Positive Allosteric Modulation of Alpha7 Nicotinic Acetylcholine Receptors Transiently Improves Memory but Aggravates Inflammation in LPS-Treated Mice

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 alpha 7 subunits (alpha 7 nAChRs) are involved in regulating cell survival, inflammation, and memory. The aim of our study was to evaluate the efficiency of alpha 7-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 alpha 7-, alpha 3-, and alpha 4-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-1 beta and IL-6 levels in the blood. It is concluded that activating alpha 7 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.