Inflammation and Connexin 43 profiles in the prefrontal cortex are relevant to stress susceptibility and resilience in mice.

Depression is a major chronic mental illness worldwide, characterized by anhedonia and pessimism. Exposed to the same stressful stimuli, some people behave normally, while others exhibit negative behaviors and psychology. The exact molecular mechanisms linking stress-induced depressive susceptibility and resilience remain unclear. Connexin 43 (Cx43) forms gap junction channels between the astrocytes, acting as a crucial role in the pathogenesis of depression. Cx43 dysfunction could lead to depressive behaviors, and depression down-regulates the expression of Cx43 in the prefrontal cortex (PFC). Besides, accumulating evidence indicates that inflammation is one of the most common pathological features of the central nervous system dysfunction. However, the roles of Cx43 and peripheral inflammation in stress-susceptible and stress-resilient individuals have rarely been investigated. Thus, animals were classified into the chronic unpredictable stress (CUS)-susceptible group and the CUS-resilient group based on the performance of behavioral tests following the CUS protocol in this study. The protein expression of Cx43 in the PFC, the Cx43 functional changes in the PFC, and the expression levels including interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, IL-2, IL-10, and IL-18 in the peripheral serum were detected. Here, we found that stress exposure triggered a significant reduction in Cx43 protein expression in the CUS-susceptible mice but not in the CUS-resilient mice accompanied by various Cx43 phosphorylation expression and the changes of inflammatory signals. Stress resilience is associated with Cx43 in the PFC and fluctuation in inflammatory signaling, showing that therapeutic targeting of these pathways might promote stress resilience.

Time-dependent dual effect of microglia in ischemic stroke.

Stroke, the third leading cause of death and disability worldwide, is classified into ischemic or hemorrhagic, in which approximately 85% of strokes are ischemic. Ischemic stroke occurs as a result of arterial occlusion due to embolus or thrombus, with ischemia in the perfusion territory supplied by the occluded artery. The traditional concept that ischemic stroke is solely a vascular occlusion disorder has been expanded to include the dynamic interaction between microglia, astrocytes, neurons, vascular cells, and matrix components forming the "neurovascular unit." Acute ischemic stroke triggers a wide spectrum of neurovascular disturbances, glial activation, and secondary neuroinflammation that promotes further injury, ultimately resulting in neuronal death. Microglia, as the resident macrophages in the central nervous system, is one of the first responders to ischemic injury and plays a significant role in post-ischemic neuroinflammation. In this review, we reviewed the mechanisms of microglia in multiple stages of post-ischemic neuroinflammation development, including acute, sub-acute and chronic phases of stroke. A comprehensive understanding of the dynamic variation and the time-dependent role of microglia in post-stroke neuroinflammation could aid in the search for more effective therapeutics and diagnostic strategies for ischemic stroke.

A novel small-molecular CCR5 antagonist promotes neural repair after stroke.

Chemokine receptor 5 (CCR5) is one of the main co-receptors of HIV-1, and has been found to be a potential therapeutic target for stroke. Maraviroc is a classic CCR5 antagonist, which is undergoing clinical trials against stroke. As maraviroc shows poor blood-brain barrier (BBB) permeability, it is of interest to find novel CCR5 antagonists suitable for neurological medication. In this study we characterized the therapeutic potential of a novel CCR5 antagonist A14 in treating ischemic stroke mice. A14 was discovered in screening millions compounds in the Chemdiv library based on the molecular docking diagram of CCR5 and maraviroc. We found that A14 dose-dependently inhibited the CCR5 activity with an IC50 value of 4.29 µM. Pharmacodynamic studies showed that A14 treatment exerted protective effects against neuronal ischemic injury both in vitro and vivo. In a SH-SY5Y cell line overexpressing CCR5, A14 (0.1, 1 µM) significantly alleviated OGD/R-induced cell injury. We found that the expression of CCR5 and its ligand CKLF1 was significantly upregulated during both acute and recovery period in focal cortical stroke mice; oral administration of A14 (20 mg·kg-1·d-1, for 1 week) produced sustained protective effect against motor impairment. A14 treatment had earlier onset time, lower onset dosage and much better BBB permeability compared to maraviroc. MRI analysis also showed that A14 treatment significantly reduced the infarction volume after 1 week of treatment. We further revealed that A14 treatment blocked the protein-protein interaction between CCR5 and CKLF1, increasing the activity of CREB signaling pathway in neurons, thereby improving axonal sprouting and synaptic density after stroke. In addition, A14 treatment remarkably inhibited the reactive proliferation of glial cells after stroke and reduced the infiltration of peripheral immune cells. These results demonstrate that A14 is a promising novel CCR5 antagonist for promoting neuronal repair after ischemic stroke. A14 blocked the protein-protein interaction between CKLF1 and CCR5 after stroke by binding with CCR5 stably, improved the infarct area and promoted motor recovery through reversing the CREB/pCREB signaling which was inhibited by activated CCR5 Gαi pathway, and benefited to the dendritic spines and axons sprouting.

Connexin 43: An Interface Connecting Neuroinflammation to Depression.

Major depressive disorder (MDD) is a leading chronic mental illness worldwide, characterized by anhedonia, pessimism and even suicidal thoughts. Connexin 43 (Cx43), mainly distributed in astrocytes of the brain, is by far the most widely and ubiquitously expressed connexin in almost all vital organs. Cx43 forms gap junction channels in the brain, which mediate energy exchange and effectively maintain physiological homeostasis. Increasing evidence suggests the crucial role of Cx43 in the pathogenesis of MDD. Neuroinflammation is one of the most common pathological features of the central nervous system dysfunctions. Inflammatory factors are abnormally elevated in patients with depression and are closely related to nearly all links of depression. After activating the inflammatory pathway in the brain, the release and uptake of glutamate and adenosine triphosphate, through Cx43 in the synaptic cleft, would be affected. In this review, we have summarized the association between Cx43 and neuroinflammation, the cornerstones linking inflammation and depression, and Cx43 abnormalities in depression. We also discuss the significant association of Cx43 in inflammation and depression, which will help to explore new antidepressant drug targets.

Mangiferin, a natural glucoxilxanthone, inhibits mitochondrial dynamin-related protein 1 and relieves aberrant mitophagic proteins in mice model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease featured to mitochondrial dysfunction in neuronal cells. Dynamin-related protein 1 (Drp1) is an important regulator of mitochondrial fission and subsequent mitophagy. Mangiferin (MGF) is a glucosyl xanthone mainly derived from Mangifera indica L., possessing multifaceted properties, e.g., antioxidant, anti-inflammatory, and enhancement of cognitive ability. Besides, it can cross the blood-brain barrier, thereby exerting a neuroprotective effect. However, so far, MGF's effect in balancing mitochondrial homeostasis via regulation of Drp1 level and mitophagic pathway in PD remains rarely reported. PURPOSE: We aimed to investigate the neuroprotective effect of MGF against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and examine the possible mechanisms. METHODS: We utilized C57BL/6 mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Behavioral parameters, containing the open field test, balance beam, pole test, and rotarod test, assessed the locomotor activity; immunohistochemistry assessed the number of TH-positive neurons; transmission electron microscopy detected ultrastructural mitochondrial morphology in the dopaminergic neuron; complex I enzymatic activity microplate assay kit measured the mitochondrial complex I activity; ATP determination kit measured ATP levels in mitochondria isolated from cells or striatal tissues; western blot measured the levels of Drp1 and mitophagic proteins. RESULTS: We observed that MGF could mitigate motor deficiency and improve the expression of tyrosine hydroxylase in the substantia nigra of MPTP-induced PD mice. Furthermore, MGF not only ameliorated mitochondrial ultrastructure, but also improved mitochondrial ATP content. Within mitochondria, MGF could reduce Drp1 expression and reverse the expressions of mitophagic proteins, including PINK1, Parkin, NIX, BNIP3, FUNDC1, and p62. CONCLUSION: Present study indicates that MGF benefits mitochondrial networks by recovering mitochondrial ultrastructure and ATP contents, reducing mitochondrial Drp1, and modulating mitophagic proteins in the MPTP-induced PD mice model, which revealed a novel acting mechanism of MGF in PD's treatment.

Ginsenoside Rg1 Plays a Neuroprotective Role in Regulating the Iron-Regulated Proteins and Against Lipid Peroxidation in Oligodendrocytes.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Progressive loss of dopaminergic neurons in the substantia nigra (SN) is one of the major pathological changes. However, the reasons for the dopaminergic neuron loss are still ambiguous and further studies are needed to evaluate the in-depth mechanisms of neuron death. Oxidative stress is a significant factor causing neuronal damage. Dopaminergic neurons in the SN are susceptible to oxidative stress, which is closely associated with iron dyshomeostasis in the brain. Ginsenoside Rg1 from ginseng plays a crucial role in neuroprotective effects through anti-inflammation and attenuating the aggregation of abnormal α-synuclein. In our study, we established a chronic PD mouse model by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine combined with probenecid and explored the effect of Rg1 on the oxidative stress and brain iron homeostasis. Rg1 was verified to improve the level of tyrosine hydroxylase and anti-oxidant stress. In addition, Rg1 maintained the iron-regulated protein homeostasis by increasing the expression of ferritin heavy chain and decreasing ferritin light chain in oligodendrocytes, especially the mature oligodendrocytes (OLs). Furthermore, Rg1 had a positive effect on the myelin sheath protection and increased the number of mature oligodendrocytes, proved by the increased staining of myelin basic protein and CC-1. In conclusion, Rg1 could play a neuroprotective role through remitting the iron-regulated protein dyshomeostasis by ferritin and against lipid peroxidation stress in oligodendrocytes.

CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurr1 signal pathways.

Neuroinflammation is closely related to the pathogenesis of neurodegenerative diseases. Activation of microglia, the resident immune cells in CNS, induces inflammatory responses, resulting in the release of neurotoxic molecules, which favors neuronal death and neurodegeneration. Nuclear receptor-related 1 (Nurr1) protein, one of the orphan nuclear receptor superfamilies, is an emerging target for neuroprotective therapy. In addition, the anti-inflammatory function of cannabinoid (CB) receptors has attracted increasing interest. As both CB receptors (especially CB2 receptor) and Nurr1 exist in microglia, and regulate a number of same molecular points such as NF-κB, we herein explored the interplay between the CB2 receptor and Nurr1 as well as the regulatory mechanisms in microglial cells. We showed that the application of CB2 receptor agonists JWH015 (1, 10 µM) significantly increased the nuclear Nurr1 protein in BV-2 cells and primary midbrain microglia. Overexpression of Nurr1 or application of Nurr1 agonist C-DIM12 (10 µM) significantly increased the mRNA level of CB2 receptor in BV-2 cells, suggesting that positive expression feedback existing between the CB2 receptor and Nurr1. After 2-AG and JWH015 activated the CB2 receptors, the levels of p-ERK, p-AKT, p-GSK-3ß in BV-2 cells were significantly increased. Using ERK1/2 inhibitor U0126 and PI3K/AKT inhibitor LY294002, we revealed that the amount of Nurr1 in the nucleus was upregulated through ß-arrestin2/ERK1/2 and PI3K/AKT/GSK-3ß signaling pathways. With these inhibitors, we found a cross-talk interaction between the two pathways, and the ERK1/2 signaling pathway played a more dominant regulatory role. Furthermore, we demonstrated that when the CB2 receptor was activated, the phagocytic function of BV-2 cells was significantly weakened; the activation of Nurr1 also inhibited the phagocytic function of BV-2 cells. Pretreatment with the signaling pathway inhibitors, especially U0126, reversed the inhibitory effect of 2-AG on phagocytosis, suggesting that CB2 receptor may regulate the phagocytic function of microglia by activating Nurr1. In conclusion, CB2 receptor or/and Nurr1-mediated signal pathways play instrumental roles in the progress of phagocytosis, which are expected to open up new treatment strategies for neurodegenerative diseases.

Inhibition of CKLF1 ameliorates hepatic ischemia-reperfusion injury via MAPK pathway.

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver resection or transplantation. However, the mechanism underlying hepatic I/R injury remains obscure. The aim of the present study was to investigate the role of Chemokine-like factor 1 (CKLF1) in hepatic I/R injury. METHODS: Rats were subjected to 70% hepatic ischemia for 90 min, followed by 6, 12, 24, 48 and 96 h of reperfusion. The expression of CKLF1 was measured by real-time PCR and western blot. The effect of C19, an antagonism peptide of CKLF1, on hepatic I/R injury was investigated. RESULTS: After subjected to 70% hepatic ischemia and reperfusion, the ALT and AST were increased. H&E results showed serious liver damage. The mRNA and protein levels of CKLF1 expression were upregulated during hepatic I/R. Immunohistochemistry staining results showed that neutrophil infiltration was increased in the ischemia lobe. MPO activity was significantly higher post reperfusion. TNF-α and IL-1ß were upregulated during hepatic I/R. C19 administration significantly reduced the level of ALT and AST, decreased the necrosis area of liver tissue. Furthermore, C19 treatment inhibited neutrophil infiltration and reduced MPO activity. Meanwhile, C19 decreased the expression of TNF-α and IL-1ß. The phosphorylation of P38, JNK were inhibited by C19 treatment. CONCLUSION: CKLF1 was upregulated during hepatic I/R. Inhibiting CKLF1 by C19, an antagonism peptide of CKLF1, could alleviate hepatic I/R injury, reduce neutrophil infiltration, decrease inflammatory response. The protective effect of C19 may related to MAPK signaling pathway.

Research on developing drugs for Parkinson's disease.

Current treatments for Parkinson's disease (PD) are mainly dopaminergic drugs. However, dopaminergic drugs are only symptomatic treatments and limited by several side effects. Recent studies into drug development focused on emerging new molecular mechanisms, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear receptor-related 1 (Nurr1), adenosine receptor A2, nicotine receptor, metabotropic glutamate receptors (mGluRs), and glucocerebrosidase (GCase). Also, immunotherapy and common pathological mechanisms shared with Alzheimer's Disease (AD) and diabetes have attracted much attention. In this review, we summarized the development of preclinical and clinical studies of novel drugs and the improvement of dopaminergic drugs to provide a prospect for PD treatment.

Tetrahydroxy stilbene glycoside attenuates acetaminophen-induced hepatotoxicity by UHPLC-Q-TOF/MS-based metabolomics and multivariate data analysis.

Tetrahydroxy stilbene glycoside (TSG) is a main active compound in Polygonum multiflorum. Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. It is considered to be safe within a therapeutic range, in case of acute intoxication hepatotoxicity occurs. This present study aims to observe TSG-provided alleviation on APAP-induced hepatoxicity in C57BL/6 mice. APAP performs extensive necrosis and dissolves nucleus suggesting liver damage from hepatic histopathology. Serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase analysis and liver histological evaluation showed that TSG reduced the hepatotoxicity induced by a toxic dose of APAP. Moreover, TSG alone had no hepatotoxicity. TSG eliminated hepatic glutathione depletion and cysteine adducts formation. It also reduced the expression of interleukin-10 and lowered the production of reactive oxygen species in liver tissues. Luminex was used to detect cytokine production in different groups. Herein, we used an untargeted metabolomics approach by performing ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry on treated mice to identify metabolic disruptions under APAP and TSG. Major alterations were observed for purine metabolism, amino acid metabolism, and fatty acid metabolism. These data provide metabolic evidence and biomarkers in the liver that the ABC transporters, Glycine serine and threonine metabolism, and Choline metabolism in cancer changed the most. These targets of metabolites have the potential to improve our understanding of homeostatic. Meanwhile, these metabolites revealed that TSG can alleviate inflammation caused by APAP and promote the activity of intrinsic antioxidants. In summary, TSG can regulate lipid metabolism, promote the production of antioxidant enzymes, and decrease the inflammatory response.

Low corticosterone levels attenuate late life depression and enhance glutamatergic neurotransmission in female rats.

Sustained elevation of corticosterone (CORT) is one of the common causes of aging and major depression disorder. However, the role of elevated CORT in late life depression (LLD) has not been elucidated. In this study, 18-month-old female rats were subjected to bilateral adrenalectomy or sham surgery. Their CORT levels in plasma were adjusted by CORT replacement and the rats were divided into high-level CORT (H-CORT), low-level CORT (L-CORT), and Sham group. We showed that L-CORT rats displayed attenuated depressive symptoms and memory defects in behavioral tests as compared with Sham or H-CORT rats. Furthermore, we showed that glutamatergic transmission was enhanced in L-CORT rats, evidenced by enhanced population spike amplitude (PSA) recorded from the dentate gyrus of hippocampus in vivo and increased glutamate release from hippocampal synaptosomes caused by high frequency stimulation or CORT exposure. Intracerebroventricular injection of an enzymatic glutamate scavenger system, glutamic-pyruvic transmine (GPT, 1 µM), significantly increased the PSA in Sham rats, suggesting that extracelluar accumulation of glutamate might be the culprit of impaired glutamatergic transmission, which was dependent on the uptake by Glt-1 in astrocytes. We revealed that hippocampal Glt-1 expression level in the L-CORT rats was much higher than in Sham and H-CORT rats. In a gradient neuron-astrocyte coculture, we found that the expression of Glt-1 was decreased with the increase of neural percentage, suggesting that impairment of Glt-1 might result from the high level of CORT contributed neural damage. In sham rats, administration of DHK that inhibited Glt-1 activity induced significant LLD symptoms, whereas administration of RIL that promoted glutamate uptake significantly attenuated LLD. All of these results suggest that glutamatergic transmission impairment is one of important pathogenesis in LLD induced by high level of CORT, which provide promising clues for the treatment of LLD.

Exogenous Adenosine Antagonizes Excitatory Amino Acid Toxicity in Primary Astrocytes.

Excitatory toxicity is still a hot topic in the study of ischemic stroke, and related research has focused mainly on neurons. Adenosine is an important neuromodulator that is known as a "biosignature" in the central nervous system (CNS). The protective effect of exogenous adenosine on neurons has been confirmed, but its mechanism remains elusive. In this study, astrocytes were pretreated with adenosine, and the effects of an A2a receptor (A2aR) inhibitor (SCH58261) and A2b receptor (A2bR) inhibitor (PSB1115) on excitatory glutamate were investigated. An oxygen glucose deprivation/reoxygenation (OGD/R) and glutamate model was generated in vitro. Post-model assessment included expression levels of glutamate transporters (glt-1), gap junction protein (Cx43) and glutamate receptor (AMPAR), Na+-K+-ATPase activity, and diffusion distance of dyes. Glutamate and glutamine contents were determined at different time points. The results showed that (1) adenosine could improve the function of Na+-K+-ATPase, upregulate the expression of glt-1, and enhance the synthesis of glutamine in astrocytes. This effect was associated with A2aR activation but not with A2bR activation. (2) Adenosine could inhibit the expression of gap junction protein (Cx43) and reduce glutamate diffusion. Inhibition of A2aR attenuated adenosine inhibition of gap junction intercellular communication (GJIC) in the OGD/R model, while it enhanced adenosine inhibition of GJIC in the glutamate model, depending on the glutamate concentration. (3) Adenosine could cause AMPAR gradually entered the nucleus from the cytoplasm, thereby reducing the expression of AMPAR on the cell membrane. Taken together, the results indicate that adenosine plays a role of anti-excitatory toxicity effect in protection against neuronal death and the functional recovery of ischemic stroke mainly by targeting astrocytes, which are closely related to A2aR. The present study provided a scientific basis for adenosine prevention and ischemic stroke treatment, thereby providing a new approach for alleviating ischemic stroke.

A bibenzyl compound 20C protects rats against 6-OHDA-induced damage by regulating adaptive immunity associated molecules.

Parkinson's disease (PD) is a neurodegenerative disease with complicated pathogenesis. A novel bibenzyl compound 2-[4-hydroxy-3-(4-hydroxyphenyl)benzyl]-4-(4-hydroxyphenyl)phenol (20C) has been shown to have some neuroprotective effects, and its mechanism still needs further research. In this study, we used a 6-hydroxydopamine (6-OHDA)-induced PD rat model to evaluate the protective effect of 20C. Our study found that 20C could improve behavioral defects in 6-OHDA-lesion rats, decrease neuroinflammation and protect their DA neurons. It could inhibit the activity of inducible nitric oxide synthase (iNOS) induced by 6-OHDA, and lead to a decrease in the expression of nitrated-α-synuclein. When exposed to AMT-an inhibitor of iNOS, the nitrated-α-synuclein in PC12 decreased, and 20C demonstrated the same function on nitrated-α-synuclein as AMT. Besides, we also found that nitrated-α-synuclein was displayed in microglia. And 20C could decrease the expression of antigen-presenting molecule major histocompatibility complex I (MHC I) in dopamine (DA) neurons and MHC II in microglia induced by 6-OHDA. So, these imply that nitrated-α-synuclein might act as an endogenous antigen activating adaptive immunity, and the neuroprotection of 20C might be associated with inhibiting the activity of iNOS, decreasing the expression of the antigen molecule nitrated-α-synuclein and the antigen presenting molecule MHC. Our results indicated that inhibiting iNOS might be an effective strategy to protect neurons from oxidative stress.

Neuroprotective triterpene saponins from the leaves of Panax notoginseng.

Two new triterpene saponins, namely notoginsenoside Ng5 (1) and notoginsenoside Ng6 (2) were isolated from the leaves of Panax notoginseng, along with five known ones. Their structures were determined by chemical methods, NMR and X-ray experiments. The absolute configuration of compound 3 with four sugar units was confirmed by single crystal X-ray analysis. Compounds 2-4 and 6 inhibited PC12 cell damage induced by serum deprivation, and increased cell viability from 58.7 ± 6.7% to 66.7 ± 4.5%, 76.1 ± 6.1%, 64.7 ± 5.2% and 67.2 ± 5.0% at 10 µM, respectively.

CKLF1/CCR5 axis is involved in neutrophils migration of rats with transient cerebral ischemia.

BACKGROUND: Chemokine-like factor 1 (CKLF1) is a chemokine increased significantly in ischemic brain poststroke. It shows chemotaxis effects on various immune cells, but the mechanisms of CKLF1 migrating neutrophils are poorly understood. Recent studies have provided evidence that CC chemokine receptor 5 (CCR5), a receptor of CKLF1, is involved in ischemic stroke. PURPOSES: To investigate the effects of HIF-1α guided AAV in ischemic brain, investigating the outcome of stroke, and examining the involvement of CKLF1/CCR5 axis in recruitment of neutrophils. RESULTS: HIF-1α guided AAV knocked down CKLF1 in ischemic area and alleviated brain damage of rats. CKLF1 migrated neutrophils through CCR5, worsening inflammatory responses. Akt/GSK-3ß pathway may involve in CKLF1/CCR5 axis guided neutrophils chemotaxis. CONCLUSIONS: CKLF1/CCR5 axis is involved in neutrophils migration of rats with transient cerebral ischemia. CKLF1/CCR5 axis may be a useful target for stroke therapy.

Connexin 43: A novel ginsenoside Rg1-sensitive target in a rat model of depression.

Our previous studies have shown that ginsenoside Rg1 (Rg1) exerts antidepressant-like effects in animal models of depression, accompanied by an improvement of astrocytic gap junction functions. However, whether connexin 43 (Cx43), the major connexin forming gap junctions between astrocytes, is the key regulator of Rg1-induced antidepressant-like effects is still unknown. In this study, we examine in vitro and in vivo the involvement of Cx43 in the antidepressant effects of Rg1. Corticosterone was used to establish an in vitro rat model of depression. Treatment with Rg1 1 h prior to corticosterone significantly improved the cell viability of astrocytes, which was significantly inhibited by carbenoxolone, a widely used gap junction inhibitor. Moreover, Rg1 treatment significantly ameliorated antidepressant-sensitive behaviours induced by infusion of carbenoxolone or Gap26, a selective inhibitor of Cx43, into the prefrontal cortex of the animals. Rg1 treatment increased the expression of Cx43 compared with Gap26 group. According to these results, the antidepressant-like effects of Rg1 were mainly mediated by Cx43-formed gap junctions.

Donepezil attenuates vascular dementia in rats through increasing BDNF induced by reducing HDAC6 nuclear translocation.

Vascular dementia (VD) is the second most common dementia disease after Alzheimer's diseases (AD) in the world. Donepezil is used to treat mild to moderate AD, and it has been shown to treat cognitive impairment and memory deficits caused by VD. However, the action mechanism of donepezil against VD has not been clarified. In this study, a bilateral common carotid artery occlusion (BCCAO) model was established in rats to simulate the pathology of VD. Two weeks after the surgery, the rats were administered donepezil (10 mg · kg-1 · d-1, ig) for 3 weeks, and then subjected to behavioral tests. We showed that donepezil treatment significantly improved the performance of BCCAO rats in Morris Water Mazes test and Step-down test. Furthermore, we showed that donepezil treatment significantly attenuated neurodegeneration and restored the synapse dendritic spines density in cortex and hippocampus. We revealed that donepezil treatment significantly increased BDNF expression in cortex and hippocampus. Interestingly, donepezil treatment significantly decreased nuclear translocation of HDAC6 and the binding between HDAC6 and BDNF promoter IV in cortex, but not in the hippocampus. The attenuated neurodegeneration by donepezil in cortex and hippocampus might due to the reduced ROS levels and increased phosphorylation of AMPK, whereas increased phosphorylation of AKT was only detected in cortex. In conclusion, our results demonstrate that donepezil attenuates neurodegeneration in cortex and hippocampus via increasing BDNF expression; the regulation of donepezil on HDAC6 occurred in cortex, but not in the hippocampus. This study further clarifies the pharmacological mechanism of donepezil, while also emphasizes the promising epigenetic regulation of HDAC6.

Role of non-coding RNA in the pathogenesis of depression.

Depression is increasingly threatening human health as a serious psychological problem. However, it is remarkable that the precise mechanism underlying depression remains unelucidated. Recent studies have clarified that non-coding RNA, including but not limited to microRNA, long non-coding RNA, and circular RNA, plays an important role in the pathogenesis of depression. The research results cited in this paper reveal the origin, expression, distribution, function, and mechanism of microRNA in the nervous system. MicroRNA is involved in regulation of life activities, including growth, immune reaction, haematopoiesis, and metabolism, which are significant for maintaining normal physiological functions. Moreover, microRNA plays an important role in cell death and proliferation, development of cancer, and disease prognosis. Here, we also introduce the general research status of long non-coding RNA and circular RNA. Next, descriptive study methods, including fluorescence quantitative polymerase chain reaction, northern blot, microarray technology, RNA-seq, and fluorescent in situ hybridization are discussed. Functional study methods are also summarized and divided into gain- and loss-of-function studies. Moreover, the roles of non-coding RNA in the pathogenesis of depression, including neurogenesis, synaptic plasticity, brain-derived neurotrophic factor expression, HPA axis regulation, neurotransmission, neuropeptide expression, neuro-inflammation, and polyamine synthesis are discussed. Nevertheless, many unknown associations between non-coding RNA and depression remain to be clarified.

Research progress on adenosine in central nervous system diseases.

As an endogenous neuroprotectant agent, adenosine is extensively distributed and is particularly abundant in the central nervous system (CNS). Under physiological conditions, the concentration of adenosine is low intra- and extracellularly, but increases significantly in response to stress. The majority of adenosine functions are receptor-mediated, and primarily include the A1, A2A, A2B, and A3 receptors (A1R, A2AR, A2BR, and A3R). Adenosine is currently widely used in the treatment of diseases of the CNS and the cardiovascular systems, and the mechanisms are related to the disease types, disease locations, and the adenosine receptors distribution in the CNS. For example, the main infarction sites of cerebral ischemia are cortex and striatum, which have high levels of A1 and A2A receptors. Cerebral ischemia is manifested with A1R decrease and A2AR increase, as well as reduction in the A1R-mediated inhibitory processes and enhancement of the A2AR-mediated excitatory process. Adenosine receptor dysfunction is also involved in the pathology of Alzheimer's disease (AD), depression, and epilepsy. Thus, the adenosine receptor balance theory is important for brain disease treatment. The concentration of adenosine can be increased by endogenous or exogenous pathways due to its short half-life and high inactivation properties. Therefore, we will discuss the function of adenosine and its receptors, adenosine formation, and metabolism, and its role for the treatment of CNS diseases (such as cerebral ischemia, AD, depression, Parkinson's disease, epilepsy, and sleep disorders). This article will provide a scientific basis for the development of novel adenosine derivatives through adenosine structure modification, which will lead to experimental applications.