Neostigmine Attenuates Proinflammatory Cytokine Expression in Preoptic Area but Not Choroid Plexus during Lipopolysaccharide-Induced Systemic Inflammation

Abstract

The study was designed to examine whether the administration of neostigmine (0.5 mg/animal), a peripheral inhibitor of acetylcholinesterase (AChE), during an immune/inflammatory challenge provoked by intravenous injection of bacterial endotoxin—lipopolysaccharide (LPS; 400 ng/kg)—attenuates the synthesis of proinflammatory cytokines in the ovine preoptic area (POA), the hypothalamic structure playing an essential role in the control of the reproduction process, and in the choroid plexus (CP), a multifunctional organ sited at the interface between the blood and cerebrospinal fluid in the ewe. Neostigmine suppressed (p < 0.05) LPS-stimulated synthesis of cytokines such as interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF) α in the POA, and this effect was similar to that induced by the treatment with systemic AChE inhibitor—donepezil (2.5 mg/animal). On the other hand, both AChE inhibitors did not influence the gene expression of these cytokines and their corresponding receptors in the CP. It was found that this structure seems to not express the neuronal acetylcholine (ACh) receptor subunit alpha-7, required for anti-inflammatory action of ACh. The mechanism of action involves inhibition of the proinflammatory cytokine synthesis on the periphery as well as inhibition of their de novo synthesis rather in brain microvessels and not in the CP. In conclusion, it is suggested that the AChE inhibitors incapable of reaching brain parenchyma might be used in the treatment of neuroinflammatory processes induced by peripheral inflammation.

Photoperiod alters the choroid plexus response to LPS-induced acute inflammation in EWES

“…The activation of the TLR signaling pathway leads to the synthesis of pro-inflammatory cytokines, type I interferon and other mediators that induce innate immune responses (Takeda et al, 2003). Indeed, the upregulation of the expression of pro-inflammatory cytokine and corresponding receptor genes was observed in the ovine ChP under LPS-challenged conditions (Kowalewska et al, 2017a;Herman et al, 2018). In ewes, the local synthesis of interleukin (IL)-1β in the ChP is an important source of IL-1β in the CSF at the onset of inflammation (Skipor et al, 2017).…”

Effect of Central Injection of Neostigmine on the Bacterial Endotoxin Induced Suppression of GnRH/LH Secretion in Ewes during the Follicular Phase of the Estrous Cycle

“…injection of LPS from Escherichia coli 055:B5 (Sigma-Aldrich, St Louis, Missouri, USA) in a dose of 400 ng/kg, dissolved in saline (0.9% w / v NaCl) (Baxter, Deerfield, Illinois, USA) at a concentration of 10 mg/L. The dose of LPS was established and used in our previous studies [10,23,24,25,29,65]. Control animals received iv.…”

“…Although some amount of pro-inflammatory cytokines occurring in the central nervous system (CNS) during an inflammatory challenge could have peripheral origin or could be secreted by the CP cells, it is believed that centrally acting inflammatory cytokines are primarily locally synthesized in CNS cells. The local synthesis of pro-inflammatory cytokines in the hypothalamus of many species, including sheep was also reported [23,24,25,26,27,28]. These central pro-inflammatory cytokines of different origins may influence the neuroendocrine system functioning because their corresponding receptors are expressed not only in the region of hypothalamus but also in the structures involved in GnRH-ergic activity [24,29,30,31].…”

“…The reduction of the pro-inflammatory cytokines synthesis is often considered by researchers as an effective strategy in the treatment of inflammatory induced neuroendocrine disorders. In our previous studies on sheep, we demonstrated that the peripheral administration of systemic acetylcholinesterase (AChE) inhibitor reduced inflammatory-induced synthesis of pro-inflammatory cytokines in the hypothalamus [23,25]. It was also found that the inhibitory effect of LPS administration on the GnRH/luteinizing hormone (LH) secretion could be terminated by peripheral treatment with AChE inhibitors [29,32].…”

“…It was also found that the inhibitory effect of LPS administration on the GnRH/luteinizing hormone (LH) secretion could be terminated by peripheral treatment with AChE inhibitors [29,32]. We also found that the reduction of pro-inflammatory cytokines concentration in the peripheral blood by neostigmine—an AChE inhibitor not able to cross the brain barriers—blocked the transition of the inflammatory signal into the brain parenchyma and was sufficient to reduce the synthesis of these mediators in the hypothalamus during acute immune stress [23]. Moreover, neostigmine treatment prevented inflammatory-dependent changes in GnRH/LH secretion [29].…”