3.4.1. Creatine

Creatine (with antioxidant properties) reduced serum levels of 8-hydroxy-2-deoxyguanosine (8-OH-2-dG) in HD patients [85,86] and is safe and tolerable at a dose of 15 g twice daily [87]. In a trial study (with HD patients), receiving a dose of 8 g/day of creatine was secure and well-tolerated but produced no marked change on the UHDRS scale [86]. A randomized double-blind study trial measuring TFC (up to 40 g daily) was terminated early due to futility criteria being reached. The use of creatine fails to delay functional decline in an early manifestation of HD [57]. In another controlled study, creatine (5 g/day; 1 year) treatment resulted in better muscle function capacity in patients with neuromuscular disease but did not show improvements in neuromuscular function and the cognitive status of stage I–III HD patients [88].

#### 3.4.2. Coenzyme Q10

Coenzyme Q10 cofactor is involved in ATP production in the electron transport chain (ETC) of mitochondria, and its supplementation in HD patients may improve mitochondrial function [89]. It was neuroprotective in R6/2 mice, delaying motor deficit, atrophy, and inclusion, and extending survival [90,91]. In a phase III randomized clinical trial, coenzyme Q10 was not effective and the trial was stopped as the futility criteria were reached (http://hdsa.org/wp-content/uploads/2015/01) [58].

#### 3.4.3. Eicosapentaenoic Acid (EPA)

Ethyl-EPA is a derivative of the n-3 polyunsaturated fatty acid EPA, which binds to the peroxisome proliferator-activated receptor of mitochondria [92]. Ethyl-EPA improves the neuronal function by inhibiting caspase and reducing mitochondrial damage by reducing the activity of the c-Jun N-terminal kinase (JNK) pathway [93,94]. Treatment with ethyl-EPA (2 g/day) showed a stable/improved motor function. However, intent-to-treat analysis showed no significant change between ethyl-EPA and placebo for total motor score 4 (TMS–4) subscale in HD patients (stage III) [95]. Patients with fewer CAG repeats showed significant improvement in TMS-4.

In a phase III, double-blind randomized control trial, ethyl-EPA did not show improvement in TMS, cognition or global impression over 6 months. After 6 months, all participants (both those in the treatment and placebo group) were given ethyl-EPA. Those in the original treatment group showed a better motor function (indicated by TMS scores). This suggests that ethyl-EPA needs a longer period before improvement can be observed which might possibly reflect a disease modification [96]. In a recent study, no significant improvement of the treatment group over placebo group was found in measures of TMS or UHDRS scores [59].

#### 3.4.4. Cystamine and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Blockers

Both cystamine and MPTP increase the survival e ffects of HD cells and inhibit oxidative damage [60].
