Abstract
Neuroinflammation accompanies or even precedes the development of cognitive changes in many brain pathologies, including Alzheimer’s disease. Therefore, dampening inflammatory reactions within the brain is a promising strategy for supporting cognitive functions in elderly people and for preventing the development of neurodegenerative disorders. Nicotinic acetylcholine receptors containing α7 subunits (α7 nAChRs) are involved in regulating cell survival, inflammation, and memory. The aim of our study was to evaluate the efficiency of α7-specific therapy at different stages of inflammation and to compare the effects of orthosteric agonist PNU282987 and type 2 positive allosteric modulator (PAM) PNU120596 in mice after a single injection of lipopolysaccharide (LPS). The data presented demonstrate that PNU282987 protected mice from LPS-induced impairment of episodic memory by decreasing IL-6 levels in the blood, stabilizing the brain mitochondria and up-regulating the brain α7-, α3-, and α4-containing nAChRs. Such treatment was efficient when given simultaneously with LPS or a week after LPS injection and was not efficient if LPS had been injected 2 months before. PNU120596 also decreased IL-6, stabilized mitochondria and up-regulated the brain nAChRs. However, its memory-improving effect was transient and disappeared after the end of the injection cycle. Moreover, cessation of PNU120596 treatment resulted in a sharp increase in IL-1β and IL-6 levels in the blood. It is concluded that activating α7 nAChRs protects the mouse brain from the pathogenic effect of LPS in the early stages of inflammation but is not efficient when irreversible changes have already occurred. The use of a PAM does not improve the effect of the agonist, possibly potentiates the effect of endogenous agonists, and results in undesirable effects after treatment cessation.
Highlights
Neuroinflammation has been shown to accompany or even to be one of the factors stimulating neurodegeneration in many brain pathologies, including Alzheimer’s disease (Chung et al, 2010; Heneka et al, 2015; Heppner et al, 2015)
The data presented here demonstrate that activating α7 nicotinic acetylcholine receptor (nAChR) with orthosteric agonist PNU282 protects the mouse brain from the pathogenic effect of LPS by decreasing the inflammatory reaction, stabilizing mitochondria, and up-regulating the brain nAChRs, resulting in memory improvement
This is in accord with previously reported data on the positive effects of α7 nAChR agonists in Alzheimer’s disease animal models (Van Kampen et al, 2004; Boess et al, 2007; Medeiros et al, 2014; Vicens et al, 2017; reviewed in Foucault-Fruchard and Antier, 2017)
Summary
Neuroinflammation has been shown to accompany or even to be one of the factors stimulating neurodegeneration in many brain pathologies, including Alzheimer’s disease (Chung et al, 2010; Heneka et al, 2015; Heppner et al, 2015). NAChRs containing α7 subunits directly interact with amyloid-beta peptides Aβ(1–40) and Aβ(1–42; Ni et al, 2013; Oz et al, 2013). These nAChRs have been shown to be related to neurodegenerative pathologies, including Alzheimer’s disease (reviewed in Skok and Lykhmus, 2016). We reported that regular injections of bacterial lipopolysaccharide (LPS) resulted in neurodegeneration in mice accompanied by the decrease of α7-containing nAChRs, accumulation of Aβ(1–42), and memory impairment (Lykhmus et al, 2015b). It was shown that even a single LPS injection results in a decline in episodic memory and changes in the nAChR composition in the brain (Lykhmus et al, 2019b)
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