Melatonin may slow disease progression in amyotrophic lateral sclerosis: Findings from the Pooled Resource Open‐Access ALS Clinic Trials database

Bald, Elizabeth; Nance, Christopher; Schultz, Jordan L.

doi:10.1002/mus.27168

Cited by 30 publications

(10 citation statements)

References 17 publications

(20 reference statements)

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“…Dopaminergic drugs, such as pramipexole, reduce oxidative stress [ 444 ] and glutamate excitotoxicity [ 445 ]. The safety and efficacy of dexpramipexole was evaluated in several phase 1, 2, and 3 clinical studies.…”

Section: Translating Theoretical Knowledge Into Therapymentioning

confidence: 99%

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

Jurcău

2021

IJMS

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As the population ages, the incidence of neurodegenerative diseases is increasing. Due to intensive research, important steps in the elucidation of pathogenetic cascades have been made and significantly implicated mitochondrial dysfunction and oxidative stress. However, the available treatment in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis is mainly symptomatic, providing minor benefits and, at most, slowing down the progression of the disease. Although in preclinical setting, drugs targeting mitochondrial dysfunction and oxidative stress yielded encouraging results, clinical trials failed or had inconclusive results. It is likely that by the time of clinical diagnosis, the pathogenetic cascades are full-blown and significant numbers of neurons have already degenerated, making it impossible for mitochondria-targeted or antioxidant molecules to stop or reverse the process. Until further research will provide more efficient molecules, a healthy lifestyle, with plenty of dietary antioxidants and avoidance of exogenous oxidants may postpone the onset of neurodegeneration, while familial cases may benefit from genetic testing and aggressive therapy started in the preclinical stage.

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Section: Translating Theoretical Knowledge Into Therapymentioning

confidence: 99%

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

Jurcău

2021

IJMS

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“…Melatonin is an antioxidant and, presumably, decreases oxidative stress [128]. ALS patients taking melatonin had a significantly decreased annualized hazard death rate and a slower rate of decline in the ALSFRS score compared with the non-melatonin users [129].…”

Section: Targeting Mitochondria As a Therapymentioning

confidence: 99%

The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS

Obrador

Palmer

López-Blanch

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with median survival of 3–5 years after the initial symptomatology. In ALS, motor neurons gradually degenerate and die. Many features of mitochondrial dysfunction are manifested in neurodegenerative diseases, including ALS. Mitochondria have shown to be an early target in ALS pathophysiology and contribute to disease progression. Disruption of their axonal transport, excessive generation of reactive oxygen species, disruption of the mitochondrial structure, dynamics, mitophagy, energy production, calcium buffering and apoptotic triggering have all been directly involved in disease pathogenesis and extensively reported in ALS patients and animal model systems. Alterations in energy production by motor neurons, which severely limit their survival capacity, are tightly linked to the redox status and mitochondria. The present review focuses on this link. Placing oxidative stress as a main pathophysiological mechanism, the molecular interactions and metabolic flows involved are analyzed. This leads to discussing potential therapeutic approaches targeting mitochondrial biology to slow disease progression.

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“…Overall, our results on melatonin's effects are in agreement with its reported multiple beneficial actions that go well beyond a mere regulation of circadian rhythms. The compound is in fact endowed with anti-inflammatory, antioxidant, and neuroprotective activity against a number of neurodegenerative conditions that share neuroinflammatory features [35,91], including Parkinson's disease [92], hypoxia [29,93], amyotrophic lateral sclerosis [94], traumatic brain injury, spinal cord injury [95], and neuropsychiatric disor-ders [96]. A role for melatonin has convincingly emerged also in AD, where an inverse correlation between melatonin levels and disease progression has been reported in patients, along with sleep-wake cycle disturbances [43,97].…”

Section: Discussionmentioning

confidence: 99%

SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aβ: An Early but Transient Response Rescued by Melatonin

et al. 2021

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Microglia represent a first-line defense in the brain. However, in pathological conditions such as Alzheimer’s disease (AD), a pro-inflammatory switch may occur, leading to loss of protective functions. Using the human microglial cell line HMC3, we showed that exposure to low concentrations of β-amyloid peptide 1-42 (Aβ42; 0.2 μM) initially (6 h) upregulated anti-inflammatory markers interleukin (IL)-4, IL-13, and brain-derived neurotrophic factor (BDNF). BDNF increase was prevented by selective inhibition of SIRT1 with EX527 (2 μM). Accordingly, these early effects were accompanied by a significant Aβ42-induced increase of SIRT1 expression, nuclear localization, and activity. SIRT1 modulation involved adenosine monophosphate-regulated kinase (AMPK), which was promptly (30 min) phosphorylated by Aβ42, while the AMPK inhibitor BML-275 (2 μM) attenuated Aβ42-induced SIRT1 increase. Initially observed microglial responses appeared transient, as microglial features changed when exposure to Aβ42 was prolonged (0.2 μM for 72 h). While SIRT1 and BDNF levels were reduced, the expression of inflammatory markers IL-1β and tumor necrosis factor (TNF)-α increased. This coincided with a rise in NF-kB nuclear localization. The effects of melatonin (1 μM) on prolonged microglial exposure to Aβ42 were analyzed for their protective potential. Melatonin was able to prolong SIRT1 and BDNF upregulation, as well as to prevent NF-kB nuclear translocation and acetylation. These effects were sensitive to the melatonin receptor antagonist, luzindole (25 μM). In conclusion, our data define an early microglial defensive response to Aβ42, featuring SIRT1-mediated BDNF upregulation that can be exogenously modulated by melatonin, thus identifying an important target for neuroprotection.

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Melatonin may slow disease progression in amyotrophic lateral sclerosis: Findings from the Pooled Resource Open‐Access ALS Clinic Trials database

Cited by 30 publications

References 17 publications

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS

SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aβ: An Early but Transient Response Rescued by Melatonin

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