Abstract
We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As α7 nAChRs are implicated in the “Cholinergic anti-inflammatory pathway”, we aimed to determine how α7 nAChR stimulation modulates microglial phenotype in an LPS-induced neuroinflammation model in adult and aged mice. For this, BALB/c mice were injected intraperitoneally with LPS (0.33 mg/kg) and treated with the α7 nAChR agonist PNU282987, using different administration protocols. LPS challenge reduced body weight and induced lethargy and social withdrawal in adult mice. Peripheral (intraperitoneal) co-administration of the α7 nAChR agonist PNU282987 with LPS, attenuated body weight loss and sickness behavior associated with LPS challenge in adult mice, and reduced microglial activation with suppression of IL-1β and TNFα mRNA levels. Furthermore, central (intracerebroventricular) administration of the α7 nAChR agonist, even 2 h after LPS injection, attenuated the decrease in social exploratory behavior and microglial activation induced by peripheral administration of LPS, although this recovery was not achieved if activation of α7 nAChRs was performed peripherally. Finally, we observed that the positive results of central activation of α7 nAChRs were lost in aged mice. In conclusion, we provide evidence that stimulation of α7 nAChR signaling reduces microglial activation in an in vivo LPS-based model, but this cholinergic-dependent regulation seems to be dysfunctional in microglia of aged mice.
Highlights
There is increasing evidence indicating that inflammation is implicated in ageing and contributes to age-related neurodegenerative diseases, to the extent that it is considered the strongest factor for predicting longevity and neurodegeneration [1]
To evaluate how microglial α7 Nicotinic acetylcholine receptors (nAChRs) signaling could be controlling neuroinflammation in vivo, we used the LPS-model that drives a transient sickness behavior response characterized by weight loss, decreased social exploratory behavior and loss of locomotor activity
The aim of this study was to analyze how microglial α7 nAChR activation controls neuroinflammation caused by LPS in vivo
Summary
There is increasing evidence indicating that inflammation is implicated in ageing and contributes to age-related neurodegenerative diseases, to the extent that it is considered the strongest factor for predicting longevity and neurodegeneration [1]. Microglia are the resident innate immune cells within the central nervous system (CNS); they derive from monocyte progenitors that originate in the embryonic yolk sac and perform a variety of functions both in health and disease. Microglia perform other essential functions such as maintaining CNS homeostasis and plasticity, guarding and remodeling synapses [4,5,6]
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