Mosaic chemotherapy strategies for developing ALS/MND therapeutic approaches: Beta-2 adrenergic agonists

Br, Brooks; Juhasz-Poscine, K; Waclawik, Andrew J.; Sanjak, Mohammed; Belden, Daryn; Roelke, K; Parnell, Jonathan; Weasler, C.

doi:10.1080/14660820050515700

Cited by 7 publications

(5 citation statements)

References 49 publications

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“…Motor neuron diseases (MNDs) are a group of incurable neurological disorders caused by the selective degeneration of motor neurons. Amyotrophic lateral sclerosis (ALS) is the most representative MNDs among adults with a incidence rate of 2–3 per 100,000 (Brooks et al, 2000 ). It is characterized by progressive muscle weakness and atrophy, loss of upper and lower motor neurons and death ensuing 3–5 years after diagnosis.…”

Section: Introductionmentioning

confidence: 99%

A plural role for lipids in motor neuron diseases: energy, signaling and structure

Schmitt

Hussain

Dupuis

et al. 2014

Front. Cell. Neurosci.

108

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Motor neuron diseases (MNDs) are characterized by selective death of motor neurons and include mainly adult-onset amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Neurodegeneration is not the single pathogenic event occurring during disease progression. There are multiple lines of evidence for the existence of defects in lipid metabolism at peripheral level. For instance, hypermetabolism is well characterized in ALS, and dyslipidemia correlates with better prognosis in patients. Lipid metabolism plays also a role in other MNDs. In SMA, misuse of lipids as energetic nutrients is described in patients and in related animal models. The composition of structural lipids in the central nervous system is modified, with repercussion on membrane fluidity and on cell signaling mediated by bioactive lipids. Here, we review the main epidemiologic and mechanistic findings that link alterations of lipid metabolism and motor neuron degeneration, and we discuss the rationale of targeting these modifications for therapeutic management of MNDs.

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Section: Introductionmentioning

confidence: 99%

A plural role for lipids in motor neuron diseases: energy, signaling and structure

Schmitt

Hussain

Dupuis

et al. 2014

Front. Cell. Neurosci.

108

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“…Respiratory insuffi ciency becomes more common as the disease progresses. Patients usually die within 3-5 years from symptom onset [48] .…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis

2005

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The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of several neurobiologically active molecules. Among them is the excitotoxin quinolinic acid (QUIN) that is known to be involved in the pathogenesis of several major inflammatory neurological diseases. In amyotrophic lateral sclerosis (ALS) degeneration of motor neurons is associated with a chronic and local inflammation (presence of activated microglia and astrocytes). There is emerging evidence that the KP is important in ALS. Recently, we demonstrated that QUIN is significantly increased in serum and CSF of ALS patients. Moreover, most of the factors associated with QUIN toxicity are found in ALS, implying that QUIN may play a substantial role in the neuropathogenesis of ALS. This review details the potential role the KP has in ALS and advances a testable hypothetical model.

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“…It is characterized by selective degeneration of upper and lower motor neurons, progressive decline of muscle strength, failure of pulmonary function and death usually within 3-5 years after the first symptoms (1). Although most cases occur sporadically, Ϸ10% of patients exhibit an autosomal dominant pattern of inheritance, and 10 -20% of these are associated with missense mutations in the gene encoding Cu͞Zn-superoxide dismutase (SOD1), the main free radical scavenging enzyme that protects cells against oxidative stress (2).…”

mentioning

confidence: 99%

Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: Benefit of a high-energy diet in a transgenic mouse model

Dupuis

Oudart

Frydman

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

487

472

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Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective loss of motor neurons and progressive muscle wasting. Growing evidence indicates that mitochondrial dysfunction, not only occurring in motor neurons but also in skeletal muscle, may play a crucial role in the pathogenesis. In this regard, the life expectancy of the ALS G93A mouse line is extended by creatine, an intracellular energy shuttle that ameliorates muscle function. Moreover, a population of patients with sporadic ALS exhibits a generalized hypermetabolic state of as yet unknown origin. Altogether, these findings led us to explore whether alterations in energy homeostasis may contribute to the disease process. Here, we show important variations in a number of metabolic indicators in transgenic ALS mice, which in all shows a metabolic deficit. These alterations were accompanied early in the asymptomatic phase of the disease by reduced adipose tissue accumulation, increased energy expenditure, and concomitant skeletal muscle hypermetabolism. Compensating this energetic imbalance with a highly energetic diet extended mean survival by 20%. In conclusion, we suggest that hypermetabolism, mainly of muscular origin, may represent by itself an additional driven force involved in increasing motor neuron vulnerability.

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Mosaic chemotherapy strategies for developing ALS/MND therapeutic approaches: Beta-2 adrenergic agonists

Cited by 7 publications

References 49 publications

A plural role for lipids in motor neuron diseases: energy, signaling and structure

A plural role for lipids in motor neuron diseases: energy, signaling and structure

Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis

Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: Benefit of a high-energy diet in a transgenic mouse model

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