Table 1.
Overview of antioxidant compounds explored in this review with a potential role in HD management.
| Antioxidant | Mechanism of Action |
Model | Effects | References |
|---|---|---|---|---|
| Vitamin C | In the presence of ROS, Vitamin C quickly oxidizes to dihydroxy ascorbic acid, acting as a regulator of redox balance in neurons | R6/2 mice | Restoration of behavioral response | [188] |
| Modulation of neuronal glucose uptake | [189] | |||
| STHdhQ cells | An early impairment of ascorbic acid uptake in HD neurons. | [190] | ||
| Modulation of neuronal glucose uptake | [189] | |||
| Selenium | Effects are mainly exerted due to the antioxidant function of selenoproteins, which help maintain the intracellular redox status and prevent cellular damage from free radicals | Quinolinic acid rat model of HD | Selenium partially protects against quinolinic acid-induced toxicity | [191] |
| 3-NP-induced HD-like rat model | Protective effects against HD-like signs induced by 3-NP in rats | [192] | ||
| N171-82Q mice | Sodium selenite supplementation decreased brain weight loss and GSSG levels, but also increased motor function | [193] | ||
| Unsaturated Fatty Acids | They display antimicrobial, antioxidant, and anti-inflammatory properties |
3-NP-induced HD-like rat model | EVOO act as a powerful brain antioxidant | [194] |
| Decreased lipid peroxidation and GSH recovery | [195] | |||
| Quinolinic acid rat model of HD | EVOO and fish-oil counteracted oxidative damage, increasing PPARg expression, and restoring rat behavior | [196] | ||
| HD patients | Restoration of the motor function | [197,198] | ||
| Creatine | It is effective against superoxide, peroxynitrite, and hydroxyl radicals | R6/2 mice | A role of metabolic dysfunction in a transgenic mouse model of HD was supported, suggesting a novel therapeutic strategy to slow the pathological process | [199] |
| N171-82Q mice | Creatine may exert therapeutic effects in HD | [200] | ||
| 3-NP-induced HD-like rat model | Creatine counteracted motor impairment and cognitive abnormalities | [201] | ||
| HD patients | Creatine supplementation significantly reduced elevated serum levels of 8-OHdG back to baseline levels seen in controls | [202] | ||
| Slowing of the ongoing cortical atrophy | [203] | |||
| Creatine monohydrate is not beneficial for slowing functional decline | [204] | |||
| Coenzyme Q10 (CoQ10) | It acts as an electron carrier in ETC 1 and reduces singlet oxygen, prevents oxidation of bases in mitochondria and formation of lipid peroxyl radicals and protein oxidation |
R6/2 mice | CoQ10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intra-nuclear inclusions | [205] |
| The combination of CoQ10 and creatine improved motor performance and promoted survival in mice | [206] | |||
| Creatine promoted survival of mice, improved the motor function, and counteracted the striatal atrophy | [203] | |||
| 3-NP-induced HD-like rat model | The combination treatment blocked 3-NP-induced impairment of glutathione homeostasis, reduced lipid peroxidation and DNA oxidative damage in the striatum | [206] | ||
| HD patients | Dosages of 2400 mg/day may provide the best balance between tolerability and blood level achieved | [207] | ||
| Idebenone | It has antioxidant properties similar to CoQ10. It is a substrate of NQO 1 and 2 | Kainic acid-induced rat model | Restoration of GAD immunoreactivity | [208] |
| HD patients | No impact for idebenone on HD patient conditions compared to the placebo controls | [209] | ||
| Curcumin | It is involved in several functions, among which are antioxidant, neuroprotective, and anti-inflammatory activities. Regulates various pathways related to cell survivor, caspases, tumor suppression, and others | Quinolinic acid model of HD in rats | Combination of curmcumin and piperine showed strong antioxidant and protective effect against quinolinic acid-induced behavioral and neurological alteration in rats | [210] |
| Drosophila HD model | Suppression of cell death | [211] | ||
| Metabolic anomalies amelioration, ROS levels reduction, and motor impairment counteraction have been obtained after curcumin administration | [212] | |||
| R6/2 mice | Overall amelioration of the HD phenotype | [213] | ||
| Grape Seed Polyphenol Extract (GSPE) | It limits lipid peroxidation and reduces inflammation | R6/2 mice | GSPE might be able to modulate the onset and/or progression of HD | [214] |
| PC-12 HD | Reduced levels of carbonyl heightened by mHtt expression and inhibited formation of mHtt aggregate | |||
| Lycopene | It exerts antioxidant effects by quenching singlet oxygen |
3-NP-induced HD-like rat model | Pretreatment improved behavioral symptoms, counteracted oxidative damage, restored the activity of mitochondrial enzymes, but also reduction in lipid peroxidation, NO and SOD levels, and behavioral impairment | [215] |
| Administration of lycopene in combination with other compounds lead to modulation of NO, resulting in restoration of behavioral and biochemical improvement | [216] | |||
| Combination treatment of lycopene and quercetin with and without poloxamer 188 in HD alleviate anxiety and depression than single drug therapy | [217] | |||
| Melatonin | It shows strong antioxidant activity by scavenging ROS/ RNS and inhibiting NOS but also protects lipids in membranes, proteins in cytosol, DNA in nucleus and mitochondria from free radical damage |
3-NP-induced HD-like rat model | Melatonin prevents the deleterious effects induced by 3-NP | [218] |
| Quinolinic acid model of HD in rats | Melatonin helps in neurotoxicity caused by quinolinic acid in rats | [219] | ||
| Kainic acid-induced rat model | Melatonin counteracted the oxidative damage promoting neuroprotection | [220] | ||
| N-Acetylcysteine | It reduces oxidative stress by decreasing ROS and lipid peroxidation, and by restoration of antioxidant enzymes |
3-NP-induced HD-like rat model | NAC treatment may be a useful therapeutic strategy against 3-NP neurotoxicity and HD | [221] |
| NAC treatment counteracted mitochondrial dysfunctions and neurobehavioral deficits | [222] | |||
| R6/1 mice | NAC rescued glutamatergic dysfunction and depressive-like behavior in HD | [223] | ||
| Rutin | It shows antioxidant, anti-inflammatory, neuroprotective, and immunomodulatory properties. | 3-NP-induced HD-like rat model | Rutin improved the behavioral alterations and restored the activities of mitochondrial complex enzymes in rat model | [224] |
| Rutin may have an important role in protecting the striatum from oxidative stress caused by 3-NP | [225] | |||
| Tauroursodeoxycholic acid (TUDCA) | A hydrophilic bile acid, has anti-inflammatory and cytoprotective effects, antioxidant effects; mechanism of action not fully defined yet | 3-NP-induced HD-like rat model | TUDCA administration counteracted apoptosis and reduced lesion volumes, but also protected against cognitive impairment and motor deficit | [226] |
| R6/2 mice | Systemic administration of TUDCA significantly counteracted striatal neuropathology, reduced apoptosis, and improved locomotor and sensorimotor deficits | [227] | ||
| Tacrolimus (FK-506) | It has anti-inflammatory and antioxidant properties via modulation of NOS and HO activities | 3-NP-induced HD-like rat model | Treatment with tacrolimus improved behavioral anomalies and restored the levels of oxidative stress markers and antioxidant enzymes such as SOD and CAT | [228] |
| Primary rat striatal neurons | Treatment with tacrolimus counteracted effects of 3-NP exposure, inducing neuroprotection and reducing apoptosis | [229] | ||
| STHdhQ cells | ||||
| Synthetic triterpenoids | Triterpenoids, particularly the analogs of CDDO, have antioxidant and anti-inflammatory properties acting via Nrf2/ARE pathway | 3-NP-induced HD-like rat model | CDDO-MA can be neuroprotective in experimental model of HD | [206] |
| N171-82Q mice | CDDO-EA and CDDO-TFEA upregulated Nrf2/ARE induced genes in the brain and peripheral tissues, reduced oxidative stress, improved motor impairment and increased longevity, also rescuing striatal atrophy in the brain and vacuolation in the brown adipose tissue | [230] | ||
| XJB-5-131 | Synthetic compound with antioxidant properties and electron scavenging ability | HD150KI mice (test) C57BL/6 mice (controls) | XJB-5-131 can suppress weight loss, ameliorate mitochondrial activity, and improve motor performance | [231] |
| HdhQ150 mice | XJB-5-131 administration led to reduced neuronal atrophy and improved motor function, but also reduced level of 8-OHdG in mitochondria and nucleus of striatal cells derived from the mice | [232] | ||
| R6/2 mice | Chronic treatment with XJB-5-131 ameliorated behavioral e physiological deficits in an age- and sex dependent manner | [233] | ||
| Probucol | Lipid-lowering agent with antioxidant and anti-inflammatory properties | 3-NP-induced HD-like rat model | Improvement in motor function and oxidative stress condition with stimulation of GPx activity | [234] |
| YAC128 transgenic HD mouse model | Chronic administration of probucol reduced the occurrence of depressive-like behaviors | [235] | ||
| BN82451 | It reduces excitotoxicity, oxidative stress, and inflammation and is also a mitochondrial protective agent | R6/2 mice | BN82451 promoted survival, improved motor function, reduced morphology loss, and reduced levels of aggregates positive to ubiquitin | [236] |
| Kynurenine-3-monooxy inhibitor: JM6 | Inhibition of KMO 2 in blood increases kynurenic acid in brain and reduces extracellular glutamate and free radical production | R6/2 mice | Administration of JM6 resulted in increased kynurenic acid levels and reduced extracellular glutamate in the brain, prolonged lifespan and prevented synaptic loss | [237] |
1 ETC: Electron Transport Chain; 2 KMO: Kynurenine Mono-Oxygenase.