Chronic but not acute nicotine treatment ameliorates acute inflammation-induced working memory impairment by increasing CRTC1 and HCN2 in adult male mice.

BACKGROUND: Systemic inflammation in which lipopolysaccharide (LPS) is released into circulation can cause cognitive dysfunction and we have previously shown that LPS impaired working memory (WM) which refers to the ability to guide incoming behavior by retrieving recently acquired information. However, the mechanism is not very clear, and currently, there is no approved strategy to improve inflammation-induced WM deficit. Notably, epidemiological studies have demonstrated a lower occurrence rate of inflammatory-related diseases in smoking patients, suggesting that inflammation-induced WM impairment may be improved by nicotine treatment. Here, our object is to investigate the effect and potential mechanisms of acute and chronic nicotine treatment on LPS-produced WM deficiency. METHODS: Delayed alternation T-maze task (DAT) was applied for evaluating WM which includes both the short-term information storage and the ability to correct errors in adult male mice. Immunofluorescence staining and immunoblotting were used for assessing the levels and distribution of CREB-regulated transcription coactivator 1 (CRTC1) and hyperpolarization-activated cation channels 2 (HCN2) in the medial prefrontal cortex (mPFC) and hippocampus. Quantitative PCR and ELISA were employed for analyzing the mRNA and protein levels of TNF-α and IL-1ß. RESULTS: Our results revealed that administration of LPS (i.p.) at a dose of 0.5 mg/kg significantly produced WM impairment in the DAT task accompanied by an increase in IL-1ß and TNF-α expression in the mPFC. Moreover, intra-mPFC infusion of IL-1Ra, an IL-1 antagonist, markedly alleviated LPS-induced WM deficiency. More important, chronic (2 weeks) but not acute nicotine (0.2 mg/kg, subcutaneous) treatment significantly alleviated LPS-induced WM deficiency by upregulating CRTC1 and HCN2. Of note, intra-mPFC infusion of HCN blocker ZD7288 produced significant WM deficiency. CONCLUSIONS: In summary, in this study, we show that chronic nicotine treatment ameliorates acute inflammation-induced working memory deficiency by increasing CRTC1 and HCN2 in adult male mice.

Targeting the blood-brain barrier to delay aging-accompanied neurological diseases by modulating gut microbiota, circadian rhythms, and their interplays.

The blood-brain barrier (BBB) impairment plays a crucial role in the pathological processes of aging-accompanied neurological diseases (AAND). Meanwhile, circadian rhythms disruption and gut microbiota dysbiosis are associated with increased morbidity of neurological diseases in the accelerated aging population. Importantly, circadian rhythms disruption and gut microbiota dysbiosis are also known to induce the generation of toxic metabolites and pro-inflammatory cytokines, resulting in disruption of BBB integrity. Collectively, this provides a new perspective for exploring the relationship among circadian rhythms, gut microbes, and the BBB in aging-accompanied neurological diseases. In this review, we focus on recent advances in the interplay between circadian rhythm disturbances and gut microbiota dysbiosis, and their potential roles in the BBB disruption that occurs in AAND. Based on existing literature, we discuss and propose potential mechanisms underlying BBB damage induced by dysregulated circadian rhythms and gut microbiota, which would serve as the basis for developing potential interventions to protect the BBB in the aging population through targeting the BBB by exploiting its links with gut microbiota and circadian rhythms for treating AAND.

Role of Crosstalk between Glial Cells and Immune Cells in Blood-Brain Barrier Damage and Protection after Acute Ischemic Stroke.

Blood-brain barrier (BBB) damage is the main pathological basis for acute ischemic stroke (AIS)-induced cerebral vasogenic edema and hemorrhagic transformation (HT). Glial cells, including microglia, astrocytes, and oligodendrocyte precursor cells (OPCs)/oligodendrocytes (OLs) play critical roles in BBB damage and protection. Recent evidence indicates that immune cells also have an important role in BBB damage, vasogenic edema and HT. Therefore, regulating the crosstalk between glial cells and immune cells would hold the promise to alleviate AIS-induced BBB damage. In this review, we first introduce the roles of glia cells, pericytes, and crosstalk between glial cells in the damage and protection of BBB after AIS, emphasizing the polarization, inflammatory response and crosstalk between microglia, astrocytes, and other glia cells. We then describe the role of glial cell-derived exosomes in the damage and protection of BBB after AIS. Next, we specifically discuss the crosstalk between glial cells and immune cells after AIS. Finally, we propose that glial cells could be a potential target for alleviating BBB damage after AIS and we discuss some molecular targets and potential strategies to alleviate BBB damage by regulating glial cells after AIS.

Nicotine Treatment Ameliorates Blood-Brain Barrier Damage After Acute Ischemic Stroke by Regulating Endothelial Scaffolding Protein Pdlim5.

Analysis of a National Institutes of Health (NIH) trial shows that cigarette smoking protected tissue plasminogen activator (tPA)-treated patients from hemorrhage transformation (HT); however, the underlying mechanism is not clear. Damage to the integrity of the blood-brain barrier (BBB) is the pathological basis of HT. Here, we investigated the molecular events of BBB damage after acute ischemic stroke (AIS) using in vitro oxygen-glucose deprivation (OGD) and in vivo mice middle cerebral artery occlusion (MCAO) models. Our results showed that the permeability of bEND.3 monolayer endothelial cells was significantly increased after being exposed to OGD for 2 h. Mice were subjected to 90-min ischemia with 45-min reperfusion, and BBB integrity was significantly damaged, accompanied by tight junction protein occludin degradation, downregulation of microRNA-21 (miR-21), transforming growth factor-ß (TGF-ß), phosphorylated Smad (p-Smad), plasminogen activator inhibitor-1 (PAI-1), and the upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that has been shown to regulate TGF-ß-Smad3 pathway. In addition, pretreatment with two-week nicotine significantly reduced AIS-induced BBB damage and its associated protein dysregulation via downregulating Pdlim5. Notably, AIS did not significantly induce BBB damage in Pdlim5 deficit mice, but overexpression of Pdlim5 in the striatum with adeno-associated virus produced BBB damage and associated protein dysregulation which could be ameliorated by two-week nicotine pretreatment. More important, AIS induced a significant miR-21 decrease, and miR-21 mimics treatment decreased AIS-induced BBB damage by decreasing Pdlim5. Together, these results demonstrate that nicotine treatment alleviates the AIS-compromised integrity of BBB by regulating Pdlim5.

CYP metabolic pathway related gene polymorphism increases the risk of embolic and atherothrombotic stroke and vulnerable carotid plaque in southeast China.

OBJECTIVE: To investigate the association of CYP metabolic pathway-related genetic polymorphisms with the susceptibility to ischemic stroke and stability of carotid plaque in southeast China. METHODS: We consecutively enrolled 294 acute ischemic stroke patients with carotid plaque and 282 controls from Wenling First People's Hospital. The patients were divided into the carotid vulnerable plaque group and stable plaque group according to the results of carotid B-mode ultrasonography. Polymorphisms of CYP3A5 (G6986A, rs776746), CYP2C9*2 (C430T, rs1799853), CYP2C9*3 (A1075C, rs1057910), and EPHX2 (G860A, rs751141) were determined using polymerase chain reaction and mass spectrometry analysis. RESULTS: EPHX2 GG may reduce the susceptibility to ischemic stroke (OR = 0.520, 95% CI: 0.288 ∼ 0.940, P = 0.030) and AA+AG may increase the risk for ischemic stroke (OR = 1.748, 95% CI: 1.001 ∼ 3.052, P = 0.050). The distribution of CYP3A5 genotypes showed significant differences between the vulnerable plaque and stable plaque groups (P = 0.026). Multivariate logistic regression analysis found that CYP3A5 GG could reduce the risk of vulnerable plaques (OR = 0.405, 95% CI: 0.178 ∼ 0.920, P = 0.031). CONCLUSION: EPHX2 G860A polymorphism may reduce the stroke susceptibility, while other SNPs of CYP genes are not associated with ischemic stroke in southeast China. Furthermore CYP3A5 polymorphism was related with carotid plaque instability.

CRTC1 is a potential target to delay aging-induced cognitive deficit by protecting the integrity of the blood-brain barrier via inhibiting inflammation.

Aging can cause attenuation in the functioning of multiple organs, and blood-brain barrier (BBB) breakdown could promote the occurrence of disorders of the central nervous system during aging. Since inflammation is considered to be an important factor underlying BBB injury during aging, vascular endothelial cell senescence serves as a critical pathological basis for the destruction of BBB integrity. In the current review, we have first introduced the concepts related to aging-induced cognitive deficit and BBB integrity damage. Thereafter, we reviewed the potential relationship between disruption of BBB integrity and cognition deficit and the role of inflammation, vascular endothelial cell senescence, and BBB injury. We have also briefly introduced the function of CREB-regulated transcription co-activator 1 (CRTC1) in cognition and aging-induced CRTC1 changes as well as the critical roles of CRTC1/cyclooxygenase-2 (COX-2) in regulating inflammation, endothelial cell senescence, and BBB injury. Finally, the underlying mechanisms have been summarized and we propose that CRTC1 could be a promising target to delay aging-induced cognitive deficit by protecting the integrity of BBB through promoting inhibition of inflammation-mediated endothelial cell senescence.

The NG2-glia is a potential target to maintain the integrity of neurovascular unit after acute ischemic stroke.

The neurovascular unit (NVU) plays a critical role in health and disease. In the current review, we discuss the critical role of a class of neural/glial antigen 2 (NG2)-expressing glial cells (NG2-glia) in regulating NVU after acute ischemic stroke (AIS). We first introduce the role of NG2-glia in the formation of NVU during development as well as aging-induced damage to NVU and accompanying NG2-glia change. We then discuss the reciprocal interactions between NG2-glia and the other component cells of NVU, emphasizing the factors that could influence NG2-glia. Damage to the NVU integrity is the pathological basis of edema and hemorrhagic transformation, the most dreaded complication after AIS. The role of NG2-glia in AIS-induced NVU damage and the effect of NG2-glia transplantation on AIS-induced NVU damage are summarized. We next discuss the role of NG2-glia and the effect of NG2-glia transplantation in oligodendrogenesis and white matter repair as well as angiogenesis which is associated with the outcome of the patients after AIS. Finally, we review the current strategies to promote NG2-glia proliferation and differentiation and propose to use the dental pulp stem cells (DPSC)-derived exosome as a promising strategy to reduce AIS-induced injury and promote repair through maintaining the integrity of NVU by regulating endogenous NG2-glia proliferation and differentiation.

Nicotine's effect on cognition, a friend or foe?

Tobacco smoking is a preventable cause of morbidity and mortality throughout the world. Smoking comes in form of absorption of many compounds, among which nicotine is the main psychoactive component of tobacco and its positive and negative reinforcement effects are proposed to be the key mechanism for the initiation and maintenance of smoking. Growing evidence suggests that the cognitive enhancement effects of nicotine may also contribute to the difficulty of quitting smoking, especially in individuals with psychiatric disorders. In this review, we first introduce the beneficial effect of nicotine on cognition including attention, short-term memory and long-term memory. We next summarize the beneficial effect of nicotine on cognition under pathological conditions, including Alzheimer's disease, Parkinson's disease, Schizophrenia, Stress-induced Anxiety, Depression, and drug-induced memory impairment. The possible mechanism underlying nicotine's effect is also explored. Finally, nicotine's detrimental effect on cognition is discussed, including in the prenatal and adolescent periods, and high-dose nicotine- and withdrawal-induced memory impairment is emphasized. Therefore, nicotine serves as both a friend and foe. Nicotine-derived compounds could be a promising strategy to alleviate neurological disease-associated cognitive deficit, however, due to nicotine's detrimental effect, continued educational programs and public awareness campaigns are needed to reduce tobacco use among pregnant women and smoking should be quitted even if it is e-cigarette, especially for the adolescents.

Nicotine pretreatment alleviates MK-801-induced behavioral and cognitive deficits in mice by regulating Pdlim5/CRTC1 in the PFC.

Increasing evidence shows that smoking-obtained nicotine is indicated to improve cognition and mitigate certain symptoms of schizophrenia. In this study, we investigated whether chronic nicotine treatment alleviated MK-801-induced schizophrenia-like symptoms and cognitive impairment in mice. Mice were injected with MK-801 (0.2 mg/kg, i.p.), and the behavioral deficits were assessed using prepulse inhibition (PPI) and T-maze tests. We showed that MK-801 caused cognitive impairment accompanied by increased expression of PDZ and LIM domain 5 (Pdlim5), an adaptor protein that is critically associated with schizophrenia, in the prefrontal cortex (PFC). Pretreatment with nicotine (0.2 mg · kg-1 · d-1, s.c., for 2 weeks) significantly ameliorated MK-801-induced schizophrenia-like symptoms and cognitive impairment by reversing the increased Pdlim5 expression levels in the PFC. In addition, pretreatment with nicotine prevented the MK-801-induced decrease in CREB-regulated transcription coactivator 1 (CRTC1), a coactivator of CREB that plays an important role in cognition. Furthermore, MK-801 neither induced schizophrenia-like behaviors nor decreased CRTC1 levels in the PFC of Pdlim5-/- mice. Overexpression of Pdlim5 in the PFC through intra-PFC infusion of an adreno-associated virus AAV-Pdlim5 induced significant schizophrenia-like symptoms and cognitive impairment. In conclusion, chronic nicotine treatment alleviates schizophrenia-induced memory deficits in mice by regulating Pdlim5 and CRTC1 expression in the PFC.

Astragaloside VI Ameliorates Post-Stroke Depression via Upregulating the NRG-1-Mediated MEK/ERK Pathway.

BACKGROUND: Post-stroke depression (PSD) has been identified as one of the most commonly occurring complications attributed to stroke. Astragaloside VI (AsVI), which is an active Radix Astragali (AR)-derived compound, has been reported to be a potential drug for post-stroke therapy, but its effects on PSD and the underlying mechanisms remain uncovered. METHODS: In this study, healthy male SD rats underwent a middle cerebral artery occlusion (MCAO) stroke model. To create a PSD model, these rats were then kept in isolated houses and subjected to chronic unpredictable mild stress. The rats were examined every five days for a series of behavioral tests of depression. The antidepressant properties of AsVI were also investigated in vitro in a corticosterone (CORT)-induced major depression model using a CCK-8 assay. The release of neurotransmitters dopamine (DA)/5-hydroxytryptamine (5-HT) was measured using HPLC. The expression of the neurotrophic factor Neuregulin 1 (NRG-1) in rat brain tissues was detected by immunostaining. The protein expression of NRG-1, p-MEK1, and p-ERK1/2 was analyzed utilizing western blotting. RESULTS: AsVI treatment significantly reduced depression-like behaviors in PSD rats and attenuated the CORT-induced apoptotic cell death in neuronal PC-12 cells. Besides, AsVI treatment remarkably prevented the decrease of the levels of DA and 5-HT in the PSD rat brains and in CORT-induced PC-12 cells. Furthermore, AsVI treatment upregulated the NRG-1-mediated MEK/ERK pathway, which is associated with the improvement of PSD. CONCLUSIONS: These findings suggest that AsVI could improve PSD at least partially by upregulating NRG-1-mediated MEK/ERK pathway. AsVI could be a novel therapeutic option for treating PSD.

Role of Glial Cell-Derived Oxidative Stress in Blood-Brain Barrier Damage after Acute Ischemic Stroke.

The integrity of the blood-brain barrier (BBB) is mainly maintained by endothelial cells and basement membrane and could be regulated by pericytes, neurons, and glial cells including astrocytes, microglia, oligodendrocytes (OLs), and oligodendrocyte progenitor cells (OPCs). BBB damage is the main pathological basis of hemorrhage transformation (HT) and vasogenic edema after stroke. In addition, BBB damage-induced HT and vasogenic edema will aggravate the secondary brain tissue damage. Of note, after reperfusion, oxidative stress-initiated cascade plays a critical role in the BBB damage after acute ischemic stroke (AIS). Although endothelial cells are the target of oxidative stress, the role of glial cell-derived oxidative stress in BBB damage after AIS also should receive more attention. In the current review, we first introduce the physiology and pathophysiology of the BBB, then we summarize the possible mechanisms related to BBB damage after AIS. We aim to characterize the role of glial cell-derived oxidative stress in BBB damage after AIS and discuss the role of oxidative stress in astrocytes, microglia cells and oligodendrocytes in after AIS, respectively.

Downregulation of CRTC1 Is Involved in CUMS-Induced Depression-Like Behavior in the Hippocampus and Its RNA Sequencing Analysis.

Chronic stress is an important risk factor for mood disorders including depression. The decreased level of CREB (cAMP-responsive element binding)-regulated transcription coactivator 1 (CRTC1) expression in hippocampus may be involved in depression-like behavior in some stress-induced depression models. But the mechanism of CRTC1 in mediating depression-like behavior remains unknown. In this study, chronic unpredictable mild stress (CUMS)-treated mice showed depression-like behavior accompanied by the downregulation of CRTC1 in the hippocampus. Adeno-associated virus (AAV)-CRTC1-mediated overexpression of CRTC1 in the hippocampus by stereotactic brain injection could significantly prevent depression-like behavior in CUMS-treated mice. The above data reveal that the downregulation of hippocampal CRTC1 expression participates in CUMS-induced depression-like behavior. In order to explore the key targets regulated by CRTC1, AAV-mediated CRTC1 short hairpin (shRNA) was constructed to achieve knockdown of CRTC1 in the hippocampus, and then the hippocampi were collected for RNA-sequencing (RNA-seq). The RNA-seq data show that upregulated genes were enriched in stress and immune system-associated GO terms and pathways such as response to stress and external stimulus and regulation of immune response and that downregulated genes were enriched in neural activity such as synaptic transmission and cognitive behavior. We further provided RT-qPCR data that the inflammation-related factors including Gpr84, Tlr2, Lyz2, and Icam1 were significantly upregulated in the hippocampus of both CUMS- and CRTC1 shRNA-induced models, some of them were also validated in protein levels by Western blotting. We propose a hypothesis that CUMS induces downregulation of CRTC1, which might lead to depression-like behavior via neuroinflammation pathway. This study provides new explanation for the inflammatory hypothesis of depression and some clues for exploring the molecular mechanism of CRTC1 regulation.

LINC00667 regulates MPP+ -induced neuronal injury in Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD), also known as paralysis tremor, is a chronic disease of the central nervous system. It has been reported that hepatocyte nuclear factor 4 alpha (HNF4A) is upregulated in PD, but its specific function has not been well explored. METHODS: We established an in vitro PD model in SH-SY5Y cells stimulated with 1-methyl-4-phenylpyridinium (MPP+ ). Meanwhile, the effect of HNF4A on MPP+ -treated SH-SY5Y cell behavior was monitored by functional assays. Mechanism assays were conducted to verify the relationship among LINC00667/miR-34c-5p/HNF4A. Rescue experiments validated the regulatory mechanism in PD model. RESULTS: The results revealed that depletion of HNF4A suppressed cell cytotoxicity and apoptosis caused by MPP+ . Knockdown of HNF4A recovered MPP+ -stimulated oxidative stress and neuroinflammation. Mechanically, HNF4A was targeted and inhibited by miR-34c-5p. Furthermore, we found that LINC00667 positively modulated HNF4A expression via sequestering miR-34c-5p in MPP+ -stimulated SH-SY5Y cells. Interestingly, the data indicated that HNF4A could transcriptionally activate LINC00667 expression. Rescue experiments presented that miR-34c-5p interference or HNF4A overexpression could mitigate the effects of LINC00667 knockdown on cell viability, cytotoxicity, cell apoptosis, oxidative stress, and neuroinflammation in MPP+ -treated SH-SY5Y cells. CONCLUSION: Our study first proved LINC00667, miR-34c-5p, and HNF4A constructed a positive feedback loop in MPP+ -treated SH-SY5Y cells, enriching our understanding of PD.

Modulation of α7nAchR by Melatonin Alleviates Ischemia and Reperfusion-Compromised Integrity of Blood-Brain Barrier Through Inhibiting HMGB1-Mediated Microglia Activation and CRTC1-Mediated Neuronal Loss.

The only food and drug administration (FDA)-approved drug currently available for the treatment of acute ischemic stroke is tissue plasminogen activator (tPA), yet the therapeutic benefits of this drug are partially outweighed by the increased risk of hemorrhagic transformation (HT). Analysis of the NIH trial has shown that cigarette smoking protected tPA-treated patients from HT; however, the underlying mechanism is not clear. Nicotinic acetylcholine receptors (nAChR) has shown anti-inflammatory effect and modulation nAChR could be a strategy to reduce ischemia/reperfusion-induced blood-brain barrier (BBB) damage. Since melatonin could regulate the expression of α7nAchR and melatonin's neuroprotective effect against ischemic injury is mediated via α7nAChR modulation, here, we aim to test the hypothesis that melatonin reduces ischemia and reperfusion (I/R)-induced BBB damage through modulation of α7nACh receptor (α7nAChR). Mice were subjected to 1.5 h ischemia and 24 h reperfusion and at the onset of reperfusion, mice received intraperitoneal administration (i.p.) of either drug or saline. Mice were randomly assigned into five groups: Saline; α7nAChR agonist PNU282987; Melatonin; Melatonin+Methyllycaconitine (MLA, α7nAChR antagonist), and MLA group. BBB permeability was assessed by detecting the extravasation of Evan's blue and IgG. Our results showed that I/R significantly increased BBB permeability accompanied by occludin degradation, microglia activation, and high mobility group box 1 (HMGB1) release from the neuron. In addition, I/R significantly induced neuronal loss accompanied by the decrease of CREB-regulated transcriptional coactivator 1 (CRTC1) and p-CREB expression. Melatonin treatment significantly inhibited the above changes through modulating α7nAChR. Taken together, these results demonstrate that melatonin provides a protective effect on ischemia/reperfusion-induced BBB damage, at least in part, depending on the modulation of α7nAChR.

Dysregulated CRTC1-BDNF signaling pathway in the hippocampus contributes to Aß oligomer-induced long-term synaptic plasticity and memory impairment.

Expression of CREB-regulated transcription coactivator 1 (CRTC1) in the hippocampus is impaired in Alzheimer's disease (AD). However, CRTC1 related mechanisms associated with long-term synaptic plasticity impairment and cognitive decline in the onset of AD are unknown. In this study, electrophysiological recordings indicated that lentivirus-mediated CRTC1 overexpression effectively ameliorates suppression of late-phase long-term potentiation (L-LTP) in rat hippocampal slices treated with oligomeric amyloid ß(1-42) peptides (oAß42) (200 nM). In addition, application of oAß42 and genetic knockdown of CRTC1 by lentivirus-mediated CRTC1-shRNA inhibit L-LTP, whereas their combination does not further impair L-LTP. Brain-derived neurotrophic factor (BDNF), an important downstream protein confers protection of CRTC1 overexpression against oAß42-induced L-LTP impairment as shown by administration of K252a (200 nM) and TrkB-FC (20 µg/ml). Furthermore, behavioral and western blotting analyses showed that CRTC1 overexpression reverses oAß42-induced hippocampal-dependent cognitive deficits, downregulation of CRTC1 and BDNF expression. Notably, CRTC1-shRNA directly elicits cognitive deficits. In summary, these findings show that hippocampal CRTC1 signaling is affected by soluble oAß, and CRTC1-BDNF pathway is involved in hippocampal L-LTP impairment and memory deficits induced by oAß42.

D1 receptor-mediated endogenous tPA upregulation contributes to blood-brain barrier injury after acute ischaemic stroke.

Blood-brain barrier (BBB) integrity injury within the thrombolytic time window is becoming a critical target to reduce haemorrhage transformation (HT). We have previously reported that BBB damage was initially damaged in non-infarcted striatum after acute ischaemia stroke. However, the underlying mechanism is not clear. Since acute ischaemic stroke could induce a significant increase of dopamine release in striatum, in current study, our aim is to investigate the role of dopamine receptor signal pathway in BBB integrity injury after acute ischaemia using rat middle cerebral artery occlusion model. Our data showed that 2-h ischaemia induced a significant increase of endogenous tissue plasminogen activator (tPA) in BBB injury area and intra-striatum infusion of tPA inhibitor neuroserpin, significantly alleviated 2-h ischaemia-induced BBB injury. In addition, intra-striatum infusion of D1 receptor antagonist SCH23390 significantly decreased ischaemia-induced upregulation of endogenous tPA, accompanied by decrease of BBB injury and occludin degradation. More important, inhibition of hypoxia-inducible factor-1 alpha with inhibitor YC-1 significantly decreased 2-h ischaemia-induced endogenous tPA upregulation and BBB injury. Taken together, our data demonstrate that acute ischaemia disrupted BBB through activation of endogenous tPA via HIF-1α upregulation, thus representing a new therapeutic target for protecting BBB after acute ischaemic stroke.

Acute Nicotine Treatment Alleviates LPS-Induced Impairment of Fear Memory Reconsolidation Through AMPK Activation and CRTC1 Upregulation in Hippocampus.

BACKGROUND: Fear memory is a fundamental capability for animals and humans to survive. Its impairment results in the disability to avoid danger. When memory is reactivated, a reconsolidation process, which can be disrupted by various stimuli, including inflammation, is required to become permanent. Nicotine has been shown to improve cognitive deficits induced by inflammation and other stimuli. Therefore, in the present study, we investigated the effect of nicotine on lipopolysaccharide (LPS)-induced impairment of fear memory reconsolidation and the underlying mechanism. METHODS: Step-through inhibitory avoidance task was recruited to study fear memory of rat, i.p. LPS (0.5 mg/kg) treatment was used to induce inflammation, and western blot and immunostaining were applied to detect protein expression and distribution in medial prefrontal cortex and hippocampus. RESULTS: Our data showed that LPS induced fear memory reconsolidation impairment without affecting retrieval. In addition, LPS significantly increased inflammation factors tumor necrosis factor-α and interleukin-1 beta and decreased CREB-regulated transcription coactivator 1 (CRTC1) expression and adenosine monophosphate-activated protein kinase (AMPK) activation in hippocampus. More importantly, LPS significantly decreased CRTC1 expression and AMPK activation in neurons by activating microglia cells. Of note, either nicotine treatment or activation of AMPK by intracerebroventricular infusion of metformin reduced LPS-induced impairment of fear memory reconsolidation and ameliorated inflammation factor tumor necrosis factor-α and interleukin-1 beta as well as the expression of CRTC1. CONCLUSIONS: In conclusion, our results showed that acute nicotine treatment alleviates LPS-induced impairment of fear memory reconsolidation through activation of AMPK and upregulation of CRTC1 in hippocampus.

NG2-glia cell proliferation and differentiation by glial growth factor 2 (GGF2), a strategy to promote functional recovery after ischemic stroke.

Stroke is the leading cause of adult disability. Spontaneous functional recovery occurs after ischemic stroke, but it is very limited. Therefore, it is urgent to find a strategy to promote functional recovery after stroke in clinical setting. Gray matter damage has received extensive attention owing to the important roles of the gray matter in synaptic plasticity, cognitive, and motor function. However, stroke also causes white matter damage, which accounts for half of the infarct volume and can be aggravated by blood brain barrier damage. Disruption of white matter integrity, which is characterized by death of oligodendrocytes (OLs), loss of myelin, and axonal injury, greatly contributes to impaired neurological function. Impaired proliferation and differentiation of OL precursor cell (OPC, NG2-glia cells) play an important role in limited functional recovery after ischemic stroke and inhibitor of differentiation 2 (ID2) is a key factor controlling NG2-glia cells differentiation. It has been reported that the number of NG2-glia cells in the peri-infarction area significantly increases after ischemic stroke and glial growth factor (GGF2) administration promotes the proliferation and differentiation of NG2-glia cells as well as functional recovery after spinal cord injury. On the basis of the important roles of GGF2 in functional recovery and those of ID2 in NG2-glia cell proliferation and differentiation, we propose that after binding with the ErBb receptor on the surface of NG2-glia cells, GGF2 promotes NG2-glia cell proliferation and differentiation, thereby repairing BBB and white matter integrity and promoting neural functional recovery after ischemic stroke.

Inhibition of Reactive Astrocytes with Fluorocitrate Ameliorates Learning and Memory Impairment Through Upregulating CRTC1 and Synaptophysin in Ischemic Stroke Rats.

Ischemic stroke often causes motor and cognitive deficits. Deregulated glia gap junction communication, which is reflected by increased protein levels of glial fibrillary acidic protein (GFAP) and connexin 43 (Cx43), has been observed in ischemic hippocampus and has been associated with cognitive impairment in animal stroke models. Here, we tested the hypothesis that reactive astrocytes-mediated loss of synaptophysin (SYP) and CREB-regulated transcription coactivator 1 (CRTC1) contribute to dysfunction in glia gap junction communication and memory impairment after ischemic stroke. Male Sprague-Dawley rats were subjected to a 90-min middle cerebral artery occlusion (MCAO) with 7-day reperfusion. Fluorocitrate (1 nmol), the reversible inhibitor of the astrocytic tricarboxylic acid cycle, was injected into the right lateral ventricle of MCAO rats once every 2 days starting immediately before reperfusion. The Morris water maze was used to assess memory in conjunction with western blotting and immunostaining to detect protein expression and distribution in the hippocampus. Our results showed that ischemic stroke caused significant memory impairment accompanied by increased protein levels of GFAP and Cx43 in hippocampal tissue. In addition, the levels of several key memory-related important proteins including SYP, CRTC1, myelin basic protein and high-mobility group-box-1 were significantly reduced in the hippocampal tissue. Of note, inhibition of reactive astrocytes with fluorocitrate was shown to significantly reverse the above noted changes induced by ischemic stroke. Taken together, our findings demonstrate that inhibiting reactive astrocytes with fluorocitrate immediately before reperfusion may protect against ischemic stroke-induced memory impairment through the upregulation of CRTC1 and SYP.

An Overview of Systematic Reviews of Chinese Herbal Medicine for Parkinson's Disease.

Parkinson's disease (PD) is a high prevalence neurodegenerative disorder without a disease-modifying therapy. Up to now, a number of systematic reviews have been conducted to evaluate efficacy and safety of Chinese herbal Medicine (CHM) for PD patients. Here, we aimed to assess the methodological quality and reporting quality of systematic reviews using an overview, and then synthesize and evaluate the available evidence level of CHM for PD. Six databases were searched from inception to September 2018. The literatures were selected and data were extracted according to prespecified criteria. A Measurement Tool to Assess Systematic Reviews (AMSTAR) was used to evaluate the quality of methodology, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to determine the evidence quality of the primary outcome measures. A total of 11 systematic reviews with 230 RCTs of CHM for PD were included. AMSTAR scores of the included reviews were range from 4 to 9. Compared with conventional western medicine (WCM), CHM paratherapy showed significant effect in improving UPDRS score, Webster scale score, PDQ-39, NMSQuest, CHM Syndrome Integral Scale, and PDSS. However, CHM monotherapy showed no difference relative to WCM according to various outcome measures. Adverse events were reported in 9 systematic reviews. The side effect in CHM paratherapy group was generally less than or lighter than that in WCM group. The quality of the evidence of primary outcomes was moderate (42%) to high (54%) according to the GRADE profiler. The present finding supported the use of CHM paratherapy for PD patients but we should treat the evidence cautiously because of the methodological flaws, whereas there is insufficient evidence of CHM monotherapy for PD.