Abstract
BackgroundChronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders. For example, overexpression of pro-inflammatory cytokines has been associated with impairments in hippocampal-dependent memory. Lipopolysaccharide (LPS) injection is a widely used model to explore the pathobiology of inflammation. LPS injection into mice causes systemic inflammation, neuronal damage, and poor memory outcomes if the inflammation is not controlled. Activation of the alpha-7 nicotinic receptor (α7) plays an anti-inflammatory role in the brain through vagal efferent nerve signaling. 4R-cembranoid (4R) is a natural compound that crosses the blood-brain barrier, induces neuronal survival, and has been shown to modulate the activity of nicotinic receptors. The purpose of this study is to determine whether 4R reduces the deleterious effects of LPS-induced neuroinflammation and whether the α7 receptor plays a role in mediating these beneficial effects.MethodsEx vivo population spike recordings were performed in C57BL/6J wild-type (WT) and alpha-7-knockout (α7KO) mouse hippocampal slices in the presence of 4R and nicotinic receptor inhibitors. For in vivo studies, WT and α7KO mice were injected with LPS for 2 h, followed by 4R or vehicle for 22 h. Analyses of IL-1β, TNF-α, STAT3, CREB, Akt1, and the long-term novel object recognition test (NORT) were performed for both genotypes. In addition, RNA sequencing and RT-qPCR analyses were carried out for 12 mRNAs related to neuroinflammation and their modification by 4R.Results4R confers neuroprotection after NMDA-induced neurotoxicity in both WT and α7KO mice. Moreover, hippocampal TNF-α and IL-1β levels were decreased with 4R treatment following LPS exposure in both strains of mice. 4R restored LPS-induced cognitive decline in NORT. There was a significant increase in the phosphorylation of STAT3, CREB, and Akt1 with 4R treatment in the WT mouse hippocampus following LPS exposure. In α7KO mice, only pAkt levels were significantly elevated in the cortex. 4R significantly upregulated mRNA levels of ORM2, GDNF, and C3 following LPS exposure. These proteins are known to play a role in modulating microglial activation, neuronal survival, and memory.ConclusionOur results indicate that 4R decreases the levels of pro-inflammatory cytokines; improves memory function; activates STAT3, Akt1, and CREB phosphorylation; and upregulates the mRNA levels of ORM2, GDNF, and C3. These effects are independent of the α7 nicotinic receptor.
Highlights
Chronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders
Our results indicate that 4R decreases the levels of pro-inflammatory cytokines; improves memory function; activates Signal transducer and activator of transcription 3 (STAT3), Serine-threonine protein kinase 1 (Akt1), and cAMP response element–binding protein (CREB) phosphorylation; and upregulates the mRNA levels of orosomucoid 2 (ORM2), glial cell line–derived neurotrophic factor (GDNF), and component 3 (C3)
4R-cembranoid neuroprotection against N-Methyl-D-aspartic acid (NMDA) in mouse hippocampal slices Figure 1 shows the structure of 4R, which consists of a 14-carbon cembrane ring substituted with two hydroxy groups, attached to carbons 4 and 6, and three methyl groups
Summary
Chronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders. Lipopolysaccharide (LPS) injection is a widely used model to explore the pathobiology of inflammation. Activation of the alpha-7 nicotinic receptor (α7) plays an anti-inflammatory role in the brain through vagal efferent nerve signaling. 4R-cembranoid (4R) is a natural compound that crosses the blood-brain barrier, induces neuronal survival, and has been shown to modulate the activity of nicotinic receptors. Lipopolysaccharide (LPS), a bacterial endotoxin, has been widely used as an in vivo animal model for investigation into peripherally and centrally induced inflammation. Transfer of peripheral inflammation to the brain by intraperitoneal injection of LPS occurs through activation of vagal afferent nerves [8]. Peripheral pro-inflammatory cytokines can bind to their respective receptors in the brain endothelium and induce NF-κβ activation or can enter the brain through the blood-brain barrier-free circumventricular organs [9]
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