Central Activation of Alpha7 Nicotinic Signaling Attenuates LPS-Induced Neuroinflammation and Sickness Behavior in Adult but Not in Aged Animals

We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As alpha 7 nAChRs are implicated in the Cholinergic anti-inflammatory pathway, we aimed to determine how alpha 7 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 alpha 7 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 alpha 7 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-1 beta and TNF alpha mRNA levels. Furthermore, central (intracerebroventricular) administration of the alpha 7 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 alpha 7 nAChRs was performed peripherally. Finally, we observed that the positive results of central activation of alpha 7 nAChRs were lost in aged mice. In conclusion, we provide evidence that stimulation of alpha 7 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.

Automated summary

The stimulation of alpha 7 nAChR signaling reduces microglial activation in an in vivo LPS-based model, but this cholinergic-dependent regulation appears to be dysfunctional in microglia of aged mice.