Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease that is characterized by the degradation of neurons throughout the central nervous system. Inflammation have been cited a key contributor to ALS neurodegeneration, but the timeline of cytokine upregulation remains unresolved. The goal of this study was to temporally examine the correlation between the varying levels of pro-inflammatory type I cytokines (IL-1β, IL-1α, IL-12, TNF-α, and GFAP) and anti-inflammatory type II cytokines (IL-4, IL-6, IL-10) throughout the progression of ALS in the SOD1 G93A mouse model. Cytokine level data from high copy SOD1 G93A transgenic mice was collected from 66 peer-reviewed studies. For each corresponding experimental time point, the ratio of transgenic to wild type (TG/WT) cytokine was calculated. One-way ANOVA and t-tests with Bonferonni correction were used to analyze the data. Meta-analysis was performed for four discrete stages: early, pre-onset, post-onset, and end stage. A significant increase in TG cytokine levels was found when compared to WT cytokine levels across the entire SOD1 G93A lifespan for majority of the cytokines. The rates of change of the individual cytokines, and type I and type II were not significantly different; however, the mean fold change of type I was expressed at significantly higher levels than type II levels across all stages with the difference between the means becoming more pronounced at the end stage. An overexpression of cytokines occurred both before and after the onset of ALS symptoms. The trend between pro-inflammatory type I and type II cytokine mean levels indicate a progressive instability of the dynamic balance between pro- and anti-inflammatory cytokines as anti-inflammatory cytokines fail to mediate the pronounced increase in pro-inflammatory cytokines. Very early immunoregulatory treatment is necessary to successfully interrupt ALS-induced neuroinflammation.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by the rapid degradation of motor neurons over the course of the disease, resulting in paralysis, respiratory failure, and death
Experimental in vivo data on cytokines levels in transgenic (TG) superoxide dismutase gene (SOD1) G93A ALS mice and wild type (WT) mice was utilized from a total of 66 peer-reviewed articles, which met the study inclusion criteria
transgenic G93A SOD1 mice (TG)/wild type mice (WT) cytokine level ratio is plotted for each specific cytokine type over the TG mouse life span (Figure 1)
Summary
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by the rapid degradation of motor neurons over the course of the disease, resulting in paralysis, respiratory failure, and death. ALS is multi-faceted pathophysiology, which includes axonal transport deficiency; upregulation of apoptotic cascades; changes. Cytokine Instability in ALS in cellular chemistry, including metallation and enzymes; cellular energetics deficiencies; excitability, including changes in neurotransmitters and transporters; inflammation, including increased microglia activation and gliosis; oxidative stress, including increases in free intracellular oxidants and antioxidants; protein deregulation, including increased protein aggregates and decreased autophagy; and systemic contributors, including those of muscular and non-neuromuscular origin (Irvin et al, 2015; Kim et al, 2015). Inflammation, or neuroinflammation, is one of the more heavily researched ALS contributors (Kim et al, 2015), which is frequently assessed in the familial or transgenic superoxide dismutase-1 guanine 93 to alanine (SOD1 G93A) murine model (Pfohl et al, 2015). The crucial role of neuroinflammation in the pathology of ALS is evident, the extent to which the inflammatory response is neurotoxic, and the balance of the inflammatory regulation and deregulation over the course of the disease progression remain unclear (McCombe and Henderson, 2011; Evans et al, 2013)
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