The Adrenergic Mechanism in the Implementation of the Cholinergic Anti-Inflammatory Pathway

Experiments on random-bred albino mice showed that application of β2ARs agonist (hexaprenaline sulfate, 1,5 μg/kg, a single dose) and α7nAChRs agonist (GTS-21, 15 mg/kg, a single dose) cause a significant decrease in the mortality of mice from experimental sepsis (i.p., E. coli O157:H7) when it is modeling 2h after using these drugs due to a decrease of the concentration of proinflammatory cytokines TNF-α, IL-1β, and IL-6 (implementation of the cholinergic anti-inflammatory pathway). It has been experimentally established that the adrenergic mechanism (action of β2ARs agonist) is an important component in the implementation of the cholinergic anti-inflammatory pathway. The combined use of β2ARs and α7nAChR agonists determines their additive effect.

When the cholinergic anti-inflammatory pathway is realized, in addition to the excitation of α7nAChRs [9][10][11][12][13][14][15][16][17][18][19], which cause the effects already mentioned, nAChRs activation of the brain substance of the adrenal glands and sympathetic ganglia occurs, which leads to the production of epinephrine and norepinephrine (NE), which activation of macrophage-monocytic system cell (MMS) adrenergic receptors and reduce the production of pro-inflammatory cytokines [19]. At this n. vagus, releasing acetylcholine (ACh) in the celiac ganglion, causes excitation of the spleen nerve, the action of NE through its efferent fibers on T lymphocytes, the production of ACh by these lymphocytes, activation of ACh of α7nAChRs of MMS cells of the spleen [9,19]. Epinephrine and NE probably activating the adrenergic receptors of cells of the MMS (direct action) [19], β2-adrenergic receptors (β2ARs) of spleen T-lymphocytes (indirect effect) [10], cause the same effect as activation of α7nAChRs, leading to reduction in the synthesis of proinflammatory cytokines by cells of the MMS [9,11,15].

Results
The use of β2ARs agonist hexaprenaline sulfate and α7nAChRs agonist (GTS-21), as well as their combination 2 hours before the sepsis modeling, caused a decrease (p<0.05) mortality after 4 h compared with control group 2 (sepsis), respectively, in 2. 13  A similar effect was caused by β2ARs agonist (hexaprenaline sulfate). There was no significant difference in mortality of mice between the parameters in these groups when using β2ARs and α7nAChRs agonists 4 and 24 h after the sepsis modeling (groups 3 and 4). It has been experimentally established that the adrenergic mechanism (action of β2ARs agonist) is an important component in the implementation of the cholinergic anti-inflammatory pathway.
The combined action (group 5) of β2ARs and α7nAChRs agonists caused a greater effect than the isolated effect of drugs.

Discussion
The data obtained suggest that the α7nAChRs agonist (GTS- 21) due to the implementation of the cholinergic anti-inflammatory pathway [6,22] leads to a decrease in mortality from sepsis [3,4,5] due to a decrease of MMS cell production of pro-inflammatory cytokines [23,24]. A similar effect was caused by β2ARs agonist (hexaprenaline sulfate). There was no significant difference in mortality of mice between the parameters in these groups (3 and 4) when using β2ARs and α7nAChRs agonists after the sepsis modeling. It has been experimentally established that the adrenergic mechanism (action of β2ARs agonist) is an important component in the implementation of the cholinergic anti-inflammatory pathway.
The literature data [6,10,25] suggest that the additive effect The described effects are enhanced by a decrease in the synthesis of proinflammatory cytokines by the α7nAChRs agonist (GTS-21), acting directly on α7nAChRs of MMS cells [6,23,25,26].
It is known that monocytes and macrophages have βARs, and their activation usually leads to anti-inflammatory effect [19] due to inhibition of the nuclear transcription factor NF-κB [27].
Mechanisms of the reduction of synthesis of proinflammatory cytokines by the action of an agonist β2ARs (action on MMS cells) currently not well understood, but research results are inconsistent [18,19].