Abstract
In the case of Parkinson’s disease (PD), epidemiological studies have reported that pesticide exposure is a risk factor for its pathology. It has been suggested that some chemical agents, such as rotenone and paraquat, that inhibit the mitochondrial respiratory chain (in the same way as the PD mimetic toxin 1-methyl-4-phenylpyridinium, MPP+) are involved in the development of PD. However, although the neurotoxic effect of such compounds has been widely reported using in vivo and in vitro experimental approaches, their direct effect on the glial cells remains poorly characterized. In addition, the extent to which these toxins interfere with the immune response of the glial cells, is also underexplored. We used mouse primary mixed glial and microglial cultures to study the effect of MPP+ and rotenone on glial activation, in the absence and the presence of a pro-inflammatory stimulus (lipopolysaccharide plus interferon-γ, LPS+IFN-γ). We determined the mRNA expression of the effector molecules that participate in the inflammatory response (pro-inflammatory cytokines and enzymes), as well as the nitric oxide (NO) and cytokine production. We also studied the phagocytic activity of the microglial cells. In addition, we evaluated the metabolic changes associated with the observed effects, through the measurement of adenosine triphosphate (ATP) production and the expression of genes involved in the control of metabolic pathways. We observed that exposure of the glial cultures to the neurotoxins, especially rotenone, impaired the pro-inflammatory response induced by LPS/IFN-γ. MPP+ and rotenone also impaired the phagocytic activity of the microglial cells, and this effect was potentiated in the presence of LPS/IFN-γ. The deficit in ATP production that was detected, mainly in MPP+ and rotenone-treated mixed glial cultures, may be responsible for the effects observed. These results show that the response of glial cells to a pro-inflammatory challenge is altered in the presence of toxins inhibiting mitochondrial respiratory chain activity, suggesting that the glial immune response is impaired by such agents. This may have relevant consequences for brain function and the central nervous system’s (CNS’s) response to insults.
Highlights
Microglia are the main endogenous immune cells of the central nervous system (CNS)
We evaluated glial cell viability after treating the mixed glial or the microglial cultures with increasing concentrations of MPP+ (10, 25, 50 and 100 μM) or rotenone (20, 40, 100 and 150 nM), both in the absence and in the presence of LPS/IFN-γ, considering the MTT assay and Propidium iodide (PI) staining
As in the case of MPP+ treatments, no alterations in MTT reduction were observed in microglial cell cultures treated with rotenone or rotenone and LPS/IFN-γ (Figure 1D)
Summary
Microglia are the main endogenous immune cells of the central nervous system (CNS). Under physiological conditions, they constantly patrol the CNS parenchyma, ready to detect alterations that could interfere with normal brain function. In response to noxious stimuli, microglial cells develop a wide range of reactive phenotypes aimed at re-establishing cerebral homeostasis and minimizing neuronal damage. In this way, they can respond to alterations in the CNS homeostasis due to the presence of exogenous pathogens or anomalous protein aggregates resulting from pathological processes. They can respond to alterations in the CNS homeostasis due to the presence of exogenous pathogens or anomalous protein aggregates resulting from pathological processes They are able to respond to neuronal damage resulting from brain lesions, brain ischemia, neurodegenerative diseases or exposure to neurotoxic agents (Salter and Stevens, 2017). Either an increase in the expression of pro-inflammatory factors (Gao et al, 2013; Yuan et al, 2013; Du et al, 2014) or no direct effect on the production of inflammatory factors (Klintworth et al, 2009) has been observed in rotenone-treated microglial cell cultures
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