Targets in ALS: designing multidrug therapies

Carrı̀, Maria Teresa; Grignaschi, Giuliano; Bendotti, Caterina

doi:10.1016/j.tips.2006.03.009

Cited by 57 publications

(53 citation statements)

References 70 publications

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“…New sets of hypotheses have been generated based on the pathogenesis of ALS and on findings from genetic, pathological, and biochemical postmortem evaluations. Drugs candidates have been chosen for their potential to reduce excitotoxicity, apoptosis, motor neuron degeneration, bioenergetics, or oxidative damage (24,62,81,132). As discussed throughout this review, oxidative stress has been implicated in the pathogenesis of ALS.…”

Section: Therapeutic Approaches To Alsmentioning

confidence: 99%

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Carter

Anklesaria

Choi

et al. 2009

Antioxidants & Redox Signaling

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Enhanced redox-stress caused by neuroinflammation, mitochondria, and NADPH oxidases has been hypothesized to play critical roles in disease progression of amyotrophic lateral sclerosis (ALS). However, distinguishing whether the redox-stress observed in ALS is due to a primary defect in cellular reactive oxygen species metabolism=catabolism, or is a secondary consequence of neuroinflammation, has been difficult and the issue remains a matter of debate. Emerging evidence suggests that defects in genes that regulate NADPH oxidases may account for at least some forms of ALS. NADPH oxidases are key signaling complexes that influence cellular responses to growth factors and cytokines. In this context, NADPH oxidase-derived reactive oxygen species exert spatial control over the redox-dependent activation of certain pro-inflammatory receptors. Understanding the biology of how NADPH oxidases control cell signaling may help to clarify how genetic determinants of ALS lead to dysregulated pro-inflammatory signaling. This review provides a framework for understanding endosomal signaling through NADPH oxidases and potential mechanisms whereby gene defects in various forms of ALS may influence this cellular process and lead to motor neuron degeneration. Lastly, this review discusses past and current efforts to treat ALS using antioxidant therapies, as well as the limitations and advantages of each of these approaches. Antioxid. Redox Signal. 11, 1569-1586.

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Section: Therapeutic Approaches To Alsmentioning

confidence: 99%

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Carter

Anklesaria

Choi

et al. 2009

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…2 Unfortunately, many patients experience loss of one or more neuronal populations due to accidents or pathological processes. For example, hippocampal and cortical neuronal death is typical of Alzheimer's disease; 3 in Parkinson's disease the dopaminergic neurons of the midbrain die by apoptosis; 4 Huntington's disease is characterized by cell death of striated neurons whereas in ALS there is loss of motoneurons; 5,6 cell loss occurs after cerebral ischemia during reperfusion and repair.…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor-1 inhibits STS-induced cell death and increases functional recovery of in vitro differentiated neurons

et al. 2008

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“…83 Moreover, combination therapy with multiple pharmacological agents may be a useful treatment approach given that several putative mechanisms may be involved in the pathogenesis of ALS. 84,85 Additive effects of combined treatment (eg, cocktail of riluzole, minocycline, and nimodipine) have been observed in mutant SOD1 mice. 85 Phase II trials designed to select the best of 2 combination treatments may represent an efficient means to test therapeutic candidates in patients with ALS and to advance the most promising candidates to evaluation in phase III trials.…”

Section: Polytherapy and Future Directionsmentioning

confidence: 99%

Managing amyotrophic lateral sclerosis: Slowing disease progression and improving patient quality of life

Brooks

2009

Annals of Neurology

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It is now possible to slow the disease progression of amyotrophic lateral sclerosis (ALS), but documented improvement in the quality of life of ALS patients has been difficult to quantitate. Putative mechanisms involved in motor neuron degeneration in ALS include oxidative damage, mitochondrial dysfunction, neuroinflammation, growth factor deficiency, and glutamate excitotoxicity. Several pharmacological agents that target these potential targets have demonstrated therapeutic potential in animal models with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Many treatments that have been moderately effective in this animal model have not been successfully translated into effective treatments for humans with ALS. Only the glutamate modulator riluzole has demonstrated efficacy in clinical trials and is approved for treating ALS. Combination treatments may represent a potential therapeutic strategy to more robustly prolong life and preserve function, but only vitamin E with riluzole has been formally studied in clinical trials, and to date, no combination treatments have been found to be more effective than currently available single agents.

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Targets in ALS: designing multidrug therapies

Cited by 57 publications

References 70 publications

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Insulin-like growth factor-1 inhibits STS-induced cell death and increases functional recovery of in vitro differentiated neurons

Managing amyotrophic lateral sclerosis: Slowing disease progression and improving patient quality of life

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