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

Olena Lykhmus,Kateryna Uspenska,Maryna Skok,Tetyana Horid’Ko,Serhiy Komisarenko,Olena Kalashnyk,Halyna Kosyakova

doi:10.3390/biom10020226

Olena Lykhmus, Kateryna Uspenska + Show 5 more

Open Access

https://doi.org/10.3390/biom10020226

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Journal: Biomolecules	Publication Date: Feb 3, 2020
Citations: 6	License type: CC BY 4.0

Affiliation: Palladin Institute of Biochemistry

Abstract

Nicotinic acetylcholine receptors of α7 subtype (α7 nAChRs) are involved in regulating neuroinflammation and cognitive functions. Correspondingly, α7-/- mice demonstrate pro-inflammatory phenotype and impaired episodic memory. In addition, nAChRs expressed in mitochondria regulate the release of pro-apoptotic factors like cytochrome c. Here we studied whether the cognitive deficiency of α7-/- mice can be cured by oral consumption of either nicotine or N-stearoylethanolamine (NSE), a lipid possessing anti-inflammatory, cannabimimetic and membrane-stabilizing activity. Mice were examined in Novel Object Recognition behavioral test, their blood, brains and brain mitochondria were tested for the levels of interleukin-6, various nAChR subtypes and cytochrome c released by ELISA. The data presented demonstrate that both substances stimulated the raise of interleukin-6 in the blood and improved episodic memory of α7-/- mice. However, NSE improved, while nicotine worsened the brain mitochondria sustainability to apoptogenic stimuli, as shown by either decreased or increased amounts of cytochrome c released. Both nicotine and NSE up-regulated α4β2 nAChRs in the brain; NSE up-regulated, while nicotine down-regulated α9-containing nAChRs in the brain mitochondria. It is concluded that the level of alternative nAChR subtypes in the brain is critically important for memory and mitochondria sustainability in the absence of α7 nAChRs.

Highlights

Nicotinic acetylcholine receptors are ligand-gated ion channels mediating fast synaptic transmission in muscles and autonomic ganglia, regulating the neurotransmitter release in the brain and involved in regulating the survival, proliferation and adhesion of many non-excitable cells [1,2,3,4]
The α7-/- mice demonstrated significantly worse episodic memory compared to the WT mice; this difference was maintained during all experimental period
According to ELISA with the cell compartment-specific antibodies, the mitochondria fraction was positive for mitochondria-specific voltage-dependent anion channels (VDAC) and negative for nuclear-specific lamin B1 and endoplasmic reticulum-specific IRE-1α, while the “non-mitochondria” fraction contained lamin 1B and IRE-1α, but not VDAC [31]

Summary

Introduction

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fast synaptic transmission in muscles and autonomic ganglia, regulating the neurotransmitter release in the brain and involved in regulating the survival, proliferation and adhesion of many non-excitable cells [1,2,3,4]. In addition to the cell plasma membrane, several nAChR subtypes, including α7-containing subtype, were found in the outer membrane of mitochondria, where they regulate the release of pro-apoptotic factors like cytochrome c (cyt c) caused by the increase of intracellular Ca2+ or reactive oxygen species [10]. The decrease of mitochondrial nAChRs observed upon inflammation was shown to be accompanied by increased cyt c release under the effect of Ca2+ or H2O2 [11]

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