Resident microglia are the major immune cells in the brain, acting as the first defense of the central nervous system. Following cerebral ischemia, microglia respond to this injury at first and ...transform from surveying microglia to active state. The activated microglia play a dual role in the ischemic injury, due to distinct microglia phenotypes, including deleterious M1 and neuroprotective M2. However, microglia show transient M2 phenotype followed by a shift to M1. The high ratio of M1 to M2 is significantly related to ischemic injury. Many signal pathways participate in the alternation of microglial phenotype, presenting potential therapeutic targets for selectively modulating M2 polarization of microglia. In this review, we discuss how the M2 phenotype mediates neuroprotective effects and summarize the alternation of signaling cascades that control microglial phenotype after ischemic stroke.
•Microglia play a dual role in ischemic stroke.•In ischemic stroke, microglia show transient neuroprotective M2 phenotype followed by a shift to destructive M1 phenotype.•Multi-signal pathways regulating the alternation of microglial phenotype are reviewed.•Selective modulation of microglia polarization to M2 phenotype may be a possible therapeutic target for ischemic stroke.
Studies have shown that the ginsenoside Rg1 can improve depressive symptoms in vitro and in vivo. However, the efficacy of Rg1on the hippocampal astrocyte gap junctions in depression are unclear. We ...mainly aimed to explore the relationship between Rg1, hippocampal astrocyte gap junctions and depression. Using primary cultured astrocytes, corticosterone (CORT) was used to induce stress. CORT (100 μM) significantly reduced the survival rate in astrocytes, and this effect was prevented by additional Rg1 administration. Interestingly, the gap junction blocker carbenoxolone (CBX) was able to revert this Rg1 effect. In in vivo models, one group was exposed to chronic unpredictable stress (CUS) for 47 days, while another group was bilaterally injected with CBX (100 μM) into the hippocampal CA1 region. Rats treated with Rg1 (20 mg/kg) showed an improvement in the sucrose preference and the forced swimming test in both models, indicating an antidepressive activity of Rg1. The levels of astrocyte gap junction connexin 43 (Cx43) were detected by immunofluorescence (IF) and western blotting. The levels of glial fibrillary acidic protein (GFAP) were detected by IF. The gap junctions in the hippocampal CA1 area were evaluated using dye transfer and electron microscopy. The reduction in Cx43 expression, the decrease in the Cx43 to GFAP ratio, the shorter dye diffusion distance, and the abnormal ultrastructure of gap junctions in rats exposed to CUS were markedly alleviated by concomitant Rg1 treatment. Taken together, the ginsenoside Rg1 could improve depression-like behavior in rats induced by astrocyte gap junction dysfunction in the hippocampus.
Mitochondria dysfunction is implicated in diverse conditions, including metabolic and neurodegenerative disorders. Mitochondrial dynamics has attracted increasing attention as to its relationship ...with mitochondria autophagy, also known as mitophagy, which is critical for degradation of dysfunctional mitochondria maintaining mitochondrial homeostasis. Mitochondrial fission and its role in clearance of injured mitochondria in acute ischemic injury, however, have not been elucidated yet. Here we showed that hypoxic/ischemic conditions led to fragmentation of mitochondria and induction of mitophagy in permanent middle cerebral artery occlusion (pMCAO) rats and oxygen–glucose deprivation (OGD) PC12 cells. Inhibition of Drp1 by pharmacologic inhibitor or siRNA resulted in accumulation of damaged mitochondria mainly through selectively blocking mitophagy without affecting mitochondrial biogenesis and non-selective autophagy. Drp1 inhibitors increased the infarct volume and aggravated the neurological deficits in a rat model of pMCAO. We demonstrated that the devastating role of disturbed mitochondrial fission by inhibiting Drp1 contributed to the damaged mitochondria-mediated injury such as ROS generation, cyt-c release and activation of caspase-3. Taken together, we proved that under hypoxic/ischemic stress a Drp1-dependent mitophagy was triggered which was involved in the removal of damaged mitochondria and cellular survival at the early stage of hypoxic/ischemic injury. Thus, Drp1 related pathway involved in selective removal of dysfunctional mitochondria is proposed as an efficient target for treatment of cerebral ischemia.
Ischemia injury induced bulk autophagy as well as selective mitophagy. Drp-1 mediated mitochondrial fission is the premise of ischemia induced mitophagy that could timely remove of the injured mitochondria and decrease the mitochondria-mediated apoptosis. Mdivi-1 selectively inhibited the translocation of Drp-1 to mitochondria and thus blocked the process of mitophagy. The accumulation of mitochondria exaggerated the ischemia injury by increasing the release of cyt-c, AIF, ROS and so on. Display omitted
•H/I lead to mitochondria fission in pMCAO rats and OGD PC12 cells.•H/I lead to mitochondria fission and mitophagy at the early stage of injury.•Inhibition of Drp1 selectively blocks mitophagy induced by H/I.•Drp1-mediated mitophagy after H/I stress is induced independent of bulk autophagy.•Inhibition of Drp1 aggravates the ischemic brain damage.
Rationale
The decrease of astrocyte number and hypothalamic-pituitary-adrenal (HPA) axis overactivity are observed in individuals with major depressive disorder. Elevated levels of glucocorticoids ...induced by hyperactivation of the HPA axis may result in glucocorticoid receptor (GR) activation. However, it is unclear whether there is a direct link between GR activation and the decrease of astrocyte number.
Methods
Animals were exposed to chronic unpredictable stress (CUS) for 28 days and treated with continuous subcutaneous injections of vehicle or corticosterone (CORT; 40 mg/kg/day) for 21 days. We then administered mifepristone on day 21 after CUS and on day 18 after the CORT treatment. We observed behavioral deficits in the sucrose preference test, open field test, and forced swim test. Protein expression was analyzed using immunofluorescence (IF) and western blot (WB).
Results
Animals exposed to CUS exhibited behavioral deficits in tests measuring anhedonia, anxiety, and despair state. They also had decreases in glial fibrillary acidic protein (GFAP) expression and numbers of GFAP-positive cells in the hippocampus. The behavioral and cellular alterations induced by CUS were reversed by subchronic treatment with the GR antagonist mifepristone. We also found that the subcutaneous injection of glucocorticoids may induce depression-like behavior and reduce GFAP protein expression in rats, which was similarly reversed by mifepristone.
Conclusions
These findings provide experimental evidence that GR activation due to elevated CORT levels induces the decrease of hippocampal astrocyte number in rats.
•Described the activities of FKN, with either beneficial or detrimental effect.•Clarified the cross-talk of FKN/CX3CR1 between neurons and glial cells.•Summarized the mechanisms of FKN/CX3CR1 in ...brain-related diseases.•Discussed the potential clinical application of FKN.
Fractalkine (CX3C chemokine ligand 1, CX3CL1) is an essential chemokine, for regulating adhesion and chemotaxis through binding to CX3CR1, which plays a critical role in the crosstalk between glial cells and neurons by direct or indirect ways in the central nervous system (CNS). Fractalkine/CX3CR1 axis regulates microglial activation and function, neuronal survival and synaptic function by controlling the release of inflammatory cytokines and synaptic plasticity in the course of the neurological disease. The multiple functions of fractalkine/CX3CR1 make it exert neuroprotective or neurotoxic effects, which determines the pathogenesis. However, the role of fractalkine/CX3CR1 in the CNS remains controversial. Whether it can be used as a therapeutic target for neurological diseases needs to be further investigated. In this review, we summarize the studies highlighting fractalkine/CX3CR1-mediated effects and discuss the potential neurotoxic and neuroprotective actions of fractalkine/CX3CR1 in brain injury for providing useful insights into the potential applications of fractalkine/CX3CR1 in neurological diseases.
Rationale
Depression is a serious neuropsychiatric disorder, which is characterized by sustaining mood disorders. Loganin, a major iridoid glycoside from Corni fructus, has a variety of ...pharmacological activities, including neuroprotective effect and hypnotic effect. However, little is known about the effects of loganin on stress-induced depression.
Objective
To investigate the effects of loganin on behavioral despair of mice, and whether serotonin (5-HT) and/or noradrenaline (NE) are involved in this process.
Methods
We tested the effectiveness of loganin using tail suspension test (TST). The possible mechanism was explored using reserpine-induced ptosis and hypothermia, and 5-HTP-induced head-twitch response in mice. The changes of 5-HT and NE in the prefrontal cortex, hippocampus, and striatum were measured through high-performance liquid chromatography (HPLC) analysis. Then, we identified the effects of depleting 5-HT and NE by PCPA (p-chlorophenylalanine) and DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) pretreatment, respectively.
Results
Loganin (12.5/50 mg/kg) induced antidepressant-like effects in mice submitted to TST. Loganin (12.5/50 mg/kg) ameliorated the reserpine-induced hypothermia and ptosis, as well as increased 5-HTP-induced head-twitch responses in mice. Loganin (50 mg/kg) significantly increased the levels of 5-HT in the prefrontal cortex, hippocampus, and striatum. Furthermore, only PCPA treatment could eliminate loganin-induced antidepressant-like effects in TST.
Conclusion
Loganin exerts antidepressant-like effect in the TST depending on 5-HT levels in the central nervous system, which provide a potential agent for depression therapy.
Phytochemical investigation of the roots of Euphorbia ebracteolata Hayata resulted in the isolation of three new rosane diterpenoids, euphebracteolatins C–E (1–3), along with fourteen known analogs ...(4–17). Their structures were determined on the basis of extensive spectroscopic analysis including HR‐ESI‐MS, 1D and 2D NMR. Euphebracteolatin C (1) contains a C‐1/C‐10 double bond and a keto group at C‐7, and euphebracteolatins D and E (2–3) possess an aromatic ring‐A in their skeleton. The plausible biogenetic pathways of all the isolates were also proposed. Furthermore, compounds 1 and 9 showed selective cytotoxicity against HepG2 cells with IC50 values of 14.29 and 12.33 μM, respectively, and 2–3 displayed moderate cytotoxicity against three human cancer lines, with IC50 values ranging from 23.69 to 39.25 μM.
Background
Major depressive disorder (MDD) remains a major public health problem worldwide. The association between MDD and the dysfunction of gap junction channels (GJCs) in glial cells, especially ...astrocytes, is still controversial.
Objective
This review provides an overview of the role of astrocyte GJCs in LMDD.
Results
Exposure to chronic unpredictable stress caused a reduction in connexin expression in the rat prefrontal cortex, a result that is consistent with clinical findings reported in postmortem studies of brains from MDD patients. Chronic antidepressant treatment in these rats increased the expression of connexins. However, pharmacological GJC blockade in normal rodents decreased connexin expression and caused depressive-like behaviors. Furthermore, GJC dysfunction affects electrical conductance, metabolic coupling and secondary messengers, and inflammatory responses, which are consistent with current hypotheses on MDD. All these results provide a comprehensive overview of the neurobiology of MDD.
Conclusion
This review supports the hypothesis that the regulation of GJCs between astrocytes could be an underlying mechanism for the therapeutic effect of antidepressants.
Increasing evidence indicates that dysfunction of glutamate receptors is involved in the pathophysiology of major depressive disorder (MDD). Although accumulating efforts have been made to elucidate ...the applications and mechanisms underlying antidepressant-like effects of ketamine, a non-selective antagonist of N-methyl-d-aspartate receptor (NMDAR), the role of specific glutamate receptor subunit in regulating depression is not completely clear. The current review aims to discuss the relationships between glutamate receptor subunits and depressive-like behaviors. Research literatures were searched from inception to July 2020. We summarized the alterations of glutamate receptor subunits in patients with MDD and animal models of depression. Animal behaviors in response to dysfunction of glutamate receptor subunits were also surveyed. To fully understand mechanisms underlying antidepressant-like effects of modulators targeting glutamate receptors, we discussed effects of each glutamate receptor subunit on serotonin system, synaptic plasticity, neurogenesis and neuroinflammation. Finally, we collected most recent clinical applications of glutamate receptor modulators and pointed out the limitations of these candidates in the treatment of MDD.
Increasing evidence has implicated astrocyte pathology in the etiopathology of major depressive disorder (MDD). In particular, dysfunction of gap junctions in astrocytes is a potential target for MDD ...treatment. However, the mechanism underlying stress-induced dysfunction of gap junctions is still unknown. We therefore studied the mechanism of stress-induced dysfunction of gap junctions in prefrontal cortical and hippocampal astrocytes. Corticosterone (CORT) was used to induce stress conditions; CORT damaged the function of gap junctions, which resulted from less distribution of connexin43 (Cx43) on membranes and the enhanced phosphorylation of Cx43 at S368. Moreover, CORT downregulated the biosynthesis of Cx43 but increased the degradation of Cx43. Interestingly, both autophagy and the proteasome system were involved in the degradation of Cx43 in prefrontal cortical astrocytes, but only the proteasome system was involved in the degradation of Cx43 in hippocampal astrocytes. CORT significantly induced the formation of annular gap junction vesicles in prefrontal cortical astrocytes; however, Cx43 mainly presented as small dots in the hippocampal astrocytes. Furthermore, CORT increased N-Cadherin expression and the interactions of Cx43 with ZO-1/drebrin in prefrontal cortical astrocytes, but these interactions were oppositely modulated in hippocampal astrocytes. In conclusion, this study clarified the alternations of the Cx43 life cycle in the prefrontal cortical and hippocampal astrocytes exposed to CORT, which may contribute to our understanding of the mechanisms underlying stress-induced dysfunction of gap junctions.
•Gap junction dysfunction in astrocytes is a potential target for MDD treatment.•The mechanism of stress-induced dysfunction of gap junctions was studied.•Corticosterone (CORT) was used to mimic aspects of stress conditions in astrocytes.•CORT induced gap junctions dysfunction by regulating Cx43 life cycle.
