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Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone - PubMed

Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone

Jonathan A Fidler et al. FASEB J. 2011 Dec.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron cell loss, muscular atrophy, and a shortened life span. Survival is highly variable, as some patients die within months, while others live for many years. Exposure to stress or the development of a nonoptimal stress response to disease might account for some of this variability. We show in the SOD1(G93A) mouse model of ALS that recurrent exposure to restraint stress led to an earlier onset of astrogliosis and microglial activation within the spinal cord, accelerated muscular weakness, and a significant decrease in median survival (105 vs. 122 d) when compared to nonstressed animals. Moreover, during normal disease course, ALS mice display a cacostatic stress response by developing an aberrant serum corticosterone circadian rhythm. Interestingly, we also found that higher corticosterone levels were significantly correlated with both an earlier onset of paralysis (males: r(2)=0.746; females: r(2)=0.707) and shorter survival times (males: r(2)=0.680; females: r(2)=0.552) in ALS mice. These results suggest that stress is capable of accelerating disease progression and that strategies that modulate glucocorticoid metabolism might be a viable treatment approach for ALS.

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Figures

Figure 1.
Figure 1.

Stress response system exerts its effects in an inverted U-shaped dose response (modified from ref. 6). A eustatic or optimum response to disease occurs when homeostatic system activity (i.e., stress response system activity) is in the middle of the curve. Allostatic or cacostatic responses to disease, which are suboptimal, occur when homeostatic activity is deficient or excessive. Both short- and long-term exposure to an allostatic state have proven to be harmful to overall health and to trigger a myriad of disease states.

Figure 2.
Figure 2.

Exposure to repeated restraint-induced stress leads to accelerated disease progression in a familial mouse model of ALS. Kaplan Meier survival analysis (A), rotarod analysis (B), and forelimb (C) and hindlimb (D) grip-strength measurements of nonstressed and chronically stressed male SOD1G93A mice. Stressed mice are indicated in gray; nonstressed in black. *P < 0.01 vs. nonstressed mice.

Figure 3.
Figure 3.

Stress and cort increase glial cell activation both in vivo and in vitro. A, B) Male SOD1G93A mice exposed to repeated restraint-induced stress displayed accelerated development of astrogliosis (A) and microglia activation (B) throughout each region of the spinal cord. C) Cort increased differentiation of neuroprogenitor cells from SOD1G93A mice into astrocytes in vitro. D, E) Cort significantly promoted glia cell activation by enhancing the release of TNF-α (D) and nitric oxide (E) from BV2 migroglia cells expressing the SOD1G93A mutation. Bars that do not share the same letter differ significantly (P<0.01).

Figure 4.
Figure 4.

ALS mice display disease-related changes in serum cort levels that negatively correlate with survival. A) Serum cort levels in male ALS mice vs. WT littermate controls at different CT points as a function of disease state (PRE, presymptomatic; SYMP, symptomatic; ES, end stage or onset of limb paralysis). *P < 0.01 vs. WT. B) Serum cort levels in ALS mice prior to ES, at ES, and moribund (MB), expressed as a percentage of WT levels. C) Linear regression analysis examining the relationship between serum cort levels 10–14 d prior to ES onset and onset of paralysis. Significant negative correlations were found for male (r2=0.746, P<0.0013) and female (r2=0.707, P<0.0023) mice. D) Linear regression analysis examining the relationship between serum cort levels 10–14 d prior to ES onset and survival. Significant negative correlations were found for male (r2=0.680, P<0.003) and female (r2=0.552, P<0.01) mice.

Figure 5.
Figure 5.

Model summarizing the influence of stress mediators on the manifestation of ALS disease features. Homeostatic disruption triggered by the presence of mutant SOD1 (mSOD1) initially leads to the release of stress mediators (e.g., cort, arginine vasopressin, corticotrophin-releasing hormone, α-melanocyte-stimulating hormone, β-endorphin, IL-6, serotonin, histamine, norepinephrine, and epinephrine) in a manner that promotes a eustatic stress response (i.e., adaptation of a new homeostatic set point that is beneficial to overall survival) to slow disease course. However, protracted homeostatic disruption inevitably leads to the cacostatic release of stress mediators. This hastens the initiation and/or progression of several disease features observed in ALS (only features known to be influenced by cort or triggered by exposure to cacostatic levels of stress mediators are listed; see text for references). Individual differences in stress response system activity (e.g., duration of the transition period between eustatic and cacostatic release of stress mediators) may account for some of the variability observed in survival of patients with ALS. Disease course is likely initiated or accelerated in individuals with a predisposition for developing ALS following recurrent exposure to physical, psychological, and metabolic stressors (e.g., through high-intensity athletic or military training) which catalyze the cacostatic release of stress mediators (e.g., cort).

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