.

Photomicrographs of Nissl-stained tissue sections from the dorsomedial aspect of the neostriatum in a littermate nonmutant transgene mouse (A), unsupplemented R6/2 mouse (B), and a combined coenzyme Q₁₀ and remacemide-treated R6/2 mouse (C) at 91 d of age. There is marked neuronal atrophy with small angulated neurons in the unsupplemented mouse (B), with relative preservation of neuronal size and number in the treated mouse (C). Scale bar (shown in A): 100 μm.

Fig. 6.

Graph of the number of huntingtin-positive aggregates in the neostriatum at 9 and 13 weeks in unsupplemented (unsup) and combined coenzyme Q₁₀ and remacemide-treated (CoQ/Rem) R6/2 mice. There was a significant (p < 0.01) delay in the formation of aggregates within the neostriatum in the combined treatment mice at both time points, in comparison with the unsupplemented mice.

Fig. 7.

Photomicrographs of immunostained huntingtin tissue sections from the dorsomedial aspect of the neostriatum at the rostral level of the anterior commissure in combined coenzyme Q₁₀ and remacemide-treated and unsupplemented R6/2 mice at 9 weeks (A and B, respectively) and at 13 weeks (C and D, respectively). There are significantly fewer huntingtin-positive aggregates in treated mice at 9 and 13 weeks (A, C) in comparison with the unsupplemented mice at the same time points (B, D). Scale bar (shown inD): 100 μm.