Preclinical and Clinical Endeavors Targeting Mitochondria

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Teresa Cunha-Oliveira	--	3213	2024-02-23 12:41:12	\|
2	format	Jason Zhu	-54 word(s)	3159	2024-02-26 03:30:58	\|

This entry is adapted from the peer-reviewed paper 10.3390/cells13030248

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target.

amyotrophic lateral sclerosis mitochondrial dysfunction neurodegeneration

1. Approaches for Direct Enhancement of Mitochondrial Function

Metabolic enhancers represent a compelling class of therapeutic interventions in the context of ALS and other neurodegenerative disorders. These approaches aim to boost cellular energy production and stimulate mitochondrial function. As metabolic deficits are a hallmark feature in ALS, emerging research suggests that enhancing metabolic pathways within mitochondria may hold the key to slowing or mitigating disease progression.

1.1. Dichloroacetate

Dichloroacetate (DCA), investigated in multiple neurodegenerative diseases ^[1], represents an alternative approach for indirectly enhancing mitochondrial function. As a pyruvate dehydrogenase kinase (PDK) inhibitor, DCA stimulates the conversion of pyruvate to acetyl coenzyme A (AcCoA), supplying additional energy substrates to the TCA cycle.

Administered to mutant SOD1^G93A or SOD1^G86R mice at 500 mg/kg/day during the pre-symptomatic stage, DCA improved survival, delayed disease onset, reduced spinal motor neuron loss, and enhanced mitochondrial function ^[2]^[3]. For example, DCA treatment in SOD1^G86R mice not only improved glycolytic capacity but also upregulated the expression of genes associated with mitochondrial biogenesis (e.g., Pgc-1α and Mfn2), believed to impede disease progression in this animal model ^[2]. Moreover, DCA (5 mM) improved the mitochondrial function of abnormal glial cells isolated from the spinal cords of adult paralytic SOD1^G93A rats, enhancing respiratory capacity and decreasing toxicity to MNs ^[4].

Additionally, administering DCA (100 mg/kg for 10 days) to symptomatic SOD1^G93A rats reduced MN degeneration, gliosis, and the number of GFAP/S100β double-labeled hypertrophic glial cells in the spinal cord. These findings indicate DCA’s potential therapeutic strategy for ALS by modulating glial metabolism and mitigating MN degeneration ^[4].

However, no clinical trials have assessed DCA effectiveness in ALS patients, necessitating further research.

1.2. Ketogenic and High-Fat Diets

Various dietary interventions aim to delay ALS progression and counteract the hypermetabolism associated with the condition. Two notable approaches include the Ketogenic Diet (KD) ^[5]^[6] and the High-Fat Diet (HFD) ^[7]^[8]^[9]^[10].

A KD, characterized by high fat intake, increases circulating ketones, while restricting carbohydrates and proteins ^[11]^[12]. The primary ketones acetoacetate and D-β-3-hydroxybutyrate, produced in the liver, serve as an energy source when glucose availability is limited ^[13]. Studies report that a KD, comprising 60% fat, 20% carbohydrates, and 20% protein, improves motor function and safeguards MNs in SOD1^G93A mice ^[5]^[6].

This diet exerts its effects partially through alterations in mitochondrial function, promoting ATP synthesis, and restoring the activity of complex I in the ETC, which is often impaired in ALS ^[6]. Furthermore, it was demonstrated that caprylic triglyceride, a precursor to ketone bodies, enhanced motor function and protected MNs in SOD1^G93A mice by boosting oxidative metabolism, thereby increasing mitochondrial basal and maximum oxygen consumption ^[5]. Converted rapidly to caprylic acid, it easily traverses membranes, becoming β-oxidized to AcCoA in the mitochondria. Consequently, it supplies ketone bodies to the TCA cycle, serving as a rapid energy source when cellular glucose levels are low. Notably, neither the KD nor caprylic triglyceride significantly altered the survival of SOD1-^G93A transgenic mice ^[5]^[6].

Regarding the HFD, studies have indicated its potential to slow disease progression in ALS mouse models. One study employing a diet composed of 47% fat, 38% carbohydrates, and 15% protein reduced disease progression in a SOD1^G93A mouse model ^[10]. Similarly, another study utilizing a HFD comprising 21% fat and 0.15% cholesterol extended the mean survival of SOD1^G86R mice ^[7]. To investigate the impact of high-caloric diets on ALS patients, a double-blinded trial known as the LIPCAL-ALS study (NCT02306590) enrolled 201 patients; participants were assigned to receive either a high-caloric fatty diet (HCFD, 405 kcal/day, 100% fat) or a placebo in conjunction with riluzole (100 mg/day). However, the results did not provide conclusive evidence of a life-prolonging effect of the diet on the overall ALS patient population. Nevertheless, post-hoc analysis revealed a significant survival benefit for a subgroup of fast-progressing patients ^[14]. Given the potential influence of caloric content on the intervention’s efficacy, a clinical Phase I LIPCALII study (NCT04172792) is set to explore whether an ultra-high caloric diet (UHCD), featuring twice the caloric content compared to LIPCAL-ALS, can be well tolerated by ALS patients over four weeks and if it can exceed the beneficial effects of LIPCAL-ALS. In another study ^[15] assessing the effects of a high-caloric nutrition protocol on ALS patients with percutaneous gastrostomy, 40 patients were randomly assigned to either a routine diet (control group) or high-caloric nutrition combined with the routine diet (Ensure group) for six months.

In summary, the mechanisms through which HFD and KD modify ALS disease progression in mouse models are unclear. However, it is suggested that the high fat content of these diets might elevate phospholipids and cholesterol, which are crucial components for axonal membrane assembly and regeneration ^[16]. In alignment with this hypothesis, it was demonstrated that abnormally elevated cholesterol levels were associated with increased survival in ALS patients, by more than 12 months, suggesting hyperlipidemia as a prognostic factor ^[17].

1.3. Acetyl-Carnitine

Acetyl-carnitine (ALC) is a crucial cellular source of acetyl groups, particularly in high-energy demanding situations, playing a pivotal role in transporting long-chain fatty acids across mitochondrial membranes and limiting β-oxidation rates ^[18].

Studies administering 50 mg/kg/day of ALC orally before disease onset significantly delayed symptoms, slowed motor function deterioration, and extended lifespan in mutant SOD1^G93A mice; subcutaneous ALC injection to symptomatic mutant SOD1^G93A mice improved survival ^[19].

In a randomized double-blind, placebo-controlled Phase II trial involving 82 patients receiving 3 g/day of ACL or a placebo with riluzole (100 mg/day), ALC demonstrated mild enhancements in ALSFRS score and respiratory capacity. Notably, it doubled the median survival range compared to the placebo group, indicating effectiveness, tolerability, and safety in ALS treatment ^[20]. A recent study involving 32 ALS patients revealed ALC’s improvement in the redox state, persisting six months post-treatment, offering potential disease biomarkers and drug effects indicators in clinical practice and trials ^[21].

2. Antioxidants

2.1. N-acetyl-L-cysteine (NAC)

N-acetyl-L-cysteine (NAC), a membrane-permeable antioxidant, replenishes cellular cysteine and glutathione pools, mitigating free radical damage ^[22]^[23]. In a preclinical study, NAC (1 mM, 24 h) attenuated mitochondrial ROS production, restored MTT reduction rates to control levels, and elevated ATP levels in human neuroblastoma SH-SY5Y cell lines harboring the SOD1^G93A mutation ^[24]. In SOD1^G93A transgenic mice, a daily dose of 2.0 mg/kg significantly extended survival and improved motor performance ^[22]. However, a double-blind, placebo-controlled clinical trial involving 110 ALS patients using subcutaneous NAC infusion (50 mg/kg daily) did not show a substantial increase in 12-month survival or disease progression slowdown ^[25]. In G93A mice, intranasal NAC administration with the nanocarrier PEG-PCL-Tat significantly increased spinal cord accumulation, extending median survival by 11.5 days. These findings highlight the potential of this approach as a promising Drug Delivery System for ALS therapeutics ^[26]. However, the potential benefits of NAC in ALS remain uncertain, necessitating further clinical trials in humans. The ability of NAC to traverse the Blood–Brain Barrier (BBB) has been a subject of controversy and is likely influenced by dosage and administration routes ^[27]. Consequently, multiple NAC derivatives have been synthesized to overcome this limitation. Important examples include N-acetylcysteine ethyl ester (NACET), which is proposed to improve pharmacokinetics but undergoes rapid transformation into NAC and cysteine resulting low plasma levels ^[28]; N-acetylcysteine butyl ester (NACBE), which is highly lipophilic and was shown to have superior effects after oxidative insult exposure compared to NAC ^[29]; and N-acetylcysteine amide (NACA), which was developed to enhance lipophilicity, membrane permeability, and the capability to traverse the BBB ^[30]. Previous studies have supported the protective properties of NACA, suggesting its potential clinical utility ^[31].

2.2. Edaravone

Edaravone, the active component of Radicut^®, is a potent free radical scavenger widely employed in the treatment of cerebral ischemia in Japan ^[32]^[33]. Its neuroprotective role arose from its ability to eliminate lipid peroxides and hydroxyl radicals ^[34]^[35]. While the precise mechanisms are not fully understood, it has been proposed that in addition to its radical-scavenging properties, edaravone might inhibit the mPTP, contributing to its neuroprotective effects ^[36]. It benefits various CNS cell types, including neurons, microglia ^[37], astrocytes ^[38], and oligodendrocytes ^[39], partly attributable to its anti-inflammatory properties ^[40]. Preclinical studies indicate improved motor function, slowed disease progression, and mitigated motor neuron degeneration in transgenic SOD1 rodent models of ALS treated with edaravone doses ranging from 1.5 to 15 mg/kg ^[41]^[42].

In an open-label Phase II study with 20 ALS patients, intravenous administration of edaravone (30 or 60 mg daily) was safe, well-tolerated, and slowed disease progression, as measured by the ALS-FRS scale, during the six-month treatment period compared to the six months before edaravone administration ^[43]. A subsequent double-blind, placebo-controlled study with 102 ALS patients showed a smaller reduction in ALSFRS-R scores in the edaravone group over a 24-week treatment period ^[33].

In a recent Phase III study (NCT01492686), a 24-week, double-blind, parallel-group study of edaravone showed less decline in ALSFRS-R scores at 6 months and less deterioration in quality of life in patients receiving edaravone compared to those receiving standard care ^[44]. Currently, edaravone is approved for ALS treatment in Japan and South Korea and it was also approved by the FDA in May 2017 ^[45]. However, the precise mechanism of action of edaravone in ALS treatment remains to be fully elucidated.

A Phase I trial of an oral formulation of edaravone (TW001) developed by the Treeway company demonstrated safety, tolerability, and adequate exposure levels ^[46]. Furthermore, in a Phase III trial (NCT04165824), oral edaravone showed a favorable safety profile in ALS patients after 48 weeks of treatment ^[47]. A recent meta-analysis ^[48] suggests potential clinical benefits of edaravone in ALS treatment, with no significant increase in adverse events or deaths in compiled randomized clinical trials. However, more high-quality research is needed for further confirmation due to the small sample sizes in the included studies.

2.3. Melatonin

Melatonin (N-acetyl-5-methoxytryptamine), a neurohormone secreted by the pineal gland, possesses ROS-scavenging activity and amphiphilic properties, permeating both lipophilic and hydrophilic cellular environments ^[49]. Its potential as an experimental drug has been explored in various neurodegenerative diseases characterized by excessive ROS production owing to its robust antioxidant properties ^[50].

In addition to acting as a potent free radical scavenger, melatonin augments cellular antioxidant defenses by stimulating vital antioxidant enzymes (SOD, glutathione peroxidase, and glutathione reductase) and elevating GSH levels ^[51]. Furthermore, melatonin plays a role in preserving mitochondrial homeostasis, decreasing free radical generation, and protecting mitochondrial ATP synthesis by stimulating the activities of complexes I and IV ^[52].

In transgenic SOD1^G93A mice, the oral administration of melatonin (57–88 mg/kg/day) at the pre-symptomatic stage delayed disease progression and extended survival ^[53]. The same study demonstrated that the rectal administration of 300 mg/day of melatonin in 31 sALS patients was well tolerated over 2 years, reducing circulating serum protein carbonyl levels. However, it did not show upregulation of genes encoding antioxidant enzymes ^[53]. The decreased oxidative damage in ALS patients under melatonin treatment, coupled with its established safety in humans, emphasizes the need for further clinical trials to elucidate its neuroprotective effects in ALS.

More recently, it was reported that administering melatonin (30 mg/kg) to pre-symptomatic SOD1^G93A-transgenic mice significantly delayed disease onset, neurological deterioration, and mortality ^[54]. These effects involved inhibition of the caspase-1/cytochrome c/caspase-3 pathways and the loss of melatonin receptor 1A. Conversely, melatonin administration (0.5, 2.5, and 50 mg/kg, i.p.) to pre-symptomatic SOD1^G93A-transgenic mice reduced their survival ^[55].

2.4. Mitochondria-Targeted Antioxidants

One promising avenue in ALS research involves mitochondria-targeted antioxidants, such as 10-(60-ubiquinonyl) decyltriphenylphosphonium, known as MitoQ. This compound features a triphenylphosphonium (TPP) functional group linked to the antioxidant ubiquinone ^[56] that penetrates biological membranes and selectively accumulates within mitochondria, driven by the ΔΨ_m ^[57]. Positioned within mitochondria, MitoQ effectively shields these critical organelles from oxidative damage ^[56]^[58].

Inside mitochondria, complex II reduces the ubiquinone moiety of MitoQ to its active ubiquinol form, bolstering the defense against oxidative damage ^[58]. Various oxidants can convert ubiquinol back to ubiquinone, efficiently reversed by the respiratory chain ^[59] and ensuring continual recycling. MitoQ efficiently mitigates oxidative damage in chronic hepatitis C virus patients, decreasing liver damage ^[60]. Additionally, it has shown promise in neurodegenerative diseases like Parkinson’s ^[61]^[62] and Alzheimer’s ^[63]^[64], by decreasing oxidative damage. However, a Phase II clinical trial for Parkinson’s disease (NCT00329056) yielded disappointing results ^[65].

Despite the setback in Parkinson’s disease trials, MitoQ has shown potential in ALS; it ameliorated nitroxidative stress and mitochondrial dysfunction in astrocytes expressing SOD1^G93A, decreasing toxicity to MNs in co-cultures ^[66]. In SOD1^G93A mice, MitoQ (500 µM) administration improved the ALS phenotype by slowing mitochondrial function decline in the spinal cord and quadriceps muscle, increasing the lifespan of the animals ^[67]. This treatment reduced nitroxidative markers and pathological signs in the spinal cord along with the recovery of neuromuscular junctions and a marked increase in hindlimb strength ^[67]. MitoQ rapidly crosses the BBB ^[63] and is well tolerated in animals and humans ^[60], with nausea being the most common side effect ^[68].

These findings underscore the potential of mitochondria-directed antioxidants as a strategy to delay ALS symptoms, warranting further development.

Another mitochondria-targeted antioxidant in ALS research is the mitochondria-targeted carboxy-proxyl (Mito-CP). Like MitoQ, this features a TPP cation covalently coupled to carboxy-proxyl nitroxide, accumulating within mitochondria ^[69]. Low doses of Mito-CP (1–10 nM) effectively prevented MN death expressing SOD1^G93A induced by proapoptotic stimuli that trigger ROS formation ^[70]. It also prevented mitochondrial dysfunction, decreasing O₂^.− production in SOD1^G93A astrocytes and promoting MN survival ^[66].

While these results are promising, further investigations are necessary to explore other mitochondriotropic compounds, focusing on reducing toxicity and enhancing therapeutic efficacy.

In addition, it is crucial to prioritize investment in the development of ALS models that faithfully represent the diverse subtypes of the disease. This approach aims to address the challenge of translating positive effects observed in preclinical trials with antioxidants into meaningful efficacy during clinical trials. These models should serve as robust platforms for conducting preclinical trials before advancing to clinical trials ^[71]. Human induced pluripotent stem cells have opened avenues to explore therapeutic development relevant to human diseases ^[72]^[73]. An example is the generation of MNs from a patient-derived iPSC line carrying the SOD1-A4V mutation that demonstrated significant disease phenotypes, including proteinopathy, structural attrition, axonopathy, synaptic pathology, and functional defects. This model holds the potential to emerge as a robust preclinical platform for evaluating the therapeutic efficacy of diverse molecules in addressing this disease ^[74].

3. Antiapoptotic Agents

3.1. mPTP-Targeting Agents

As discussed in Section 2.8, emerging evidence points towards the involvement of mPTP in ALS pathogenesis. Initial studies used CsA, which, when administered intracerebroventricularly (25 µg every other day) at the symptomatic stage in SOD1^G93A mice, extended their survival ^[75]. Similarly, intracerebroventricular administration of CsA (20 µg/mouse/week) in pre-symptomatic SOD1^G93A mice delayed the onset of hindlimb weakness, prolonged the time from onset to paralysis, and extended life span ^[76]. However, it is important to note that CyA struggles to cross the BBB ^[76]^[77] and its benefits could be confounded by its immunosuppressant effects due to calcineurin inhibition. Therefore, it is advisable to explore other mPTP inhibitors that lack calcineurin effects.

One such strategy involves mPTP stabilization using cholest-4-en-3-one oxime, known as olesoxime (TRO19622), which binds to VDAC and TSPO ^[78]^[79]. Subcutaneous administration of TRO19622 (3 or 30 mg/kg) in pre-symptomatic SOD1^G93A mice improved motor function and prolonged survival ^[80]. Additionally, administration of TRO19622 (600 mg/kg of food pellets) in pre-symptomatic SOD1^G93A mice delayed muscle denervation, decreased astrogliosis, prevented microglia activation, and protected MNs in the lumbar spinal cord, suggesting its potential as a neuroprotective agent to delay ALS neurodegeneration ^[81]. However, a Phase II–III clinical trial failed to demonstrate efficacy in 512 ALS patients receiving 330 mg TRO19622 daily compared to a matching placebo group receiving 50 mg riluzole twice a day for 18 months. None of the assessed parameters, including slow vital capacity, manual muscle testing, and rates of deterioration of ALSFRS-R scores, revealed a significant clinical benefit of TRO19622 treatment compared with the placebo, except for a minimal increase in the ALSFRS-R global score over 9 months ^[82]. Several factors may explain the absence of clinical efficacy, including differences in the timing of administration relative to disease onset, the limitations of animal models in predicting clinical outcomes ^[83], and the need for further investigation into the survival-promoting effects of TRO19622 on human MNs derived from ALS patient induced pluripotent stem cells ^[84].

Another compound of interest is GNX-4728, a cinnamic anilide derivative that inhibits mPTP opening and has shown promise in the SOD^G93A mouse model. Systemic treatment with GNX-4728 (15 mg/kg) in C57BL/6 mice significantly increased mitochondrial calcium retention capacity (CRC) in the heart and brain. Importantly, the increase in CRC in the brain suggests its potential to cross the BBB ^[85]. Furthermore, systemic administration of GNX-4728 (300 µg every other day, i.p.) in pre-symptomatic SOD1^G37R mice delayed disease onset, increased lifespan, protected against motor neuron and mitochondrial degeneration, attenuated spinal cord inflammation, and preserved neuromuscular junction (NMJ) innervation in the diaphragm in ALS mice ^[85].

These findings highlight the potential of mPTP-targeting agents as a therapeutic approach in ALS, with the need for further research to optimize their clinical translation.

3.2. Rasagiline

Rasagiline, a monoamine oxidase B inhibitor primarily used to treat Parkinson’s disease ^[86]^[87], has shown neuroprotective properties beyond its MAO inhibitory activity ^[88]. In vitro studies suggest its neuroprotective role, partly mediated by anti-apoptotic properties ^[89]^[90]^[91]. Rasagiline may protect mitochondria by preventing mPTP opening, inhibiting caspase 3 activation ^[90], or by upregulating the anti-apoptotic Bcl-2 and Bcl-xL genes and downregulating the pro-apoptotic Bad and Bax genes ^[91].

In ALS, oral rasagiline (0.5–2 mg/kg/day), administered alone or with riluzole (30 mg/kg/day) at the pre-symptomatic stage, improved motor performance and extended survival in SOD1^G93A mice ^[92]. A Phase II clinical trial involving 23 ALS patients receiving rasagiline (2 mg/day) showed increased ΔΨ_m and oxygen radical antioxidant capacity (ORAC) in lymphocytes and a decrease in the apoptotic marker Bcl-2/Bax ratio ^[93]. While this trial did not find significant improvements in the rate of ALSFRS-R score decline, it did identify differences in symptom duration among patients administered who received rasagiline compared to placebo controls (NCT01232738) ^[93]. This raises the question of whether rasagiline-induced mitochondrial changes could slow motor function decline and extend ALS patient survival.

However, another Phase II clinical trial involving 80 ALS patients receiving rasagiline (2 mg/day for 12 months) did not demonstrate improvements in mitochondrial and molecular biomarkers (ΔΨ_m, ORAC, and Bcl-2/Bax ratio) or differences in the average 12-month ALSFRS-R slope between the rasagiline and placebo groups. Variability among patients and differences in sample processing timing at various centers involved in this clinical trial (NCT01786603) may explain the discrepant results regarding rasagiline’s impact on mitochondrial markers ^[94].

Post-hoc analysis of a Phase II clinical trial involving 252 patients (NCT01879241) suggested that 1 mg of rasagiline, in addition to riluzole (100 mg/day), could slow disease progression in patients with normal to fast disease progression. This effect was observed in function (ALSFRS-R decline at 6, 12, and 18 months) and survival (at 6 and 12 months) ^[95].

In conclusion, rasagiline’s effects in ALS research reveal its complex potential as a therapeutic agent, with varying outcomes in clinical trials. Further research and careful patient stratification are essential to unlock its full therapeutic benefits in ALS treatment.

References

Jha, M.K.; Jeon, S.; Suk, K. Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders. Curr. Neuropharmacol. 2012, 10, 393–403.
Palamiuc, L.; Schlagowski, A.; Ngo, S.T.; Vernay, A.; Dirrig-Grosch, S.; Henriques, A.; Boutillier, A.L.; Zoll, J.; Echaniz-Laguna, A.; Loeffler, J.P.; et al. A Metabolic Switch toward Lipid Use in Glycolytic Muscle Is an Early Pathologic Event in a Mouse Model of Amyotrophic Lateral Sclerosis. EMBO Mol. Med. 2015, 7, 526–546.
Miquel, E.; Cassina, A.; Martinez-Palma, L.; Bolatto, C.; Trias, E.; Gandelman, M.; Radi, R.; Barbeito, L.; Cassina, P. Modulation of Astrocytic Mitochondrial Function by Dichloroacetate Improves Survival and Motor Performance in Inherited Amyotrophic Lateral Sclerosis. PLoS ONE 2012, 7, e34776.
Martinez-Palma, L.; Miquel, E.; Lagos-Rodriguez, V.; Barbeito, L.; Cassina, A.; Cassina, P. Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis. Neurotherapeutics 2019, 16, 203–215.
Zhao, W.; Varghese, M.; Vempati, P.; Dzhun, A.; Cheng, A.; Wang, J.; Lange, D.; Bilski, A.; Faravelli, I.; Pasinetti, G.M. Caprylic Triglyceride as a Novel Therapeutic Approach to Effectively Improve the Performance and Attenuate the Symptoms Due to the Motor Neuron Loss in ALS Disease. PLoS ONE 2012, 7, e49191.
Zhao, Z.; Lange, D.J.; Voustianiouk, A.; MacGrogan, D.; Ho, L.; Suh, J.; Humala, N.; Thiyagarajan, M.; Wang, J.; Pasinetti, G.M. A Ketogenic Diet as a Potential Novel Therapeutic Intervention in Amyotrophic Lateral Sclerosis. BMC Neurosci. 2006, 7, 29.
Dupuis, L.; Oudart, H.; Rene, F.; Gonzalez de Aguilar, J.L.; Loeffler, J.P. Evidence for Defective Energy Homeostasis in Amyotrophic Lateral Sclerosis: Benefit of a High-Energy Diet in a Transgenic Mouse Model. Proc. Natl. Acad. Sci. USA 2004, 101, 11159–11164.
Pedersen, W.A.; Mattson, M.P. No Benefit of Dietary Restriction on Disease Onset or Progression in Amyotrophic Lateral Sclerosis Cu/Zn-Superoxide Dismutase Mutant Mice. Brain Res. 1999, 833, 117–120.
Hamadeh, M.J.; Rodriguez, M.C.; Kaczor, J.J.; Tarnopolsky, M.A. Caloric Restriction Transiently Improves Motor Performance but Hastens Clinical Onset of Disease in the Cu/Zn-Superoxide Dismutase Mutant G93A Mouse. Muscle Nerve 2005, 31, 214–220.
Mattson, M.P.; Cutler, R.G.; Camandola, S. Energy Intake and Amyotrophic Lateral Sclerosis. Neuromol. Med. 2007, 9, 17–20.
Tefera, T.W.; Borges, K. Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments. Front. Neurosci. 2016, 10, 611.
Branco, A.F.; Ferreira, A.; Simoes, R.F.; Magalhaes-Novais, S.; Zehowski, C.; Cope, E.; Silva, A.M.; Pereira, D.; Sardao, V.A.; Cunha-Oliveira, T. Ketogenic Diets: From Cancer to Mitochondrial Diseases and Beyond. Eur. J. Clin. Investig. 2016, 46, 285–298.
Laffel, L. Ketone Bodies: A Review of Physiology, Pathophysiology and Application of Monitoring to Diabetes. Diabetes Metab. Res. Rev. 1999, 15, 412–426.
Ludolph, A.C.; Dorst, J.; Dreyhaupt, J.; Weishaupt, J.H.; Kassubek, J.; Weiland, U.; Meyer, T.; Petri, S.; Hermann, A.; Emmer, A.; et al. Effect of High-Caloric Nutrition on Survival in Amyotrophic Lateral Sclerosis. Ann. Neurol. 2020, 87, 206–216.
Wang, S.; Yuan, T.; Yang, H.; Zhou, X.; Cao, J. Effect of Complete High-Caloric Nutrition on the Nutritional Status and Survival Rate of Amyotrophic Lateral Sclerosis Patients after Gastrostomy. Am. J. Transl. Res. 2022, 14, 7842–7851.
Vance, J.E.; Campenot, R.B.; Vance, D.E. The Synthesis and Transport of Lipids for Axonal Growth and Nerve Regeneration. Biochim. Biophys. Acta 2000, 1486, 84–96.
Dupuis, L.; Corcia, P.; Fergani, A.; Gonzalez De Aguilar, J.L.; Bonnefont-Rousselot, D.; Bittar, R.; Seilhean, D.; Hauw, J.J.; Lacomblez, L.; Loeffler, J.P.; et al. Dyslipidemia Is a Protective Factor in Amyotrophic Lateral Sclerosis. Neurology 2008, 70, 1004–1009.
Onofrj, M.; Ciccocioppo, F.; Varanese, S.; di Muzio, A.; Calvani, M.; Chiechio, S.; Osio, M.; Thomas, A. Acetyl-L-Carnitine: From a Biological Curiosity to a Drug for the Peripheral Nervous System and Beyond. Expert Rev. Neurother. 2013, 13, 925–936.
Kira, Y.; Nishikawa, M.; Ochi, A.; Sato, E.; Inoue, M. L-Carnitine Suppresses the Onset of Neuromuscular Degeneration and Increases the Life Span of Mice with Familial Amyotrophic Lateral Sclerosis. Brain Res. 2006, 1070, 206–214.
Beghi, E.; Pupillo, E.; Bonito, V.; Buzzi, P.; Caponnetto, C.; Chio, A.; Corbo, M.; Giannini, F.; Inghilleri, M.; Bella, V.L.; et al. Randomized Double-Blind Placebo-Controlled Trial Of Acetyl-L-Carnitine for ALS. Amyotroph. Lateral Scler. Front. Degener. 2013, 14, 397–405.
Grossini, E.; De Marchi, F.; Venkatesan, S.; Mele, A.; Ferrante, D.; Mazzini, L. Effects of Acetyl-L-Carnitine on Oxidative Stress in Amyotrophic Lateral Sclerosis Patients: Evaluation on Plasma Markers and Members of the Neurovascular Unit. Antioxidants 2023, 12, 1887.
Andreassen, O.A.; Dedeoglu, A.; Klivenyi, P.; Beal, M.F.; Bush, A.I. N-Acetyl-L-Cysteine Improves Survival and Preserves Motor Performance in an Animal Model of Familial Amyotrophic Lateral Sclerosis. Neuroreport 2000, 11, 2491–2493.
Burgunder, J.M.; Varriale, A.; Lauterburg, B.H. Effect of N-Acetylcysteine on Plasma Cysteine and Glutathione Following Paracetamol Administration. Eur. J. Clin. Pharmacol. 1989, 36, 127–131.
Beretta, S.; Sala, G.; Mattavelli, L.; Ceresa, C.; Casciati, A.; Ferri, A.; Carri, M.T.; Ferrarese, C. Mitochondrial Dysfunction Due to Mutant Copper/Zinc Superoxide Dismutase Associated with Amyotrophic Lateral Sclerosis Is Reversed by N-Acetylcysteine. Neurobiol. Dis. 2003, 13, 213–221.
Louwerse, E.S.; Weverling, G.J.; Bossuyt, P.M.; Meyjes, F.E.; de Jong, J.M. Randomized, Double-Blind, Controlled Trial of Acetylcysteine in Amyotrophic Lateral Sclerosis. Arch. Neurol. 1995, 52, 559–564.
Kurano, T.; Kanazawa, T.; Iioka, S.; Kondo, H.; Kosuge, Y.; Suzuki, T. Intranasal Administration of N-Acetyl-L-Cysteine Combined with Cell-Penetrating Peptide-Modified Polymer Nanomicelles as a Potential Therapeutic Approach for Amyotrophic Lateral Sclerosis. Pharmaceutics 2022, 14, 2590.
Bavarsad Shahripour, R.; Harrigan, M.R.; Alexandrov, A.V. N-Acetylcysteine (NAC) in Neurological Disorders: Mechanisms of Action and Therapeutic Opportunities. Brain Behav. 2014, 4, 108–122.
Giustarini, D.; Milzani, A.; Dalle-Donne, I.; Tsikas, D.; Rossi, R. N-Acetylcysteine Ethyl Ester (NACET): A Novel Lipophilic Cell-Permeable Cysteine Derivative with an Unusual Pharmacokinetic Feature and Remarkable Antioxidant Potential. Biochem. Pharmacol. 2012, 84, 1522–1533.
Kularatne, R.N.; Bulumulla, C.; Catchpole, T.; Takacs, A.; Christie, A.; Stefan, M.C.; Csaky, K.G. Protection of Human Retinal Pigment Epithelial Cells from Oxidative Damage Using Cysteine Prodrugs. Free Radic. Biol. Med. 2020, 152, 386–394.
Sunitha, K.; Hemshekhar, M.; Thushara, R.M.; Santhosh, M.S.; Yariswamy, M.; Kemparaju, K.; Girish, K.S. N-Acetylcysteine Amide: A Derivative to Fulfill the Promises of N-Acetylcysteine. Free Radic. Res. 2013, 47, 357–367.
Atlas, D. Emerging Therapeutic Opportunities of Novel Thiol-Amides, NAC-Amide (AD4/NACA) and Thioredoxin Mimetics (TXM-Peptides) for Neurodegenerative-Related Disorders. Free Radic. Biol. Med. 2021, 176, 120–141.
Shichinohe, H.; Kuroda, S.; Yasuda, H.; Ishikawa, T.; Iwai, M.; Horiuchi, M.; Iwasaki, Y. Neuroprotective Effects of the Free Radical Scavenger Edaravone (MCI-186) in Mice Permanent Focal Brain Ischemia. Brain Res. 2004, 1029, 200–206.
Abe, K.; Itoyama, Y.; Sobue, G.; Tsuji, S.; Aoki, M.; Doyu, M.; Hamada, C.; Kondo, K.; Yoneoka, T.; Akimoto, M.; et al. Confirmatory Double-Blind, Parallel-Group, Placebo-Controlled Study of Efficacy and Safety of Edaravone (MCI-186) in Amyotrophic Lateral Sclerosis Patients. Amyotroph. Lateral Scler. Front. Degener. 2014, 15, 610–617.
Mizuno, A.; Umemura, K.; Nakashima, M. Inhibitory Effect of MCI-186, a Free Radical Scavenger, on Cerebral Ischemia Following Rat Middle Cerebral Artery Occlusion. Gen. Pharmacol. 1998, 30, 575–578.
Yamamoto, T.; Yuki, S.; Watanabe, T.; Mitsuka, M.; Saito, K.I.; Kogure, K. Delayed Neuronal Death Prevented by Inhibition of Increased Hydroxyl Radical Formation in a Transient Cerebral Ischemia. Brain Res. 1997, 762, 240–242.
Takayasu, Y.; Nakaki, J.; Kawasaki, T.; Koda, K.; Ago, Y.; Baba, A.; Matsuda, T. Edaravone, a Radical Scavenger, Inhibits Mitochondrial Permeability Transition Pore in Rat Brain. J. Pharmacol. Sci. 2007, 103, 434–437.
Banno, M.; Mizuno, T.; Kato, H.; Zhang, G.; Kawanokuchi, J.; Wang, J.; Kuno, R.; Jin, S.; Takeuchi, H.; Suzumura, A. The Radical Scavenger Edaravone Prevents Oxidative Neurotoxicity Induced by Peroxynitrite and Activated Microglia. Neuropharmacology 2005, 48, 283–290.
Wang, Q.; Zhang, X.; Chen, S.; Zhang, X.; Zhang, S.; Youdium, M.; Le, W. Prevention of Motor Neuron Degeneration by Novel Iron Chelators in SOD1(G93A) Transgenic Mice of Amyotrophic Lateral Sclerosis. Neurodegener. Dis. 2011, 8, 310–321.
Miyamoto, N.; Maki, T.; Pham, L.D.; Hayakawa, K.; Seo, J.H.; Mandeville, E.T.; Mandeville, J.B.; Kim, K.W.; Lo, E.H.; Arai, K. Oxidative Stress Interferes with White Matter Renewal after Prolonged Cerebral Hypoperfusion in Mice. Stroke 2013, 44, 3516–3521.
Zhang, M.; Teng, C.H.; Wu, F.F.; Ge, L.Y.; Xiao, J.; Zhang, H.Y.; Chen, D.Q. Edaravone Attenuates Traumatic Brain Injury through Anti-Inflammatory and Anti-Oxidative Modulation. Exp. Ther. Med. 2019, 18, 467–474.
Aoki, M.; Warita, H.; Mizuno, H.; Suzuki, N.; Yuki, S.; Itoyama, Y. Feasibility Study for Functional Test Battery of SOD Transgenic Rat (H46R) and Evaluation of Edaravone, a Free Radical Scavenger. Brain Res. 2011, 1382, 321–325.
Ito, H.; Wate, R.; Zhang, J.; Ohnishi, S.; Kaneko, S.; Ito, H.; Nakano, S.; Kusaka, H. Treatment with Edaravone, Initiated at Symptom Onset, Slows Motor Decline and Decreases SOD1 Deposition in ALS Mice. Exp. Neurol. 2008, 213, 448–455.
Yoshino, H.; Kimura, A. Investigation of the Therapeutic Effects of Edaravone, a Free Radical Scavenger, on Amyotrophic Lateral Sclerosis (Phase II Study). Amyotroph. Lateral Scler. 2006, 7, 241–245.
Tanaka, M.; Akimoto, M.; Palumbo, J.; Sakata, T. A Double-Blind, Parallel-Group, Placebo-Controlled, 24-Week, Exploratory Study of Edaravone (MCI-186) for the Treatment of Advanced Amyotrophic Lateral Sclerosis (ALS) (P3.191). Neurology 2016, 86.
Hardiman, O.; van den Berg, L.H. Edaravone: A New Treatment for ALS on the Horizon? Lancet Neurol. 2017, 16, 490–491.
CPHI-Online. Treeway Announces Positive Data from Two Separate Phase I Tw001 Clinical Trials. Available online: https://www.cphi-online.com/treeway-announces-positive-data-from-two-separate-news038315.html (accessed on 23 January 2024).
Genge, A.; Pattee, G.L.; Sobue, G.; Aoki, M.; Yoshino, H.; Couratier, P.; Lunetta, C.; Petri, S.; Selness, D.; Bidani, S.; et al. Oral Edaravone Demonstrated a Favorable Safety Profile in Patients with Amyotrophic Lateral Sclerosis after 48 Weeks of Treatment. Muscle Nerve 2023, 67, 124–129.
Gao, M.; Zhu, L.; Chang, J.; Cao, T.; Song, L.; Wen, C.; Chen, Y.; Zhuo, Y.; Chen, F. Safety and Efficacy of Edaravone in Patients with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis. Clin. Drug Investig. 2023, 43, 1–11.
Tan, D.X.; Reiter, R.J.; Manchester, L.C.; Yan, M.T.; El-Sawi, M.; Sainz, R.M.; Mayo, J.C.; Kohen, R.; Allegra, M.; Hardeland, R. Chemical and Physical Properties and Potential Mechanisms: Melatonin as a Broad Spectrum Antioxidant and Free Radical Scavenger. Curr. Top. Med. Chem. 2002, 2, 181–197.
Ganie, S.A.; Dar, T.A.; Bhat, A.H.; Dar, K.B.; Anees, S.; Zargar, M.A.; Masood, A. Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders. Rejuvenation Res. 2016, 19, 21–40.
Pandi-Perumal, S.R.; BaHammam, A.S.; Brown, G.M.; Spence, D.W.; Bharti, V.K.; Kaur, C.; Hardeland, R.; Cardinali, D.P. Melatonin Antioxidative Defense: Therapeutical Implications for Aging and Neurodegenerative Processes. Neurotox. Res. 2013, 23, 267–300.
Leon, J.; Acuna-Castroviejo, D.; Escames, G.; Tan, D.X.; Reiter, R.J. Melatonin Mitigates Mitochondrial Malfunction. J. Pineal Res. 2005, 38, 1–9.
Weishaupt, J.H.; Bartels, C.; Polking, E.; Dietrich, J.; Rohde, G.; Poeggeler, B.; Mertens, N.; Sperling, S.; Bohn, M.; Huther, G.; et al. Reduced Oxidative Damage in ALS by High-Dose Enteral Melatonin Treatment. J. Pineal Res. 2006, 41, 313–323.
Zhang, Y.; Cook, A.; Kim, J.; Baranov, S.V.; Jiang, J.; Smith, K.; Cormier, K.; Bennett, E.; Browser, R.P.; Day, A.L.; et al. Melatonin Inhibits the Caspase-1/Cytochrome C/Caspase-3 Cell Death Pathway, Inhibits MT1 Receptor Loss and Delays Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis. Neurobiol. Dis. 2013, 55, 26–35.
Dardiotis, E.; Panayiotou, E.; Feldman, M.L.; Hadjisavvas, A.; Malas, S.; Vonta, I.; Hadjigeorgiou, G.; Kyriakou, K.; Kyriakides, T. Intraperitoneal Melatonin Is Not Neuroprotective in the G93ASOD1 Transgenic Mouse Model of Familial ALS and May Exacerbate Neurodegeneration. Neurosci. Lett. 2013, 548, 170–175.
Murphy, M.P.; Smith, R.A. Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations. Annu. Rev. Pharmacol. Toxicol. 2007, 47, 629–656.
Finichiu, P.G.; James, A.M.; Larsen, L.; Smith, R.A.; Murphy, M.P. Mitochondrial Accumulation of a Lipophilic Cation Conjugated to an Ionisable Group Depends on Membrane Potential, pH Gradient and pK(a): Implications for the Design of Mitochondrial Probes and Therapies. J. Bioenerg. Biomembr. 2013, 45, 165–173.
Kelso, G.F.; Porteous, C.M.; Coulter, C.V.; Hughes, G.; Porteous, W.K.; Ledgerwood, E.C.; Smith, R.A.; Murphy, M.P. Selective Targeting of a Redox-Active Ubiquinone to Mitochondria within Cells: Antioxidant and Antiapoptotic Properties. J. Biol. Chem. 2001, 276, 4588–4596.
Cocheme, H.M.; Kelso, G.F.; James, A.M.; Ross, M.F.; Trnka, J.; Mahendiran, T.; Asin-Cayuela, J.; Blaikie, F.H.; Manas, A.R.; Porteous, C.M.; et al. Mitochondrial Targeting of Quinones: Therapeutic Implications. Mitochondrion 2007, 7, S94–S102.
Smith, R.A.; Murphy, M.P. Animal and Human Studies with the Mitochondria-Targeted Antioxidant MitoQ. Ann. N. Y. Acad. Sci. 2010, 1201, 96–103.
Solesio, M.E.; Prime, T.A.; Logan, A.; Murphy, M.P.; Del Mar Arroyo-Jimenez, M.; Jordan, J.; Galindo, M.F. The Mitochondria-Targeted Anti-Oxidant MitoQ Reduces Aspects of Mitochondrial Fission in the 6-OHDA Cell Model of Parkinson’s Disease. Biochim. Biophys. Acta 2013, 1832, 174–182.
Ghosh, A.; Chandran, K.; Kalivendi, S.V.; Joseph, J.; Antholine, W.E.; Hillard, C.J.; Kanthasamy, A.; Kanthasamy, A.; Kalyanaraman, B. Neuroprotection by a Mitochondria-Targeted Drug in a Parkinson’s Disease Model. Free Radic. Biol. Med. 2010, 49, 1674–1684.
McManus, M.J.; Murphy, M.P.; Franklin, J.L. The Mitochondria-Targeted Antioxidant MitoQ Prevents Loss of Spatial Memory Retention and Early Neuropathology in a Transgenic Mouse Model of Alzheimer’s Disease. J. Neurosci. 2011, 31, 15703–15715.
Manczak, M.; Mao, P.; Calkins, M.J.; Cornea, A.; Reddy, A.P.; Murphy, M.P.; Szeto, H.H.; Park, B.; Reddy, P.H. Mitochondria-Targeted Antioxidants Protect against Amyloid-Beta Toxicity in Alzheimer’s Disease Neurons. J. Alzheimer’s Dis. 2010, 20 (Suppl. S2), S609–S631.
Snow, B.J.; Rolfe, F.L.; Lockhart, M.M.; Frampton, C.M.; O’Sullivan, J.D.; Fung, V.; Smith, R.A.; Murphy, M.P.; Taylor, K.M.; Protect Study, G. A Double-Blind, Placebo-Controlled Study to Assess the Mitochondria-Targeted Antioxidant MitoQ as a Disease-Modifying Therapy in Parkinson’s Disease. Mov. Disord. 2010, 25, 1670–1674.
Cassina, P.; Cassina, A.; Pehar, M.; Castellanos, R.; Gandelman, M.; de Leon, A.; Robinson, K.M.; Mason, R.P.; Beckman, J.S.; Barbeito, L.; et al. Mitochondrial Dysfunction in SOD1G93A-Bearing Astrocytes Promotes Motor Neuron Degeneration: Prevention by Mitochondrial-Targeted Antioxidants. J. Neurosci. 2008, 28, 4115–4122.
Miquel, E.; Cassina, A.; Martinez-Palma, L.; Souza, J.M.; Bolatto, C.; Rodriguez-Bottero, S.; Logan, A.; Smith, R.A.; Murphy, M.P.; Barbeito, L.; et al. Neuroprotective Effects of the Mitochondria-Targeted Antioxidant MitoQ in a Model of Inherited Amyotrophic Lateral Sclerosis. Free Radic. Biol. Med. 2014, 70, 204–213.
Gane, E.J.; Weilert, F.; Orr, D.W.; Keogh, G.F.; Gibson, M.; Lockhart, M.M.; Frampton, C.M.; Taylor, K.M.; Smith, R.A.; Murphy, M.P. The Mitochondria-Targeted Anti-Oxidant Mitoquinone Decreases Liver Damage in a Phase II Study of Hepatitis C Patients. Liver Int. 2010, 30, 1019–1026.
Zielonka, J.; Joseph, J.; Sikora, A.; Hardy, M.; Ouari, O.; Vasquez-Vivar, J.; Cheng, G.; Lopez, M.; Kalyanaraman, B. Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. Chem. Rev. 2017, 117, 10043–10120.
Pehar, M.; Vargas, M.R.; Robinson, K.M.; Cassina, P.; Diaz-Amarilla, P.J.; Hagen, T.M.; Radi, R.; Barbeito, L.; Beckman, J.S. Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis. J. Neurosci. 2007, 27, 7777–7785.
Cunha-Oliveira, T.; Montezinho, L.; Mendes, C.; Firuzi, O.; Saso, L.; Oliveira, P.J.; Silva, F.S.G. Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention. Oxidative Med. Cell. Longev. 2020, 2020, 5021694.
Xu, X.L.; Yi, F.; Pan, H.Z.; Duan, S.L.; Ding, Z.C.; Yuan, G.H.; Qu, J.; Zhang, H.C.; Liu, G.H. Progress and Prospects in Stem Cell Therapy. Acta Pharmacol. Sin. 2013, 34, 741–746.
Ohnuki, M.; Takahashi, K. Present and Future Challenges of Induced Pluripotent Stem Cells. Philos. Trans. R. Soc. B Biol. Sci. 2015, 370, 20140367.
Kim, B.W.; Ryu, J.; Jeong, Y.E.; Kim, J.; Martin, L.J. Human Motor Neurons with SOD1-G93A Mutation Generated from CRISPR/Cas9 Gene-Edited iPSCs Develop Pathological Features of Amyotrophic Lateral Sclerosis. Front. Cell. Neurosci. 2020, 14, 604171.
Keep, M.; Elmer, E.; Fong, K.S.; Csiszar, K. Intrathecal Cyclosporin Prolongs Survival of Late-Stage ALS Mice. Brain Res. 2001, 894, 327–331.
Karlsson, J.; Fong, K.S.; Hansson, M.J.; Elmer, E.; Csiszar, K.; Keep, M.F. Life Span Extension and Reduced Neuronal Death after Weekly Intraventricular Cyclosporin Injections in the G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. J. Neurosurg. 2004, 101, 128–137.
Kirkinezos, I.G.; Hernandez, D.; Bradley, W.G.; Moraes, C.T. An ALS Mouse Model with a Permeable Blood-Brain Barrier Benefits from Systemic Cyclosporine A Treatment. J. Neurochem. 2004, 88, 821–826.
Martin, L.J. The Mitochondrial Permeability Transition Pore: A Molecular Target for Amyotrophic Lateral Sclerosis Therapy. Biochim. Biophys. Acta 2010, 1802, 186–197.
Martin, L.J. Olesoxime, a Cholesterol-Like Neuroprotectant for the Potential Treatment of Amyotrophic Lateral Sclerosis. IDrugs 2010, 13, 568–580.
Bordet, T.; Buisson, B.; Michaud, M.; Drouot, C.; Galea, P.; Delaage, P.; Akentieva, N.P.; Evers, A.S.; Covey, D.F.; Ostuni, M.A.; et al. Identification and Characterization of Cholest-4-En-3-One, Oxime (TRO19622), a Novel Drug Candidate for Amyotrophic Lateral Sclerosis. J. Pharmacol. Exp. Ther. 2007, 322, 709–720.
Sunyach, C.; Michaud, M.; Arnoux, T.; Bernard-Marissal, N.; Aebischer, J.; Latyszenok, V.; Gouarne, C.; Raoul, C.; Pruss, R.M.; Bordet, T.; et al. Olesoxime Delays Muscle Denervation, Astrogliosis, Microglial Activation and Motoneuron Death in an ALS Mouse Model. Neuropharmacology 2012, 62, 2346–2352.
Lenglet, T.; Lacomblez, L.; Abitbol, J.L.; Ludolph, A.; Mora, J.S.; Robberecht, W.; Shaw, P.J.; Pruss, R.M.; Cuvier, V.; Meininger, V.; et al. A Phase II–III Trial of Olesoxime in Subjects with Amyotrophic Lateral Sclerosis. Eur. J. Neurol. 2014, 21, 529–536.
Scott, S.; Kranz, J.E.; Cole, J.; Lincecum, J.M.; Thompson, K.; Kelly, N.; Bostrom, A.; Theodoss, J.; Al-Nakhala, B.M.; Vieira, F.G.; et al. Design, Power, and Interpretation of Studies in the Standard Murine Model of ALS. Amyotroph. Lateral Scler. 2008, 9, 4–15.
Yang, Y.M.; Gupta, S.K.; Kim, K.J.; Powers, B.E.; Cerqueira, A.; Wainger, B.J.; Ngo, H.D.; Rosowski, K.A.; Schein, P.A.; Ackeifi, C.A.; et al. A Small Molecule Screen in Stem-Cell-Derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS. Cell Stem Cell 2013, 12, 713–726.
Martin, L.J.; Fancelli, D.; Wong, M.; Niedzwiecki, M.; Ballarini, M.; Plyte, S.; Chang, Q. GNX-4728, a Novel Small Molecule Drug Inhibitor of Mitochondrial Permeability Transition, Is Therapeutic in a Mouse Model of Amyotrophic Lateral Sclerosis. Front. Cell. Neurosci. 2014, 8, 433.
Parkinson Study, G. A Controlled Trial of Rasagiline in Early Parkinson Disease: The Tempo Study. Arch. Neurol. 2002, 59, 1937–1943.
Olanow, C.W.; Rascol, O.; Hauser, R.; Feigin, P.D.; Jankovic, J.; Lang, A.; Langston, W.; Melamed, E.; Poewe, W.; Stocchi, F.; et al. A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson’s Disease. N. Engl. J. Med. 2009, 361, 1268–1278.
Youdim, M.B.; Weinstock, M. Molecular Basis of Neuroprotective Activities of Rasagiline and the Anti-Alzheimer Drug TV3326 . Cell. Mol. Neurobiol. 2001, 21, 555–573.
Maruyama, W.; Akao, Y.; Youdim, M.B.; Davis, B.A.; Naoi, M. Transfection-Enforced Bcl-2 Overexpression and an Anti-Parkinson Drug, Rasagiline, Prevent Nuclear Accumulation of Glyceraldehyde-3-Phosphate Dehydrogenase Induced by an Endogenous Dopaminergic Neurotoxin, N-methyl(R)salsolinol. J. Neurochem. 2001, 78, 727–735.
Maruyama, W.; Youdim, M.B.; Naoi, M. Antiapoptotic Properties of Rasagiline, N-Propargylamine-1(R)-Aminoindan, and Its Optical (S)-isomer, TV1022. Ann. N. Y. Acad. Sci. 2001, 939, 320–329.
Youdim, M.B.; Amit, T.; Falach-Yogev, M.; Bar Am, O.; Maruyama, W.; Naoi, M. The Essentiality of Bcl-2, PKC and Proteasome-Ubiquitin Complex Activations in the Neuroprotective-Antiapoptotic Action of the Anti-Parkinson Drug, Rasagiline. Biochem. Pharmacol. 2003, 66, 1635–1641.
Waibel, S.; Reuter, A.; Malessa, S.; Blaugrund, E.; Ludolph, A.C. Rasagiline Alone and in Combination with Riluzole Prolongs Survival in an ALS Mouse Model. J. Neurol. 2004, 251, 1080–1084.
Macchi, Z.; Wang, Y.; Moore, D.; Katz, J.; Saperstein, D.; Walk, D.; Simpson, E.; Genge, A.; Bertorini, T.; Fernandes, J.A.; et al. A Multi-Center Screening Trial of Rasagiline in Patients with Amyotrophic Lateral Sclerosis: Possible Mitochondrial Biomarker Target Engagement. Amyotroph. Lateral Scler. Front. Degener. 2015, 16, 345–352.
Statland, J.M.; Moore, D.; Wang, Y.; Walsh, M.; Mozaffar, T.; Elman, L.; Nations, S.P.; Mitsumoto, H.; Fernandes, J.A.; Saperstein, D.; et al. Rasagiline for Amyotrophic Lateral Sclerosis: A Randomized, Controlled Trial. Muscle Nerve 2019, 59, 201–207.
Ludolph, A.C.; Schuster, J.; Dorst, J.; Dupuis, L.; Dreyhaupt, J.; Weishaupt, J.H.; Kassubek, J.; Weiland, U.; Petri, S.; Meyer, T.; et al. Safety and Efficacy of Rasagiline as an Add-on Therapy to Riluzole in Patients with Amyotrophic Lateral Sclerosis: A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled, Phase 2 Trial. Lancet Neurol. 2018, 17, 681–688.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Neurosciences; Endocrinology & Metabolism; Cell Biology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Teresa Cunha-Oliveira

Liliana Montezinho

Rui F. Simões

Marcelo Carvalho

Elisabete Ferreiro

Filomena S. G. Silva

View Times: 168

Entry Collection: Neurodegeneration

Update Date: 26 Feb 2024

Table of Contents