The Mechanisms of the Cholinergic Anti-inflammatory Pathway after Acute Intoxication of Organophosphorus Compounds

Organophosphate compounds (OPC) are widely used in agriculture, various industries and households, can cause environmental pollution, as well as acute and chronic intoxications [1-3]. Anticholinesterase drugs used in medicine have almost the same toxicodynamics as OPC [2-5]. More than 200 thousand people per year die from organophosphate insecticide intoxications in the world, mainly as a result of poisoning when used with safety violations [6]. The possibility of using OPC. in local armed conflicts for terrorist and criminal purposes is not excluded [2,6-8], and the occurrence of emergency situations at facilities engaged in the destruction of chemical weapons, in particular OPC, in accordance with international agreements [2,3]. In this case, possible group and mass acute intoxications of OPC [2,3]. Acute and chronic OPC intoxications reduce the humoral and cellular immune response [2,3], however, the study of the mechanisms of realization established by the 1987 “paradoxical effect” of OPC deserves attention-cholinergic stimulation significantly reduced the mortality of mice from sepsis [9]. Thus, we discovered the cholinergic anti-inflammatory mechanism (effect).


Introduction
Organophosphate compounds (OPC) are widely used in agriculture, various industries and households, can cause environmental pollution, as well as acute and chronic intoxications [1][2][3]. Anticholinesterase drugs used in medicine have almost the same toxicodynamics as OPC [2][3][4][5]. More than 200 thousand people per year die from organophosphate insecticide intoxications in the world, mainly as a result of poisoning when used with safety violations [6]. The possibility of using OPC. in local armed conflicts for terrorist and criminal purposes is not excluded [2,[6][7][8], and the occurrence of emergency situations at facilities engaged in the destruction of chemical weapons, in particular OPC, in accordance with international agreements [2,3]. In this case, possible group and mass acute intoxications of OPC [2,3]. Acute and chronic OPC intoxications reduce the humoral and cellular immune response [2,3], however, the study of the mechanisms of realization established by the 1987 "paradoxical effect" of OPC deserves attention-cholinergic stimulation significantly reduced the mortality of mice from sepsis [9]. Thus, we discovered the cholinergic anti-inflammatory mechanism (effect).

Aim of the study
The aim of the study was to determine the implementation mechanisms of the cholinergic anti-inflammatory pathway after acute intoxication with organophosphorus compounds by comparative assessment influences OPC and m1AChRs agonist, α7nAChRs agonist, epinephrine, norepinephrine, β2ARs agonist on mortality of mice after sepsis and concentration of proinflammatory cytokines in the blood.

Series of Experiments
The parameters of TNF-α, IL-1β and IL-6 after administration of β2ARs agonist (hexoprenaline sulfate) 4 h after sepsis modeling (group 8) decreased compared with the parameters of the control group 2, respectively, in 3.7; 2.8 and 7.1 times (p<0.05). A decrease in blood levels of proinflammatory cytokines was detected 24 h after sepsis modeling compared with the corresponding values after 4 h, while the concentrations of TNF-α, IL-1β and IL-6 remained below the values of group 2, respectively, in 1.5 (p>0, 05); 2.1 and 3.2 times (p <0.05). The IL-1β and IL-6 blood concentrations in groups 3, 4, 5, 6, 7 and 8 were significantly higher (p <0.05) than the corresponding values of the control group 1. The TNF-α, IL-1β and IL-6 blood concentrations after acute intoxication of OPC, the effects of the agonist m1AChRs (TBPB), α7nAChR agonist (GTS-21), epinephrine, NE and β2ARs agonist (hexoprenaline sulfate) after modeling sepsis 2 h after administration of OPC (DDVP) and these drugs (groups 3, 4, 5, 6, 7, 8) decreased approximately equally compared with the reduction after the modeling sepsis (group 2; without the use of drugs).
There is reason to conclude that the mechanism for reducing mortality in mice with acute intoxication of OPC from sepsis is due to activation in the brain m1AChRs (the first link of the cholinergic anti-inflammatory pathway) [2,16,17], α7nAChR MMS cells [12,17,19], as well as β2ARs macrophages and monocytes (due to the excitation of the sympathetic nervous system) and the action of norepinephrine on T lymphocytes of the spleen, [2,12,13,18]. The implementation of the reduction of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and others (the occurrence of anti-inflammatory effect) is provided by JAK2 kinase, STAT3 transcription factor, transcription factor NF-κB) [2,12,[17][18][19][20][21]22]. In addition, the decrease in mortality from sepsis after acute intoxication of OPC due to the suppression of the synthesis of proinflammatory cytokines is also associated with the effect of corticosteroids (activation of the hypothalamic-pituitary-adrenal system) [2,3,19,18].

Conclusion
Reduced mortality of mice from sepsis and the blood concentration of proinflammatory cytokines TNF-α, IL-1β, IL-6 after acute intoxication of organophosphorus compounds is due to the implementation of the cholinergic anti-inflammatory pathway: activation of m-acetylcholinergic receptors type 1 (m1AChRs) of the brain and α7n-acetylcholine receptors (α7nAChRs) of the monocyte-macrophage system, as well as stimulation of the sympathetic nervous system, β2-adrenoreceptors (β2ARs) T lymphocytes, macrophages and monocytes.