Region-Specific Impact of Repeated Synthetic Cannabinoid Exposure and Withdrawal on Endocannabinoid Signaling, Gliosis, and Inflammatory Markers in the Prefrontal Cortex and HippocampusVadas, López-Gambero, Vargas
et alBiomolecules (2025) 15 (3)
Abstract: Synthetic cannabinoid use raises concerns about its neuroinflammatory effects, including molecular adaptations of the endocannabinoid system (ECS) in the brain. This study investigates the pharmacological effects of 14-day repeated intraperitoneal administration, as well as 14-day administration followed by a 7-day withdrawal period of two synthetic cannabinoids: WIN55,212-2 and HU-210. The study assessed gene expression and protein markers related to the ECS, gliosis, and inflammation in two brain regions critical for cognitive processes and memory-key components of addiction pathways-the prefrontal cortex (PFC) and the hippocampus of rats. Our findings showed that repeated WIN55,212-2 administration induced adaptations in the ECS and reduced IBA1, a glial protein marker, along with inflammatory responses likely mediated through CB2 activity. Notably, regional differences emerged in the hippocampus, where repeated administration of WIN55,212-2 and HU-210 increased IBA1 and inflammatory markers, effects unrelated to CB2 activity. Withdrawal from WIN55,212-2 in the PFC, as well as from both compounds in the hippocampus, decreased IBA1 levels. This was associated with altered protein expression of cannabinoid-synthesizing and degrading enzymes, favoring acylethanolamide synthesis. These findings highlight region-specific effects of synthetic cannabinoids on cannabinoid signaling, gliosis, and inflammation. Further research is needed to elucidate the long-term neurobiological consequences of synthetic cannabinoid use and withdrawal.
Resident Macrophages in the Cervical Sympathetic Ganglia Participate in P2Y12 Receptor Mediated Diabetic Cardiac Autonomic NeuropathyDu, Yang, Rao
et alMol Neurobiol (2025)
Abstract: Diabetic cardiac autonomic neuropathy (DCAN) represents a significant and prevalent complication of diabetes. Further research is required to ascertain the role of the P2Y12 receptor, which is expressed on macrophages and satellite glial cells (SGCs), in the pathophysiology of DCAN. The objective of this study was to ascertain whether resident macrophages in the superior cervical ganglion (SCG) are involved in the pathological changes associated with DCAN, which are mediated by the P2Y12 receptor in satellite glial cells (SGCs). The findings showed that DCAN rats had higher sympathetic nerve discharge activity than the control group. Furthermore, the expression of P2Y12 receptor, glial fibrillary acidic protein (GFAP), macrophage-like targets (colony-stimulating factor 1 receptor (CSF1R), colony-stimulating factor 1 (CSF1)), and interleukin-34 (IL-34) in SCG among DCAN rats was clearly elevated. Moreover, co-expression levels of NeuN and CSF1 in neurons, P2Y12 and GFAP as well as P2Y12 and IBA-1 in SCGs were increased. However, treatment with P2Y12 shRNA led to significant reductions in all above parameters. The action mechanism may involve reducing the expression of P2Y12 receptors in macrophages and SGCs, decreasing the expression of CSF1 in SCG neurons to weaken the CSF1-CSF1R signal, inhibiting the activation of macrophages and SGCs, and reducing the release of inflammatory factors. This ultimately alleviated abnormal neuronal excitation in SCG and maintaining balance in cardiac autonomic nervous activity. Therefore, targeting the P2Y12 receptor to disrupt the resident macrophages participate in pathological changes, may be an effective approach for improving DCAN.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Electroacupuncture mitigates cognitive impairments in chronic hypoxia-induced mice by modulating neuroinflammationWan, Zhuang, Li
et alIBRO Neurosci Rep (2025) 18, 432-442
Abstract: This study investigates the therapeutic effects and mechanisms of electroacupuncture (EA) on cognitive impairment induced by chronic hypoxia (CH) in mice. Chronic hypoxia was simulated by exposing mice to a 10 % oxygen environment for 8 hours daily over 3 months. The cognitive functions of the mice were assessed through behavioral tests, including the open field test (OFT), Y-maze, and Morris water maze (MWM). Results showed that CH induced significant anxiety-like behaviors and memory impairments in mice. EA treatment, targeting the Baihui (GV20), Shenting (GV24), and Zusanli (ST36) acupoints, significantly ameliorated these behavioral deficits. Histological analyses using HE staining, Nissl staining, and TUNEL assays demonstrated that EA reduced neuronal damage, apoptosis, and myelin loss in the cerebral cortex and hippocampus. Additionally, EA treatment significantly lowered the expression of the pro-inflammatory cytokine TNF-α in brain tissues, suggesting its anti-inflammatory effects. Immunofluorescence and Western blot analyses revealed that EA inhibited the overactivation of microglia and astrocytes in the CH model. Specifically, EA suppressed the expression of Iba1 and GFAP, markers of microglial and astrocytic activation, respectively. Furthermore, EA promoted the polarization of microglia towards the M2 anti-inflammatory phenotype by downregulating iNOS and upregulating Arg1. Similarly, EA reduced the expression of C3, a marker of A1 astrocytes, thereby preventing astrocytic polarization towards the pro-inflammatory state. Organotypic brain slice cultures subjected to oxygen-glucose deprivation (OGD) confirmed that electrical stimulation, akin to EA, inhibited the activation of microglia and astrocytes under hypoxic conditions. In conclusion, EA improves cognitive function in CH-induced mice by reducing neuroinflammation, inhibiting glial cell overactivation, and promoting anti-inflammatory phenotypes. These findings highlight EA's potential as a therapeutic intervention for cognitive impairments related to chronic hypoxia.© 2025 The Authors.
The liver-brain axis under the influence of chronic Opisthorchis felineus infection combined with prolonged alcoholization in miceAvgustinovich, Chadaeva, Kizimenko
et alVavilovskii Zhurnal Genet Selektsii (2025) 29 (1), 92-107
Abstract: Our purpose was to model a combination of a prolonged consumption of ethanol with Opisthorchis felineus infection in mice. Four groups of C57BL/6 mice were compiled: OF, mice infected with O. felineus for 6 months; Eth, mice consuming 20 % ethanol; Eth+OF, mice subjected to both adverse factors; and CON, control mice not exposed to these factors. In the experimental mice, especially in Eth+OF, each treatment caused well-pronounced periductal and cholangiofibrosis, proliferation of bile ducts, and enlargement of areas of inflammatory infiltration in the liver parenchyma. Simultaneously with liver disintegration, the infectious factor caused - in the frontal cerebral cortex - the growth of pericellular edema (OF mice), which was attenuated by the administration of ethanol (Eth+OF mice). Changes in the levels of some proteins (Iba1, IL-1β, IL-6, and TNF) and in mRNA expression of genes Aif1, Il1b, Il6, and Tnf were found in the hippocampus and especially in the frontal cortex, implying region-specific neuroinflammation. Behavioral testing of mice showed that ethanol consumption influenced the behavior of Eth and Eth+OF mice in the forced swimming test and their startle reflex. In the open field test, more pronounced changes were observed in OF mice. In mice of all three experimental groups, especially in OF mice, a disturbance in the sense of smell was detected (fresh peppermint leaves). The results may reflect an abnormality of regulatory mechanisms of the central nervous system as a consequence of systemic inflammation under the combined action of prolonged alcohol consumption and helminth infection.Copyright © AUTHORS.
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