Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2

Abstract

BackgroundCerebral hypoperfusion is a pivotal risk factor for vascular dementia (VD), for which effective therapy remains inadequate. Persistent inflammatory responses and excessive chemotaxis of microglia/macrophages in the brain may accelerate the progression of VD. Endocannabinoids are involved in neuronal protection against inflammation-induced neuronal injury. Cannabinoids acting at cannabinoid receptor 2 (CB2R) can decrease inflammation. Based on the identification of paeoniflorin (PF) as a CB2R agonist, we investigated the neuroprotective and microglia/macrophages M1 to M2 polarization promoting effects of PF in a permanent four-vessel occlusion rat model.MethodsOne week after surgery, PF was intraperitoneally administered at a dose of 40 mg/kg once a day for 28 successive days. The effects of PF on memory deficit were investigated by a Morris water maze test, and the effects of PF on hippocampal neuronal damage were evaluated by light microscope and electron microscope. The mRNA and protein expression levels of key molecules related to the M1/M2 polarization of microglia/macrophages were assessed by RT-qPCR and Western blotting, respectively.ResultsAdministration of PF could significantly attenuate cerebral hypoperfusion-induced impairment of learning and memory and reduce the morphological and ultrastructural changes in the hippocampal CA1 region of rats. Moreover, PF promoted an M1 to M2 phenotype transition in microglia/macrophages in the hippocampus of rats. In addition to its inhibitory property against proinflammatory M1 mediator expression, such as IL-1β, IL-6, TNF-α and NO, PF dramatically up-regulated expression of anti-inflammatory cytokines IL-10 and TGF-β1. Importantly, CB2R antagonist AM630 abolished these beneficial effects produced by PF on learning, memory and hippocampus structure in rats, as well as the polarization of microglia/macrophages to the M2 phenotype. Additionally, PF treatment significantly inhibited cerebral hypoperfusion-induced mTOR/NF-κB proinflammatory pathway and enhanced PI3K/Akt anti-inflammatory pathway. Effects of PF on these signaling pathways were effectively attenuated when rats were co-treated with PF and AM630, indicating that the mTOR/NF-κB and PI3K/Akt signaling pathways were involved in the PF effects through CB2R activation.ConclusionThese findings demonstrated PF exerts its neuroprotective effect and shifts the inflammatory milieu toward resolution by modulation of microglia/macrophage polarization via CB2R activation.Electronic supplementary materialThe online version of this article (10.1186/s13020-018-0173-1) contains supplementary material, which is available to authorized users.

Cannabinoid 2 receptor attenuates inflammation during skin wound healing by inhibiting M1 macrophages rather than activating M2 macrophages

“…However, persistent and excessive inflammatory responses can aggravate tissue injury, lead to chronic inflammation, and thereby prevent the routine process of tissue repair. To reduce inflammation and promote wound healing in the later stage of inflammation, macrophages are transformed into an M2 phenotype by an alternative activation pathway and secrete anti-inflammatory cytokines, such as Arg-1, IL-4, IL-10, transforming growth factor-β1, and Ym1 [ 17 , 19 , 26 , 27 ]. Therefore, the dynamic equilibrium between M1 and M2 macrophages is vital for wound healing and tissue homeostasis.…”

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

“…Paeoniflorin, an active ingredient in a traditional Chinese medicine, was reported to be a CB2R agonist that modulates the M2 phenotype evidenced by an increase in M2 markers, including Arg1, Ym1, IL-10, and TGF-β1, and a decrease in M1 markers, including IL-1β, IL-6, and TNFα, in a middle cerebral artery occlusion (MCAO) model. These modulatory effects were reversed by co-treatment with AM630 (109). However, it is unknown whether this compound is a CB2R agonist, despite its ability to increase CB2R expression.…”

Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists

“…Actually, from a therapeutic point of view, targeting CB 1 has poor prospects due to the widespread distribution in brain and in both neurons and glia, to the psychotropic properties of agonists (phytocannabinoids or synthetic CB 1 R agonists) and also due to the side effects occurring after administration to humans of rimonabant, a selective CB 1 R ligand (Sam, Salem, & Ghatei, ). Recently it has been demonstrated that activation of CB 2 R by paeoniflorin, one of the major constituents of Paeonia lactiflora , regulates the polarization of microglia/macrophages in hippocampus (CA1 region) in vascular dementia models, (Luo et al, )). In conclusion, our data support the view that, via microglia, A 2A R antagonists may enhance the action of cannabinoids in CB 2 R and the final output is neuroprotective.…”

“…Recently it has been demonstrated that activation of CB 2 R by paeoniflorin, one of the major constituents of Paeonia lactiflora, regulates the polarization of microglia/macrophages in hippocampus (CA1 region) in vascular dementia models, (Luo et al, 2018)). In conclusion, our data support the view that, via microglia, A…”