Table 2.
Preclinical and clinical studies with different antioxidant therapies for ALS.
| Antioxidant | Preclinical animal or cellular model/ clinical trial | Dose/concentration (treatment time) | Effects | Reference |
|---|---|---|---|---|
| Vitamin E | SOD1G93A transgenic mice | 200 UI/Kg (starting at 30 days of age) | (i) Slowed disease progression, delayed (ii) Disease onset, did not affect survival time |
[140] |
| RCT | 500 mg twice daily—5000 mg/day (18 months) | (i) Did not affect the quality of life (ii) Did not affect survival time (iii) Slowed ALS progression |
[147–149] | |
| N-Acetyl-L-cysteine (NAC) | SH-SY5Y cells with SOD1G93A | 1 mM (24 h) | (i) Reduction mROS (ii) Increased ATP levels (iii) Increased viability |
[155] |
| SOD1G93A transgenic mice | 2 mg/kg/day (from 4-5 weeks of age) | (i) Prolonged the survival time (ii) Improved motor performance |
[153] | |
| RCT | 50 mg/kg s.c. infusion (12 months) | (i) Did not affect survival time (ii) Did not affect disease progression |
[156] | |
| Coenzyme Q10 | SOD1G93A transgenic mice | 200 mg/kg daily (from 50 days after birth) | (i) Prolonged the survival time | [159] |
| SOD1G93A transgenic mice | 800 mg/kg/daily (from symptom onset) | (i) No effect on survival time | [160] | |
| RCT, NCT00243932 | 2700 mg/kg, three times daily (9 months) | (i) No significant differences between treatment and placebo groups | [164, 165] | |
| Nrf2/ARE modulators | ||||
| WN1316 | SOD1H46R and SOD1G93A transgenic mice | 1-100 μg/kg/day (from 21–22 weeks of age) | (i) Improved motor function, prolonged survival time; reduced motor neuron loss, gliosis, and oxidative damage | [170] |
| Dimethoxy curcumin | NSC-34 cell lines transfected with M337V or Q331K mutant TDP-43 | 15 μM (3 days) | (i) Improved mitochondrial dysfunction | [173] |
| Nanocurcumin (SinaCurcumin) | RCL | 80 mg/day (3 months) | (i) Improved the probability of survival time | [174] |
| Curcumin (Brainoil) | RCL | 600 mg/day (6 months) | (i) Slowed disease progression, reduced oxidative stress | [175] |
| CDDO-EA, CDDO-TFEA | SOD1G93A transgenic mice | 80 mg/kg/day (starting at 30 days of age or from the onset of the disease) | (i) At presymptomatic age: enhanced motor performance and prolonged survival time (ii) At symptomatic age: slowed disease progression |
[178] |
| S(+9)-apomorphine | Fibroblasts from ALS patients | (i) Reduced oxidative stress, improved survival after oxidative insult | [179] | |
| SOD1G93A transgenic mice | 5 mg/kg/day s.c. (from day 21 until end) | (i) Enhanced motor performance, slowed disease progression | [179] | |
| EGCG | Neuronal-differentiated VSC 4.1 cells with SOD1G93A | 20, 40, 50, 100 μM (2 h) | (i) Reduced H2O2-induced cell death | [182] |
| SOD1G93A transgenic mice | 2.9 μM/g/day 10 mg/kg/day (from presymptomatic stage) |
(i) Delayed disease onset and prolonged survival time | [183, 184] | |
| RPPX | SOD1G93A transgenic mice | 100 mg/kg/day, p.o (from day 45) | (i) Enhanced motor performance and prolonged survival time | [187] |
| SOD1G93A transgenic mice | 200 mg/kg/day (from day 55 until 180 days) | (i) No effect was observed on disease progression or survival | [193] | |
| RCT, phase II | 50 mg/day or 300 mg/day (24 weeks) | (i) Beneficial effects on functional decline and survival | [191] | |
| RCT, phase III (NCT01281189) | 150 mg/twice daily (12-18 months) | (i) Did not show any efficacy on functional and survival assessment | [192] | |
| Melatonin | SOD1G93A transgenic mice | 57–88 mg/kg/day, p.o. (from presymptomatic stage) | (i) Slowed disease progression and prolonged survival time | [54] |
| SOD1G93A transgenic mice | 30 mg/kg/day, i.p. (from six weeks of age) | (i) Delayed disease onset, slowed disease progression, and neurological deterioration and mortality | [198] | |
| SOD1G93A transgenic mice | 0.5, 2.5 and 50 mg/kg (from presymptomatic stage) | (i) Increased the motoneuron loss and lipid peroxidation, reduced survival time | [199] | |
| NOX | SOD1G93A transgenic mice | Deletion of NOX | (i) Slowed disease progression and prolonged survival time | [112, 113] |
| Apocynin | MO59J glial cells and SH-SY neuronal cells overexpressing mutant SOD1 | 100 μM | (i) Decreased O2.- levels and increased cell viability | [114] |
| SOD1G93A transgenic mice | 30, 150, and 300 mg/kg/day (from 2 weeks of age) | (i) Decreased ROS levels, increased neurons in the spinal cord, prolonged survival time, and slowed disease progression | [114] | |
| SOD1G93A transgenic mice | 300 mg/kg/day (from 21 days of age) | (i) Failed to significantly prolong survival time | [205] | |
| Cocultured hESC-derived motor neurons with human primary astrocytes expressing SOD1G37R | 300 μM (48 h pretreatment) | (i) Prevented motor neuron loss (ii) Decreased ROS levels |
[203] | |
| AEOL10150 | SOD1G93A transgenic mice | Initial dose of 5.0 mg/kg and a maintenance dose of 2.5 mg/kg/day i.p. (from the onset of the disease) | (i) Reduced oxidative stress, enhanced motor performance, prevented motor neuron loss, prolonged survival time | [210] |
| SOD1G93A transgenic mice | 2.5 mg/kg/day i.p. (from the onset of the disease) | (i) Reduced astrogliosis, prevented motor neuron loss, prolonged survival time | [211] | |
| Edaravone | SH-SY5Y cells | 25 μM (8 h) | (i) Reduced H2O2-induced cell death | [218] |
| SOD1G93A transgenic mice | 5 mg/kg/day and 15 mg/kg/day i.p. (from the onset of the disease) | (i) Slowed motor decline, prevented motor neuron loss, slowed disease progression | [224] | |
| SOD1H46R transgenic rats | 1.5 or 3.0 mg/kg/h i.v. continuous infusion (1 h per day) for 2 days, followed by a 2-day holiday (y from 18 weeks of age to the day of loss of righting reflex) | (i) Improved motor function | [223] | |
| Open-label phase II | 30 mg or 60 mg/day i.v. (6 months) two weeks of administration followed by a two-week observation period (4 weeks cycle repeated six times) | (i) Slowed disease progression (using ALSFRS-R) (ii) Reduced 3-NT levels in cerebrospinal fluid |
[225] | |
| RCT, phase III, NCT00330681 | 60 mg/day i.v. during 60 min (24-week treatment) | (i) Did not significantly reduce the ALSFRS-R score. Significant differences observed when analyzing a subgroup of patients (scored of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, disease duration of 2 years or less) | [213] | |
| RCT, phase III, NCT01492686 | 60 mg/day i.v. during 60 min (24-week treatment) | (i) Slowed disease progression (using ALSFRS-R) in a well-defined population of ALS patients | [5] | |
| Riluzole | Mixed mouse cortical culture | 30 or 100 μM (30 min treatment) | (i) Blocked phorbol 12-myristate | [233] |
| Cortical cultures | 1-30 μM (24 h treatment) | (i) Attenuated neuronal death induced by 30 μM kainate or NMDA, but not that by 100 μM NMDA (ii) Attenuated nonexcitotoxic oxidative injury induced by exposure to FeCl3 in the presence of MK-801 and CNQX (iii) Reduced Fe3+-induced lipid peroxidation, and inhibited cytosolic phospholipase A2 |
[234] | |
| Rats | 21.35 μmol/kg (every two days, lasting for 4 weeks) | (i) Antagonized methylmercury-induced oxidative through elevation of GSH synthesis by activating of glutamate transporters | [235] | |
| Human SH-SY5Y neuroblastoma cells | 1-10 μM | (i) Counteracted the effects of H2O2 exposure (ii) Demonstrated direct antioxidant defense capacities against acute oxidative, but not on nitrosative stress |
[236] | |
| SOD1G93A model, the TDP-43A315T model, and FUS (1-359) model | 22 mg/kg (in drinking water from symptom onset) | (i) Had no significant benefit on lifespan in any of the ALS mouse models tested | [237] | |
| NAD+/SIRT1 modulators | ||||
| NMN and NR | SOD1G93 mice astrocytes | 5 mM (24 h pretreatment) | Increased total and mitochondrial NAD+ content in, increased oxidative resistance and reversal of astrocyte toxicity towards cocultured motor neurons | [248] |
| NR | SOD1G93A transgenic mice | 400 mg/kg/day | NR supplementation delayed motor neuron degeneration, decreased markers of neuroinflammation in the spinal cord, modified muscle metabolism, and prolonged survival time | [249] |
| EH301 | RCT, NCT03489200 | 1200 mg (4 months) | Slowed the progression of ALS (using ALSFRS-R) | [253] |
| Mitochondria-Targeted Antioxidants | ||||
| MitoQ | ||||
| SOD1G93A rat astrocytes | 10–100 nM (24 h pretreatment) | Reduced nitroxidative stress and mitochondrial dysfunction. Restored motor neuron survival in cocultures | [264] | |
| SOD1G93A motor neurons | 1-10 pM (48 h pretreatment) | Prevented NGF-induced neuron loss | [268] | |
| SOD1G93A transgenic mice | 500 μM (from 90 days of age) | Slowed decline of mitochondrial function, reduced nitroxidative markers and pathological signs in the spinal cord, neuromuscular junctions were recovered associated with a significant increase in hindlimb strength, prolonged survival time | [265] | |
| Mito-CP | SOD1G93A rat astrocytes | 10–100 nM (24 h pretreatment) | Reduced nitroxidative stress and mitochondrial dysfunction. Restored motor neuron survival in cocultures | [264] |
| SOD1G93A motor neurons | 100-1000 pM (48 h pretreatment) | Prevented NGF-induced neuron loss | [268] | |
| SS-31 | N2a cells overexpressing SOD1G93A | 1, 10, or 100 μM (6 h pretreatment) | Reduced H2O2-induced cell death | [269] |
| SOD1G93A transgenic mice | 5 mg/kg/day i.p. (from 30 days of age) | Decreased cell loss, decreased markers of oxidative stress in the lumbar spinal cord, improved motor function, and prolonged survival time | [269] |
RTC: double-blind randomized controlled trial; mROS: mitochondrial ROS production; s.c: subcutaneous; p.o.: oral; i.p: intraperitoneal; i.v.: intravenous; WN1316:2-[mesityl(methyl)amino]-N-[4-(pyridin-2-yl)-1H-imidazol-2-yl] acetamide trihydrochloride; CDDO-EA: 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid ethylamide; CDDO-TFEA:2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid trifluoroethylamide; EGCG: epigallocatechin-3-gallate; RPPX: dexpramipexole; NOX: nicotinamide adenine dinucleotide phosphate oxidase; ROS: reactive oxygen species; AEOL10150: manganese [III] tetrakis[N-N′-diethylimidazolium-2-yl]porphyrin; Edaravone: 3-methyl-1-phenyl-2-pyrazolin-5-one; ALSFRS-R: revised ALS functional rating scale; 3-NT: 3-nitrotyrosine; NMDA: N-methyl-D-aspartate; CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione; MK-801: (5R,10S) (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate; MitoQ: [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl]triphenylphosphonium methane sulfonate; Mito-CP: mitochondria-targeted carboxy-proxyl; SS-31: cell-permeable peptide antioxidant D-ArgDmt-Lys-Phe-NH2; NMN and NR: nicotinamide mononucleotide and nicotinamide riboside.