Macrophage Migration Inhibitory Factor as a Potential Plasma Biomarker of Cognitive Impairment in Cerebral Small Vessel Disease.

As the pathogenesis of cerebral small vessel disease with cognitive impairment (CSVD-CI) remains unclear, identifying effective biomarkers can contribute to the clinical management of CSVD-CI. This study recruited 54 healthy controls (HCs), 60 CSVD-CI patients, and 57 CSVD cognitively normal (CSVD-CN) patients. All participants underwent neuropsychological assessments and multimodal magnetic resonance imaging. Macrophage migration inhibitory factors (MIFs) were assessed in plasma. The least absolute shrinkage and selection operator model was used to determine a composite marker. Compared with HCs or CSVD-CN patients, CSVD-CI patients had significantly increased plasma MIF levels. In CSVD-CI patients, plasma MIF levels were significantly correlated with multiple cognitive assessment scores, plasma levels of blood-brain barrier (BBB)-related indices, white matter hyperintensity Fazekas scores, and the mean amplitude of low-frequency fluctuation in the right superior temporal gyrus. Higher plasma MIF levels were significantly associated with worse global cognition and information processing speed in CSVD-CI patients. The composite marker (including plasma MIF) distinguished CSVD-CI patients from CSVD-CN and HCs with >80% accuracy. Meta-analysis indicated that blood MIF levels were significantly increased in CSVD-CI patients. In conclusion, plasma MIF is a potential biomarker for early identification of CSVD-CI. Plasma MIF may play a role in cognitive decline in CSVD through BBB dysfunction and changes in white matter hyperintensity and brain activity.

Potential Association of Neutrophil Extracellular Traps With Cognitive Impairment in Cerebral Small Vessel Disease.

No acceptable biomarker can facilitate the early identification of cognitive impairment associated with cerebral small vessel disease (CSVD) in the older persons. The neutrophil extracellular traps (NETs) in the inflammation response of circulatory and central systems are essential in destroying the blood-brain barrier. The present study aims to explore the potential associations of plasma NETs with cognitive performance in CSVD. We recruited 146 CSVD patients and 66 healthy controls (HCs), and comprehensive neuropsychological assessments and multimodal magnetic resonance imaging were conducted. Three NETs markers, namely citrullination of histone H3, neutrophil elastase-DNA, and myeloperoxidase (MPO)-DNA, and 4 oxidative stress-related indexes in plasma samples, were measured. The plasma levels of 3 NETs markers were more significantly elevated in CSVD patients than in HCs. Significant correlations of the 3 NETs markers were observed with multiple cognitive domain scores. Furthermore, higher plasma malondialdehyde and NETs levels were significantly associated with the worse Montreal Cognitive Assessment scores among CSVD patients. Moreover, plasma MPO-DNA levels significantly mediated the effect of the amplitude of low-frequency fluctuation value within the bilateral caudate and the scores of global cognitive function, executive function, and information processing speed. Additionally, a panel of 3 NETs markers had the highest area under the curve value to distinguish the cognitively impaired CSVD patients from HCs and nonimpaired ones. Therefore, plasma NETs may be potential biomarkers for early diagnosis of CSVD-related cognitive impairment. Activated lipid peroxidation in circulation and impaired caudate function support potential associations of plasma NETs in cognitively impaired CSVD patients.

Alteration and clinical potential in gut microbiota in patients with cerebral small vessel disease.

Background: Cerebral small vessel disease (CSVD) is a cluster of microvascular disorders with unclear pathological mechanisms. The microbiota-gut-brain axis is an essential regulatory mechanism between gut microbes and their host. Therefore, the compositional and functional gut microbiota alterations lead to cerebrovascular disease pathogenesis. The current study aims to determine the alteration and clinical value of the gut microbiota in CSVD patients. Methods: Sixty-four CSVD patients and 18 matched healthy controls (HCs) were included in our study. All the participants underwent neuropsychological tests, and the multi-modal magnetic resonance imaging depicted the changes in brain structure and function. Plasma samples were collected, and the fecal samples were analyzed with 16S rRNA gene sequencing. Results: Based on the alpha diversity analysis, the CSVD group had significantly decreased Shannon and enhanced Simpson compared to the HC group. At the genus level, there was a significant increase in the relative abundances of Parasutterella, Anaeroglobus, Megasphaera, Akkermansia, Collinsella, and Veillonella in the CSVD group. Moreover, these genera with significant differences in CSVD patients revealed significant correlations with cognitive assessments, plasma levels of the blood-brain barrier-/inflammation-related indexes, and structural/functional magnetic resonance imaging changes. Functional prediction demonstrated that lipoic acid metabolism was significantly higher in CSVD patients than HCs. Additionally, a composite biomarker depending on six gut microbiota at the genus level displayed an area under the curve of 0.834 to distinguish CSVD patients from HCs using the least absolute shrinkage and selection operator (LASSO) algorithm. Conclusion: The evident changes in gut microbiota composition in CSVD patients were correlated with clinical features and pathological changes of CSVD. Combining these gut microbiota using the LASSO algorithm helped identify CSVD accurately.

Combination of platelet-to-lymphocyte ratio and D-dimer for the identification of cardiogenic cerebral embolism in non-valvular atrial fibrillation.

Background: Non-valvular atrial fibrillation (NVAF) is the most common cause of cardiogenic cerebral embolism (CCE). However, the underlying mechanism between cerebral embolism and NVAF is indefinite, and there is no effective and convenient biomarker to identify potential risk of CCE in patients with NVAF in clinic. The present study aims to identify risk factors for interpreting the potential association of CCE with NVAF and providing valuable biomarkers to predict the risk of CCE for NVAF patients. Methods: 641 NVAF patients diagnosed with CCE and 284 NVAF patients without any history of stroke were recruited in the present study. Clinical data including demographic characteristics, medical history, and clinical assessments, were recorded. Meanwhile, Blood cell counts, lipid profiles, high-sensitivity C-reactive protein, and coagulation function-related indicators were measured. Least absolute shrinkage and selection operator (LASSO) regression analysis was utilized to build a composite indicator model based on the blood risk factors. Results: (1) CCE patients had significantly increased neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), and D-dimer levels as compared with patients in the NVAF group, and these three indicators can distinguish CCE patients from ones in the NVAF group with an area under the curve (AUC) value of over 0.750, respectively. (2) Using the LASSO model, a composite indicator, i.e., the risk score, was determined based on PLR and D-dimer and displayed differential power for distinguishing CCE patients from NVAF patients with an AUC value of over 0.934. (3) The risk score was positively correlated with the National Institutes of Health Stroke Scale and CHADS2 scores in CCE patients. (4) There was a significant association between the change value of the risk score and the recurrence time of stroke in initial CCE patients. Conclusions: The PLR and D-dimer represent an aggravated process of inflammation and thrombosis in the occurrence of CCE after NVAF. The combination of these two risk factors can contribute to identifying the risk of CCE for patients with NVAF with an accuracy of 93.4%, and the greater in change of composite indicator, the shorter in the recurrence of CCE for NVAF patients.

Trimethylamine N-oxide predicts stroke severity in diabetic patients with acute ischaemic stroke and is related to glycemic variability.

BACKGROUND AND PURPOSE: The present study analyzed the relationship between circulating trimethylamine N-oxide (TMAO) levels and stroke severity in diabetic patients with acute ischaemic stroke. A further aim was to investigate whether higher TMAO levels were associated with platelet aggregation and glycemic variability. METHODS: This was a cross-sectional analysis of 108 patients with type 2 diabetes mellitus (DM) undergoing acute ischaemic stroke and 60 healthy controls. Fasting plasma TMAO was measured using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. RESULTS: Plasma TMAO levels of patients with acute ischaemic stroke were significantly higher than those of healthy controls. Amongst stroke patients, 50 were defined as undergoing mild stroke, and their plasma TMAO levels were lower compared to those with moderate to severe stroke. Platelet aggregation and mean amplitude of glycemic excursions were both correlated with plasma TMAO levels and these relationships remained significant in multiple linear regression analyses. Moreover, in streptozotocin-induced diabetic rats fed a diet enriched with choline to increase TMAO synthesis, platelet aggregation was significantly increased in the DM + choline and fluctuating DM (FDM) + choline groups compared to the control group. This increase was abolished in rats receiving oral antibiotics, which markedly reduced plasma TMAO levels. Importantly, compared with the DM + choline group, the FDM + choline group displayed significantly elevated TMAO levels and higher platelet aggregation. CONCLUSIONS: Our results demonstrated that higher plasma TMAO levels were associated with stroke severity and suggested a novel link between plasma TMAO levels and glycemic variability in diabetic patients with acute ischaemic stroke.

The acute-to-chronic glycemic ratio correlates with the severity of illness at admission in patients with diabetes experiencing acute ischemic stroke.

Acute hyperglycemia is a powerful indicator of the severity of acute ischemic stroke (AIS); however, the relationship between these two factors is not very clear in patients with diabetes. We aimed to retrospectively evaluate data from 335 consecutive patients who experienced AIS from November 2015 to November 2016 to investigate whether a comprehensive assessment of blood glucose levels is a more valuable indicator of the severity of AIS or the presence of acute hyperglycemia in patients with diabetes. We collected demographic data, clinical manifestation information, clinical scores, and laboratory data [including fasting blood glucose and glycated hemoglobin (HbA1c) levels]. We estimated prehospital mean blood glucose concentrations using the following formula [1.59 * HbA1c (%) - 2.59] to calculate the "Acute-to-Chronic Glycemic Ratio" (AC ratio). The AC ratio differed significantly among patients grouped according to the National Institutes of Health Stroke Scale/Score (NIHSS) at admission (admission NIHSS) (p = 0.006). Univariate regression analysis revealed a correlation between the AC ratio and admission NIHSS [standardized ß-coefficient (Std. B) = 0.164, p = 0.004]. The adjusted linear regression analysis revealed a correlation between both HbA1c (Std. B = 0.368, p = 0.038) and the AC ratio (Std. B = 0.262, p = 0.022) and admission NIHSS. The AC ratio (Std. B = 0.161, p = 0.012) was related to admission NIHSS in the stepwise variable selection. For an admission NIHHS > 4, the AC ratio (Std. B = 0.186, p = 0.047) was related to admission NIHSS in the stepwise variable selection. The AC ratio (Std. B = 1.163, p = 0.006 and Std. B = 0.565, p = 0.021, respectively) were related to admission NIHSS in both large-artery atherosclerosis (LAA) and small-vessel occlusion (SVO) subgroups. Thus, the AC ratio is related to admission NIHSS in patients with diabetes who experienced AIS and may be a better indicator of severity than acute blood glucose levels.

Potential of brain age in identifying early cognitive impairment in subcortical small-vessel disease patients.

Background: Reliable and individualized biomarkers are crucial for identifying early cognitive impairment in subcortical small-vessel disease (SSVD) patients. Personalized brain age prediction can effectively reflect cognitive impairment. Thus, the present study aimed to investigate the association of brain age with cognitive function in SSVD patients and assess the potential value of brain age in clinical assessment of SSVD. Materials and methods: A prediction model for brain age using the relevance vector regression algorithm was developed using 35 healthy controls. Subsequently, the prediction model was tested using 51 SSVD patients [24 subjective cognitive impairment (SCI) patients and 27 mild cognitive impairment (MCI) patients] to identify brain age-related imaging features. A support vector machine (SVM)-based classification model was constructed to differentiate MCI from SCI patients. The neurobiological basis of brain age-related imaging features was also investigated based on cognitive assessments and oxidative stress biomarkers. Results: The gray matter volume (GMV) imaging features accurately predicted brain age in individual patients with SSVD (R 2 = 0.535, p < 0.001). The GMV features were primarily distributed across the subcortical system (e.g., thalamus) and dorsal attention network. SSVD patients with age acceleration showed significantly poorer Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA) scores. The classification model based on GMV features could accurately distinguish MCI patients from SCI patients (area under the curve = 0.883). The classification outputs of the classification model exhibited significant associations with MoCA scores, Trail Making Tests A and B scores, Stroop Color and Word Test C scores, information processing speed total scores, and plasma levels of total antioxidant capacity in SSVD patients. Conclusion: Brain age can be accurately quantified using GMV imaging data and shows potential clinical value for identifying early cognitive impairment in SSVD patients.

Blocking the EGFR/p38/NF-κB signaling pathway alleviates disruption of BSCB and subsequent inflammation after spinal cord injury.

Epidermal growth factor receptor (EGFR) activation is involved in blood spinal cord barrier (BSCB) disruption and secondary injury after spinal cord injury (SCI). However, the underlying mechanisms of EGFR activation mediating BSCB disruption and secondary injury after SCI remain unclear. An in vitro model of oxygen and glucose deprivation/reoxygenation (OGD/R) induced BSCB damage and in vivo rat SCI model were employed to define the role of EGFR/p38/NF-κB signal pathway activation and its induced inflammatory injury in main cellular components of BSCB. Genetic regulation (lentivirus delivered shRNA and overexpression system) or chemical intervention (agonist or inhibitor) were applied to activate or inactivate EGFR and p38 in astrocytes and microvascular endothelial cells (MEC) under which conditions, the expression of pro-inflammatory factors (TNF-α, iNOS, COX-2, and IL-1ß), tight junction (TJ) protein (ZO-1 and occludin), nuclear translocation of NF-κB and permeability of BSCB were analyzed. The pEGFR was increased in astrocytes and MEC which induced the activation of EGFR and p38 and NF-κB nuclear translocation. The activation of EGFR and p38 increased the TNF-α, iNOS, COX-2, and IL-1ß responsible for the inflammatory injury and reduced the ZO-1 and occludin which caused BSCB disruption. While EGFR or p38 inactivation inhibited NF-κB nuclear translocation, and markedly attenuated the production of pro-inflammatory factors and the loss of TJ protein. This study suggests that the EGFR activation in main cellular components of BSCB after SCI mediates BSCB disruption and secondary inflammatory injury via the EGFR/p38/NF-κB pathway.

Fluid-Attenuated Inversion Recovery Vascular Hyperintensity as a Potential Predictor for the Prognosis of Acute Stroke Patients After Intravenous Thrombolysis.

BACKGROUND: Fluid-attenuated inversion recovery vascular hyperintensity (FVH) can reflect the collateral status, which may be a valuable indicator to predict the functional outcome of acute stroke (AS) patients. METHODS: A total of 190 AS patients with large vessel occlusion (LVO) were retrospectively investigated. All patients completed a 6-month follow-up and their modified Rankin Scale (mRS) scores were recorded at 1, 3, and 6 months after intravenous thrombolysis (IVT). Based on their mRS at 3 months, patients were divided into two groups: poor prognosis (131 patients; 68.9% of all subjects) and favorable prognosis (59 patients; 31.1% of all subjects). The death records of 28 patients were also analyzed in the poor prognosis group. RESULTS: (1) Univariate and multivariate analyses showed that the higher National Institutes of Health Stroke Scale (NIHSS) score at admission, higher fasting blood glucose, and lower FVH score were independent risk factors to predict the poor prognosis of IVT. (2) Survival analysis indicated that FVH score was the only baseline factor to predict the 6-month survival after IVT. (3) Baseline FVH score had great prediction performance for the prognosis of IVT (area under the curve = 0.853). (4) Baseline FVH score were negatively correlated with the NIHSS score at discharge and mRS score at 1, 3, and 6 months. CONCLUSION: Among various baseline clinical factors, only the FVH score might have implications for 3-month outcome and 6-month survival of AS patients after IVT. Baseline FVH score showed great potential to predict the prognosis of the AS patients.

Ningdong Granule Upregulates the Striatal DA Transporter and Attenuates Stereotyped Behavior of Tourette Syndrome in Rats.

This study aimed to evaluate the possible mechanism of Ningdong granule (NDG) for the treatment of Tourette syndrome (TS). The rats with stereotyped behavior were established by microinjection with TS patients' sera; then, the model rats were divided into NDG and haloperidol (Hal) group, and the nonmedication model rats were regarded as treatment control (TS group). The stereotyped behavior of the rats was recorded, the level of dopamine (DA) in striatum, and the content of homovanillic acid (HVA) in sera were tested, and dopamine transporter (DAT) expression was measured in the study. The experimental results showed that NDG effectively inhibited the stereotyped behavior (P < 0.01), decreased the levels of DA in the striatum (P < 0.05), increased the content of sera HVA (P < 0.01), and enhanced the protein and mRNA expression of DAT in the striatum (P < 0.01). Additionally, the results also revealed Hal could improve the stereotyped behavior as well but had no remarkable influence on DAT expression and DA metabolism. In conclusion, NDG attenuates stereotyped behavior, and its mechanism of action might be associated with the upregulation of DAT expression to regulate DA metabolism in the brain.

Long-term self-renewal of naïve neural stem cells in a defined condition.

During embryonic development, neural stem cells (NSCs) emerge as early as the neural plate stage and give rise to the nervous system. Early-stage NSCs express Sry-related-HMG box-1 (Sox1) and are biased towards neuronal differentiation. However, long-term maintenance of early-stage NSCs in vitro remains a challenge. Here, we report development of a defined culture condition for the long-term maintenance of Sox1-positive early-stage mouse NSCs. The proliferative ability of these Sox1-positive NSCs was confirmed by clonal propagation. Compared to the NSCs cultured using the traditional culture condition, the long-term self-renewing Sox1-positive NSCs efficiently differentiate into neurons and exhibit an identity representative of the anterior and midbrain regions. These early-stage Sox1-positive NSCs could also be switched to late-stage NSCs by being cultured with bFGF/EGF, which can then differentiate into astrocytes and oligodendrocytes. The long-term self-renewing Sox1-positive NSCs were defined as naïve NSCs, based on their high neuronal differentiation capacity and anterior regional identity. This culture condition provides a robust platform for further dissection of the NSC self-renewal mechanism and promotes potential applications of NSCs for cell-based therapy on nervous system disorders.

The microenvironment following oxygen glucose deprivation/re-oxygenation-induced BSCB damage in vitro.

OBJECTIVE: To characterize the microenvironment following blood-spinal cord barrier (BSCB) damage and to evaluate the role of BSCB disruption in secondary damage of spinal cord injury (SCI). METHODS: A model of BSCB damage was established by co-culture of primary microvascular endothelial cells and glial cells obtained from rat spinal cord tissue followed by oxygen glucose deprivation/re-oxygenation (OGD/R). Permeability was evaluated by measuring the transendothelial electrical resistance (TEER) and the leakage test of Fluorescein isothiocyanate-dextran (FITC-dextran). The expression of tight junction (TJ) proteins (occludin and zonula occludens-1 (ZO-1) were evaluated by Western blot and immunofluorescence microscopy. Proinflammatory factors (TNF-α, iNOS, COX-2 and IL-1ß), leukocyte chemotactic factors (MIP-1α, MIP-1ß) and leukocyte adhesion factors (ICAM-1, VCAM-1) were detected in the culture medium under different conditions by enzyme-linked immuno sorbent assay (ELISA). RESULTS: The model of BSCB damage induced by OGD/R was successfully constructed. The maximum BSCB permeability occurred 6-12 hours but not within the first 3 h after OGD/R-induced damage. Likewise, the most significant period of TJ protein loss was also detected 6-12 hours after induction. During the hyper-acute period (3 h) following OGD/R-induced damage of BSCB, leukocyte chemotactic factors and leukocyte adhesion factors were significantly increased in the BSCB model. Pro-inflammation factors (TNF-α, IL-1ß, iNOS, COX-2), leukocyte chemotactic factors (MIP-1α, MIP-1ß) and leukocyte adhesion factors (ICAM-1, VCAM-1) were also sharply produced during the acute period (3-6 hours) and maintained plateau levels 6-12 hours following OGD/R-induced damage, which overlapped with the period of BSCB permeability maximum. A negative linear correlation was observed between the abundance of proinflammatory factors and the expression of TJ proteins (ZO-1 and occludin) and transepithelial electrical resistance (TEER), and a positive linear correlation was found with transendothelial FITC-dextran. CONCLUSIONS: Secondary damage continues after primary BSCB damage induced by OGD/R, exhibiting close ties with inflammation injury.

The initial glycemic variability is associated with early neurological deterioration in diabetic patients with acute ischemic stroke.

The association between glycemic variability and early neurological deterioration (END) in acute ischemic stroke remains unclear. This study attempted to explore whether initial glycemic variability increases END in diabetic patients with acute ischemic stroke. We enrolled type 2 diabetic patients undergoing acute ischemic stroke from November 2015 to November 2016. A total of 336 patients within 72 h from stroke onset were included. The serum glucose levels were checked four times per day during the initial 3 hospital days. The standard deviation of blood glucose (SDBG) values and the mean amplitude of glycemic excursions (MAGE) were calculated for glycemic variability. END was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) ≥ 2 points between hospital days 0 and 5. The frequencies of END and HbA1c were significantly different in subjects grouped according to tertiles of MAGE (9.09, 12.07 and 50.00%, p < 0.001 for END; 7.36 ± 1.91, 7.83 ± 1.93 and 8.56 ± 1.79, p < 0.001 for HbA1c). Compared to patients without END, patients with END had significantly higher HbA1c levels (8.30 ± 1.92 vs 7.80 ± 1.93, p = 0.043), increased SDBG (3.42 ± 1.14 vs 2.60 ± 0.96, p < 0.001), and increased MAGE (6.46 ± 2.09 vs 4.59 ± 1.91, p < 0.001). In a multivariable logistic regression, stroke etiology (OR 0.675; 95% CI 0.485-0.940, p = 0.020), baseline NIHSS (OR 1.086; 95% CI 1.004-1.175, p = 0.040), and MAGE (OR 1.479; 95% CI 1.162-1.882, p = 0.001) were significantly associated with END. Initial glycemic variability is associated with END in diabetic patients with acute ischemic stroke.

Modulation of GSK-3ß/ß-Catenin Signaling Contributes to Learning and Memory Impairment in a Rat Model of Depression.

Background: It is widely accepted that cognitive processes, such as learning and memory, are affected in depression, but the molecular mechanisms underlying the interactions of these 2 disorders are not clearly understood. Recently, glycogen synthase kinase-3 beta (GSK-3ß)/ß-catenin signaling was shown to play an important role in the regulation of learning and memory. Methods: The present study used a rat model of depression, chronic unpredictable stress, to determine whether hippocampal GSK-3ß/ß-catenin signaling was involved in learning and memory alterations. Results: Our results demonstrated that chronic unpredictable stress had a dramatic influence on spatial cognitive performance in the Morris water maze task and reduced the phosphorylation of Ser9 of GSK-3ß as well as the total and nuclear levels of ß-catenin in the hippocampus. Inhibition of GSK3ß by SB216763 significantly ameliorated the cognitive deficits induced by chronic unpredictable stress, while overexpression of GSK3ß by AAV-mediated gene transfer significantly decreased cognitive performance in adult rats. In addition, chronic unpredictable stress exposure increased the expression of the canonical Wnt antagonist Dkk-1. Furthermore, chronic administration of corticosterone significantly increased Dkk-1 expression, decreased the phosphorylation of Ser9 of GSK-3ß, and resulted in the impairment of hippocampal learning and memory. Conclusions: Our results indicate that impairment of learning and memory in response to chronic unpredictable stress may be attributed to the dysfunction of GSK-3ß/ß-catenin signaling mediated by increased glucocorticoid signaling via Dkk-1.

Blood oxygen level-dependent signals via fMRI in the mood-regulating circuit using two animal models of depression are reversed by chronic escitalopram treatment.

BACKGROUND: People exposed to stressful experience are at increased risk of the development of depression. A number of functional imaging studies have found disturbances in the mood-regulating circuit of the stress-exposed depressed patients, although few animal imaging studies have been undertaken addressing the brain functional changes of depression. METHODS: Two rat models of depression: maternal separation (MS) and chronic unpredictable mild stress (CUMS), imitating early life stress and adult stress respectively, were administered with escitalopram. The differences in functional brain changes were determined by blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). RESULTS: Increased BOLD activation was observed in some brain regions of MS and CUMS animals, such as the bilateral hypothalamus, limbic system, hippocampus and frontal lobe, which were parts of mood-regulating circuit. Furthermore, the MS- and CUMS-induced increases in BOLD activation were partially attenuated by chronic escitalopram treatment. CONCLUSIONS: These results suggested hyperactivation of mood-regulating circuit at baseline in the depressed animals exposed to stressful experience, and escitalopram can at least partially reverse these effects.

The Role of the Two-Pore Domain Potassium Channel TREK-1 in the Therapeutic Effects of Escitalopram in a Rat Model of Poststroke Depression.

AIM: Poststroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. TREK-1, a two-pore-domain potassium channel, has been implicated in the pathogenesis of stroke and depression. The aim of this study was to investigate whether TREK-1 plays a role in the therapeutic effects of the selective serotonin reuptake inhibitor (SSRI) escitalopram in a rat PSD model. METHODS: The whole-cell patch-clamp technique was performed to assess the effect of escitalopram on recombinant TREK-1 currents in HEK293 cells. The expression of TREK-1 mRNA and protein was measured in the hippocampus and prefrontal cortex (PFC), and neural stem cell (NSC) proliferation was detected in the hippocampal dentate gyrus (DG) in PSD rats after 3 weeks of escitalopram administration. RESULTS: Escitalopram reversibly inhibited TREK-1 currents in a concentration-dependent manner. Chronic treatment with escitalopram significantly reversed the reductions in weight gain, locomotor activity, and sucrose preference in PSD rats. The expressions of TREK-1 mRNA and protein were significantly increased in hippocampal CA1, CA3, DG, and PFC in PSD rats, with the exception of TREK-1 mRNA in hippocampal CA1. NSC proliferation was significantly decreased in hippocampal DG of PSD rats. Escitalopram significantly reversed the regional increases of TREK-1 expression and the reduction of hippocampal NSC proliferation in PSD rats. CONCLUSION: TREK-1 plays an important role in the therapeutic effects of the SSRI escitalopram in PSD model, making TREK-1 an attractive candidate molecule for further understanding the pathophysiology and treatment of PSD.

Fluoxetine regulates neurogenesis in vitro through modulation of GSK-3ß/ß-catenin signaling.

BACKGROUND: It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3ß)/ß-catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. METHODS: The aim of this study was to determine whether GSK-3ß/ß-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine's regulation of GSK-3ß/ß-catenin signaling pathway were also examined. RESULTS: Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3ß and increasing the level of nuclear ß-catenin. The overexpression of a stabilized ß-catenin protein (ΔN89 ß-catenin) significantly increased NPC proliferation, while inhibition of ß-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced up-regulation of both phosphorylation of Ser9 on GSK-3ß and nuclear ß-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635. CONCLUSIONS: The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3ß/ß-catenin signaling pathway that links postsynaptic 5-HT1A receptor activation.

Induced neural stem cells generated from rat fibroblasts.

The generation of induced tissue-specific stem cells has been hampered by the lack of well-established methods for the maintenance of pure tissue-specific stem cells like the ones we have for embryonic stem (ES) cell cultures. Using a cocktail of cytokines and small molecules, we demonstrate that primitive neural stem (NS) cells derived from mouse ES cells and rat embryos can be maintained. Furthermore, using the same set of cytokines and small molecules, we show that induced NS (iNS) cells can be generated from rat fibroblasts by forced expression of the transcriptional factors Oct4, Sox2 and c-Myc. The generation and long-term maintenance of iNS cells could have wide and momentous implications.

Learning and memory alterations are associated with hippocampal N-acetylaspartate in a rat model of depression as measured by 1H-MRS.

It is generally accepted that cognitive processes, such as learning and memory, are affected in depression. The present study used a rat model of depression, chronic unpredictable mild stress (CUMS), to determine whether hippocampal volume and neurochemical changes were involved in learning and memory alterations. A further aim was to determine whether these effects could be ameliorated by escitalopram treatment, as assessed with the non-invasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Our results demonstrated that CUMS had a dramatic influence on spatial cognitive performance in the Morris water maze task, and CUMS reduced the concentration of neuronal marker N-acetylaspartate (NAA) in the hippocampus. These effects could be significantly reversed by repeated administration of escitalopram. However, neither chronic stress nor escitalopram treatment influenced hippocampal volume. Of note, the learning and memory alterations of the rats were associated with right hippocampal NAA concentration. Our results indicate that in depression, NAA may be a more sensitive measure of cognitive function than hippocampal volume.

Fluoxetine attenuates the inhibitory effect of glucocorticoid hormones on neurogenesis in vitro via a two-pore domain potassium channel, TREK-1.

RATIONALE: Sustained stress and elevated glucocorticoid reduces neurogenesis, whereas chronic treatment with antidepressants increases neurogenesis and blocks the effects of stress. Recently, TREK-1, a two-pore domain (K(2)p) potassium channel, has been shown to be involved in the mechanisms of major depression. OBJECTIVES: This study aimed to investigate whether TREK-1 is involved in the alteration of neurogenesis according to glucocorticoids and antidepressants. RESULTS: The present study addressed the expression of TREK-1 in neural stem cells (NSCs) and found TREK-1 was only associated with NSC proliferation. Bupivacaine and curcumin, two strong TREK-1 channel inhibitors, significantly increased embryonic NSC viability and proliferation while transfection of hTREK-1 decreased cell proliferation in embryonic NSCs. Dexamethasone, a glucocorticoid hormone receptor agonist, upregulated both protein and mRNA levels of TREK-1 leading to decreased NSC proliferation which could be reversed by bupivacaine. Fluoxetine, a serotonin reuptake inhibitor antidepressant that has been previously found to inhibit TREK-1 channels, robustly, could attenuate the upregulation of TREK-1 expression and the inhibition of NSC proliferation induced by dexamethasone. CONCLUSIONS: Taken together, these data suggest that TREK-1 is associated with NSC proliferation and probably is a modulator of the effect that fluoxetine attenuates the inhibitory neurogenesis induced by glucocorticoid hormones.