|(1) Riluzole||Glutamate excitotoxicity||Decreases the presynaptic release of glutamate||Significantly delayed onset and slowed down loss of motor function in preclinical trials||Treatment is safe and well tolerated, with moderate increased survival time of 2–9 months||Due to loss of efficacy, research of effects in older patients, in bulbar ALS, and in patients with advanced ALS is needed|| |
|Ceftriaxone|| ||Increases activity and gene expression of EAAT2 glutamate transporter||Increased levels of EAAT2, delayed motor neuron loss, and increased survival time in mSOD1 mice||Phase III RCT completed 2012. Study results were negative||Requires intravenous injection. Limited safety profile in humans. Ceftriaxone is known to have excellent CNS penetration.||NCT00349622|
|Arimoclomol||Protein aggregation||Inhibition of protein aggregation by inducing heat shock proteins during cellular stress.||Significantly increased survival time in mSOD1 mice when given before or at symptom onset||Safe and well tolerated in phase II clinical trial. Currently recruiting patients for a phase II/III RCT||Given that presymptomatic administration is not possible in humans, the drug could be less efficient. Good CNS penetration||NCT00706147|
Oxidative stress and mitochondrial dysfunction.
Chirally pure R-enantiomer of pramipexole which is used in parkinson's disease
|The precise mechanism of action is unclear||In mSOD1 mice, the drug revealed increased survival, antioxidant, anti-apoptotic, and neuroprotective effects||Clinical trials observed: slowed disease progression, slowed functional decline, and decreased mortality. A large-scale phase III study started in 2011||Safe and well tolerated in a two-part phase II study||NCT01281189|
|(2) AEOL-10150||Oxidative stress||Antioxidant analogous to the catalytic site of superoxide dismutase. Neutralizes reactive oxygen species||Three different mice models showed beneficial effects when given at symptom onset. Significant increased survival time||Phase 1 study was safe and well tolerated. Further studies were suspended due to financial reasons||Given that presymptomatic administration is not possible in humans, the drug could be less efficient|| |
|Creatine||Oxidative stress and mitochondrial dysfunction||Stabilizes the mitochondrial transition pore and facilitates mitochondrial ATP synthesis. Antioxidant properties||Increased survival time in transgenic mSOD1 mice when given before disease onset|| |
Several phase II clinical trials gave negative results.
Clinical trials with higher doses and combination with tamoxifen are ongoing
Oral administration, elevated brain penetration, and good safety profile.
Given that presymptomatic administration is not possible in humans, the drug could be less efficient
|(3) Celecoxib||Cox-2 inhibitor||Inhibition of cyclooxygenase-2 and hence inhibition of prostaglandin triggered glutamate excitotoxicity and oxidative stress||Positive preclinical studies on mSOD1 transgenic mice. Increased survival and motor neuron protection||A phase III RCT showed no beneficial effects on patients with ALS||Cox-2 inhibition cannot be rejected as a viable CNS target because the lack of detectable action of celecoxib in the CNS limited the phase III clinical trial|| |
|(4) Minocycline|| |
Apoptosis and microglial modulation.
|Modulate microglial activation via TLR4 receptor inhibition. Inhibition of cytochrome c and caspase-3 activation||Beneficial effects in preclinical trials||Safe and well tolerated in phase II clinical trials. A phase III RCT revealed greater and faster declinein patients with ALS||Due to alterations in microglial phenotypes, timing of administration might be crucial to the outcome!|| |
|(5) Glatiramer acetate|| |
Treatment for multiple sclerosis
|Enhances regulatory T-cell immunity and stimulates TH2 cells. May have anti-glutaminergic and growth factor stimulating effects||Conflicting results, some mice models showed increased survival time, while others did not||A phase III RCT showed no beneficial effects. Extrapolation from preclinical data showed the doses used were too low, making the results inconclusive||Administered as subcutaneous injections||NCT00326625|
|Pioglitazone|| ||A peroxisome proliferator-activated receptor-γ agonist with potent anti-inflammatory effects||Improved muscle strength, delayed disease onset, and prolonged survival in SOD1 transgenic mice||Phase I/II RCT combining pioglitazone and tretinoin in patients on riluzole. Study results were negative|| || |
|Cyclosporine A||Immunosuppressive agent||Binds small intracellular regulatory proteins, leading to inhibition of the phosphatase calcineurin and T-cell activation||Increased survival time in transgenic mice with permissive BBB||Early studies showed no beneficial effects in patients with ALS||Cannot pass the blood–brain barrier! Neuroprotective effects from this drug are therefore limited, unless the blood–brain barrier is compromised|| |