Available evidence suggests that adjunctive treatment with immunomodulatory medications may be effective in the treatment of major depressive disorder (MDD). A pilot trial of the tetracycline minocycline as adjunctive treatment in treatment-resistant depression (TRD), produced promising results, however, a larger scale trial is needed to confirm the antidepressant actions of this drug.

Accumulating evidences have suggested that anxiety-like behavior and impairment of learning and memory are key symptoms of post-traumatic stress disorder (PTSD), and pharmacological treatment can ameliorate anxiety and cognitive impairments. Recent studies have shown that minocycline exhibits anxiolytic effects. The aims of the present study were to determine whether minocycline administration would alter anxiety-like behavior and cognitive deficits induced by inescapable foot shock (IFS) and to explore the underlying mechanisms. Male Wistar rats were exposed to the IFS protocol for a period of 6 days to induce PTSD. The PTSD-like behavior was tested using the open field test, elevated plus maze test, and Morris water maze test. The effects of minocycline on pro-inflammatory cytokines, activation of microglia, and NF-κB in the PFC and hippocampus were also examined. Treatment with minocycline significantly reversed the IFS induced behavioral and cognitive parameters (impaired learning and memory function) in stressed rats. Additionally, IFS was able to increase pro-inflammatory cytokines, activate microglia, and enhance NF-κB levels, while minocycline significantly reversed these alterations. Taken together, our results suggest that the anxiolytic effect of minocycline is related to its ability to decrease the levels of pro-inflammatory cytokines and inhibit activation of microglia and NF-κB in the PFC and hippocampus.

Aims: Expression of inflammatory cytokines in the brain has been reported to be involved in the pathogenesis of and susceptibility to depression. Jumonji domain-containing 3 (Jmjd3), which is a histone H3 lysine 27 (H3K27) demethylase and can regulate microglial activation, has been regarded as a crucial element in the expression of inflammatory cytokines. Furthermore, recent studies highlighted the fact that lipopolysaccharides induce depressive-like behaviors and higher Jmjd3 expression and lower H3K27me3 expression in the brain. However, whether the process of Jmjd3 mediating inflammatory cytokines was involved in the susceptibility to depression due to early-life stress remained elusive. Methods: Rats exposed to chronic unpredictable mild stress (CUMS) in adolescence were used in order to detect dynamic alterations in depressive-like behaviors and expression of cytokines, Jmjd3, and H3K27me3 in the prefrontal cortex and hippocampus. Moreover, minocycline, an inhibitor of microglial activation, was employed to observe the protective effects. Results: Our results showed that CUMS during the adolescent period induced depressive-like behaviors, over-expression of cytokines, and increased Jmjd3 and decreased H3K27me3 expression in the prefrontal cortex and hippocampus of both adolescent and adult rats. However, minocycline relieved all the alterations. Conclusion: The study revealed that Jmjd3 might be involved in the susceptibility to depressive-like behaviors by modulating H3K27me3 and pro-inflammatory cytokine expression in the prefrontal cortex and hippocampus of rats that had been stressed during early adolescence.

Brain ischemia causes irreversible damage to functional neurons in cases of infarct. Promoting endogenous neurogenesis to replace necrotic neurons is a promising therapeutic strategy for ischemia patients. The neuroprotective role of sevoflurane preconditioning implies that it might also enhance endogenous neurogenesis and functional restoration in the infarct region. By using a transient middle cerebral artery occlusion (tMCAO) model, we discovered that endogenous neurogenesis was enhanced by sevoflurane preconditioning. This enhancement process is characterized by the promotion of neuroblast proliferation within the subventricular zone (SVZ), migration and differentiation into neurons, and the presence of astrocytes and oligodendrocytes at the site of infarct. The newborn neurons in the sevoflurane preconditioning group showed miniature excitatory postsynaptic currents (mEPSCs), increased synaptophysin and PSD95 staining density, indicating normal neuronal function. Furthermore, long-term behavioral improvement was observed in the sevoflurane preconditioning group consistent with endogenous neurogenesis. Further histological analyses showed that sevoflurane preconditioning accelerated microglial activation, including migration, phagocytosis and secretion of brain-derived neurotrophic factor (BDNF). Intraperitoneal injection of minocycline, a microglial inhibitor, suppressed microglial activation and reversed neurogenesis. Our data showed that sevoflurane preconditioning promoted microglial activities, created a favorable microenvironment for endogenous neurogenesis and accelerated functional reconstruction in the infarct region.

Bone cancer pain (BCP) is one of the most common types of pain in cancer patients which compromises the patient's functional status, quality of life, and survival. Central hyperalgesia has increasingly been identified as a crucial factor of BCP, especially in the medial prefrontal cortex (mPFC) which is the main cortical area involved in the process of pain and consequent negative emotion. To explore the genetic changes in the mPFC during BCP occurrence and find possible targets for prediction, we performed transcriptome sequencing of mPFC in the BCP rat model and found a total of 147 differentially expressed mRNAs (DEmRNAs). A protein-protein interaction (PPI) network revealed that the DEmRNAs mainly participate in the inflammatory response. Meanwhile, microglia and astrocytes were activated in the mPFC of BCP rats, further confirming the presence of neuroinflammation. In addition, Gene Ontology (GO) analysis showed that DEmRNAs in the mPFC are mainly involved in antigen processing, presentation of peptide antigen, and immune response, occurring in the MHC protein complex. Besides, the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that DEmRNAs are mainly enriched in the pathways of phagosome, staphylococcus aureus infection, and antigen processing, in which MHCII participate. Furthermore, immunostaining showed that MHCII is mainly located in the microglia. Microglia are believed to be involved in antigen processing, a key cause of BCP. In vivo, minocycline (MC) treatment inhibits the activation of microglia and reduces the expression of MHCII and proinflammatory cytokines, thereby alleviating BCP and pain-related anxiety. Taken together, our study identified differentially expressed genes in the BCP process and demonstrated that the activation of microglia participates in the inflammatory response and antigen process, which may contribute to BCP.