Cannabinoid receptor 2 deficiency enhances isoflurane-induced spatial cognitive impairment in adult mice by affecting neuroinflammation, neurogenesis and neuroplasticity

Abstract

Isoflurane (Iso) is a commonly used inhalational anesthetic and is associated with the incidence of postoperative cognitive dysfunction (POCD). Cannabinoid receptor 2 (CB2R) was previously reported to have a promising neuroprotective function in cases of POCD, but the specific mechanisms have remained to be fully explored. The aim of the present study was to investigate the effect of CB2R deficiency on spatial cognitive performance in adult mice exposed to Iso. A total of 20 adult CB2R knockout (KO) and 20 wildtype (WT) mice were exposed to Iso (1.4% in oxygen for 4 h) or 100% oxygen. The Morris water maze (MWZ) test was performed 10 days after Iso exposure. Immunofluorescence staining and reverse transcription-quantitative PCR were performed to assess the expression of microglial marker ionized calcium-binding adaptor molecule-1 (Iba1) and the mRNA expression levels of microglial phenotype markers (M1: Interleukin-6, tumor necrosis factor-α, inducible nitric oxide synthase; M2: Chitinase-3 like protein) in the hippocampus. Changes in hippocampal neurogenesis and neuroplasticity were assessed by 5-bromodeoxyuridine (BrdU) immunostaining and Golgi staining. Compared with control mice, WT Iso-exposed mice had impaired spatial performance in the MWZ test. Furthermore, hippocampal Iba1 immunoreactivity and the number of microglial branches were notably increased in Iso-exposed WT mice. This was paralleled by significant upregulation of M1-associated markers and downregulation of M2-associated markers in the hippocampus. An obviously reduced number of BrdU + neurons and decreased spine density were observed in WT Iso-exposed mice compared with control mice. Of note, CB2R deficiency exacerbated the spatial cognition impairment induced by Iso in the MWZ test. The alterations in the activation, morphology and M1 polarization of microglia, the number of BrdU + neurons and spine density were more pronounced in CB2R-deficient Iso-exposed KO mice than in WT Iso-exposed mice. These results suggested that CB2R has a crucial role in Iso-induced cognitive impairment, which may be related to changes in hippocampal neuroinflammation, neurogenesis and neuroplasticity.

Isoflurane and Sevoflurane Induce Cognitive Impairment in Neonatal Rats by Inhibiting Neural Stem Cell Development Through Microglial Activation, Neuroinflammation, and Suppression of VEGFR2 Signaling Pathway

“…In the granule cells, expression of the calcium-binding protein, calretinin, is observed between the 2nd and 4th weeks of neurogenesis (Zhao et al 2008). It has been shown that isoflurane or sevoflurane can induce inhibition of neurogenesis in the hippocampus of rodent animals (Jia et al 2020;Li et al 2021a).…”

Interaction between Prenatal and Postnatal Exposure to High-Fructose Corn Syrup Increases Gene Expression of <i>Tnfa</i> in Hippocampus of Offspring

“…16 HFCS consumption induces neuroinflammation in the hippocampus (3). This is characterized by the expression of pro-inflammatory cytokines and subsequent hippocampal dysfunction including cognitive decline and reduction of neurogenesis (19,20). To investigate the synergistic effect of prenatal and postnatal HFCS intake on the hippocampus, we analyzed the mRNA expression levels of Tnfa, Il1b, and Il6 in the hippocampus of offspring.…”

Cannabinoid type-2 receptors: An emerging target for regulating schizophrenia-relevant brain circuits

“…Both male and female CB2 –/– mice also show impairments in social memory, however, female CB2 –/– mice have significantly higher levels of synapsin-I immunoreactivity in the hippocampus ( Komorowska-Müller et al, 2021b ), highlighting a need to understand sex-specific differences in CB2 receptor function, an area that is currently under-studied. Additionally, in a model of postoperative cognitive dysfunction (POCD), CB2 –/– mice are more vulnerable to isoflurane (Iso)-induced spatial learning and memory impairments compared to WT mice ( Li et al, 2021 ), again suggesting a key role for CB2 receptors in regulating hippocampal-dependent behaviors. While more studies are needed to elucidate the utility of targeting CB2 receptors in treating schizophrenia, these studies collectively indicate that targeting CB2 receptors may represent a novel mechanism to achieve both antipsychotic and pro-cognitive efficacy.…”

“…In addition, CB2 appears to play important roles in microglial activation, inflammation, and cognitive disruptions observed following post-operative stress. The expression of CB2 receptors in the hippocampus is upregulated in mice following surgery, and post-operative administration of the CB2 agonist JWH133 can both decrease the expression of pro-inflammatory cytokines and alleviate surgery-induced hippocampal-dependent memory loss ( Sun et al, 2017 ; Li et al, 2021 ). The ability of CB2 receptors to regulate inflammatory processes could have utility in treating numerous diseases including Alzheimer’s disease ( Wu et al, 2013 ), postoperative recovery ( Sun et al, 2017 ), and neuropathic pain ( Cabanero et al, 2020 ).…”