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

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.

Different Effects of Nicotine and N-Stearoyl-ethanolamine on Episodic Memory and Brain Mitochondria of α7 Nicotinic Acetylcholine Receptor Knockout Mice

“…These studies pushed us to search the approaches to overcome the pathological effects of neuroinflammation and α7 nAChR deficiency. In particular, it was shown that neuroinflammation can be prevented or even cured by activating α7 nAChRs with orthosteric agonist [36] or by up-regulating alternative nAChR subtypes with the growth factors produced by mesenchymal stem cells [37]. One of our previous papers described the efficiency of NSE to prevent neuroinflammation in the wild-type mice either treated with LPS of immunized with α7 nAChR extracellular domain 1-208 [22].…”

Changing Functional Signatures of Microglia along the Axis of Brain Aging

“…However, in contrast to the stable and continuous pro-cognitive and anti-inflammatory effect of the agonist, the pro-cognitive effect of the type 2 PAM was transient and disappeared a week after the end of the injection cycle. Moreover, cessation of PNU120596 treatment resulted in a sharp increase of IL-1β and IL-6 levels in the blood of mice [ 142 ]. This result puts in doubt the idea of using type 2 PAMs instead of orthosteric α7 nAChR agonists for neuroprotection.…”

Homomeric and Heteromeric α7 Nicotinic Acetylcholine Receptors in Health and Some Central Nervous System Diseases

“…Due to their strategic location and enrichment in areas involved in working memory acquisition, maintenance, and retrieval, nAChRs in the hippocampus and cerebral cortex play major roles in cognition and mnemonic functions [ 19 , 20 ] and modulate prefrontal cortex functions involved in consciousness [ 21 ]. At present, we probably know only a fraction of the roles played by nAChR subtypes in the functioning of the human brain [ 22 ].…”