Abstract
In order to fulfill their evolutionary role as support cells, astrocytes have to tolerate intense oxidative stress under conditions of brain injury and disease. It is well known that astrocytes exposed to mild oxidative stress are preconditioned against subsequent stress exposure in dual hit models. However, it is unclear whether severe oxidative stress leads to stress tolerance, stress exacerbation, or no change in stress resistance in astrocytes. Furthermore, it is not known whether reactive astrocytes surviving intense oxidative stress can still support nearby neurons. The data in this Brief Report suggest that primary cortical astrocytes surviving high concentrations of the oxidative toxicant paraquat are completely resistant against subsequent oxidative challenges of the same intensity. Inhibitors of multiple endogenous defenses (e.g., glutathione, heme oxygenase 1, ERK1/2, Akt) failed to abolish or even reduce their stress resistance. Stress-reactive cortical astrocytes surviving intense oxidative stress still managed to protect primary cortical neurons against subsequent oxidative injuries in neuron/astrocyte co-cultures, even at concentrations of paraquat that otherwise led to more than 80% neuron loss. Although our previous work demonstrated a lack of stress tolerance in primary neurons exposed to dual paraquat hits, here we show that intensely stressed primary neurons can resist a second hit of hydrogen peroxide. These collective findings suggest that stress-reactive astroglia are not necessarily neurotoxic, and that severe oxidative stress does not invariably lead to stress exacerbation in either glia or neurons. Therefore, interference with the natural functions of stress-reactive astrocytes might have the unintended consequence of accelerating neurodegeneration.
Highlights
According to the dual-hit theory of neurodegeneration, cellular exposure to severe stress—defined as stress that is lethal to some fraction of the cellular population—may render neurons more sensitive to subsequent challenges, leading to stress-induced exacerbation of cellular toxicity (Cory-Slechta et al, 2005; Carvey et al, 2006; Hawkes et al, 2007; Zhu et al, 2007; Boger et al, 2010; Gao et al, 2011)
Apart from proteotoxic stress, oxidative stress is another major hallmark of brain injury and disease, and it is not known whether primary astrocytes surviving severe oxidative toxicity exhibit stress tolerance, stress exacerbation, or no change in response to a second stressor
We examined the response to dual hits of hydrogen peroxide in primary cortical neurons, and we discovered that the neurons surviving a first hit of 6.25 μM or higher did not respond to a second hit of 12.5 μM with significant additional cell loss according to the microtubule associated protein-2 (MAP2) InCell Western viability assay (Supplementary Figures S2F,G)
Summary
According to the dual-hit theory of neurodegeneration, cellular exposure to severe stress—defined as stress that is lethal to some fraction of the cellular population—may render neurons more sensitive to subsequent challenges, leading to stress-induced exacerbation of cellular toxicity (Cory-Slechta et al, 2005; Carvey et al, 2006; Hawkes et al, 2007; Zhu et al, 2007; Boger et al, 2010; Gao et al, 2011). The first objective of the present study was to test the hypothesis that primary cortical astrocytes surviving severe oxidative toxicity tolerate a second oxidative hit of the same intensity with no additional cell loss. The second objective of the present study was to determine if reactive cortical astrocytes surviving paraquat exposure would subsequently injure or protect primary cortical neurons. The answer to this question has clinical implications, as pharmacological inhibition of stressreactive astrocytes might have negative consequences on the progression of neurodegenerative disorders if reactive astrocytes continue to protect neighboring neurons under conditions of severe oxidative injury
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