Current Neurovascular Research - Volume 17, Issue 3, 2020

Background: Depression and anxiety after stroke are common conditions that are likely to be neglected. Abnormal red blood cell (RBC) indices may be associated with neuropsychiatric disorders. However, the association of RBC indices with post-stroke depression (PSD) and poststroke anxiety (PSA) has not been sufficiently investigated. Methods: We aimed to investigate the trajectory of post-stroke depression and anxiety in our follow- up stroke clinic at 1, 3, and 6 months, and the association of RBC indices with these. One hundred and sixty-two patients with a new diagnosis of ischemic stroke were followed up at 1, 3, and 6 months, and underwent Patient Health Questionnaire-9 (PHQ-9) and the general anxiety disorder 7-item (GAD-7) questionnaire for evaluation of depression and anxiety, respectively. First, we used Kaplan-Meier analysis to investigate the accumulated incidences of post-stroke depression and post-stroke anxiety. Next, to explore the association of RBC indices with psychiatric disorders after an ischemic stroke attack, we adjusted for demographic and vascular risk factors using multivariate Cox regression analysis. Results: Of the 162 patients with new-onset of ischemic stroke, we found the accumulated incidence rates of PSD (1.2%, 17.9%, and 35.8%) and PSA (1.2%, 13.6%, and 15.4%) at 1, 3, and 6 months, respectively. The incident PSD and PSA increased 3 months after a stroke attack. Multivariate Cox regression analysis indicated independent positive associations between PSD risk and higher mean corpuscular volume (MCV) (OR=1.42, 95% CI=1.16-1.76), older age (OR=2.63, 95% CI=1.16-5.93), and a negative relationship between male sex (OR=0.95, 95% CI=0.91-0.99) and PSA. Conclusion: The risks of PSD and PSA increased substantially 3 months beyond stroke onset. Of the RBC indices, higher MCV, showed an independent positive association with PSD.

Background: Atrial fibrillation (AF) is the most common cardiac rhythm disorder associated with stroke. Increased risk of stroke is the same regardless of whether the AF is permanent or paroxysmal. However, detecting paroxysmal AF is challenging and resource intensive. We aimed to develop a predictive model for AF in patients with acute ischemic stroke, which could improve the detection rate of paroxysmal AF. Methods: We analyzed 10,034 adult patients with acute ischemic stroke. Differences in clinical characteristics between the patients with and without AF were analyzed in order to develop a predictive model of AF. The associated factors for AF were analyzed using multivariate logistic regression and classification and regression tree (CART) analyses. We used another dataset, which enrolled 860 acute ischemic stroke patients without AF at baseline, to test whether the developed model could improve the detection rate of paroxysmal AF. Among the study population, 1,658 patients (16.5%) had AF. Results: Multivariate logistic regression revealed that sex, age, body weight, hypertension, diabetes mellitus, hyperlipidemia, pulse rate at admission, respiratory rate at admission, systolic blood pressure at admission, diastolic blood pressure at admission, National Institute of Health Stroke Scale (NIHSS) score at admission, total cholesterol level, triglyceride level, aspartate transaminase level, and sodium level were major factors associated with AF. CART analysis identified NIHSS score at admission, age, triglyceride level, and aspartate transaminase level as important factors for AF to classify the patients into subgroups. Conclusion: When selecting the high-risk group of patients (with an NIHSS score >12 and age >64.5 years, or with an NIHSS score ≤12, age >71.5 years, and triglyceride level ≤61.5 mg/dL) according to the CART model, the detection rate of paroxysmal AF was approximately double in the acute ischemic stroke patients without AF at baseline.

Background: Cardiopulmonary bypass (CPB) caused postoperative cognitive dysfunction (POCD) was characterized by hippocampus apoptosis, which seriously limited the therapeutic efficacy and utilization of CPB in clinic. Recent data indicated that sevoflurane anesthesia might alleviate CPB-induced POCD, however, the underlying mechanisms are still unclear. Methods: In the present study, the in vivo CPB-POCD models were established by using aged Sprague-Dawley (SD) male rats and the in vitro hypoxia/reoxygenation (H/R) models were inducted by using the primary hippocampus neuron (PHN) cells. Results: The results showed that CPB impaired cognitive functions and induced hippocampus apoptosis in rat models, which were alleviated by pre-treating rats with low-dose sevoflurane. In addition, the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signal pathway was inactivated in the hippocampus tissues of CPB-POCD rats, which were rescued by low-dose sevoflurane treatment. Of note, the PI3K/AKT inhibitor (LY294002) abrogated the protective effects of low-dose sevoflurane on CPB-POCD rats. Consistently, the in vitro results showed that H/R treatment induced cell apoptosis and inhibited cell viability in PHN cells, which were attenuated by low-dose sevoflurane. Similarly, LY294002 abrogated the inhibiting effects of low-dose sevoflurane on H/R-induced PHN cell death. Conclusion: Taken together, low-dose sevoflurane attenuated CPB-induced POCD by inhibiting hippocampus apoptosis through activating PI3K/AKT signal pathway.

Objective: It is reported that miR-26a-5p could regulate neuronal development, but its underlying mechanisms in Alzheimer’s disease (AD) progression is unclear. Methods: APP (swe)/PS1 (ΔE9) transgenic mice served as AD mice. Morris water maze test was used to measure the spatial learning and memory ability of mice. The expressions of miR-26a-5p, DYRK1A, phosphorylated-Tau, Aβ40, and Aβ42 were detected. The relationship between miR- 26a-5p and DYRK1A was explored using dual luciferase reporter assay. The effects of miR-26a- 5p on AD mice was determined. Results: AD mice walked a lot of wrong ways to find the platform area and the latency time to reach the platform was longer. There was low expression of MiR-26a-5p in AD mice. Overexpression of miR-26a-5p inhibited Tau phosphorylation and Aβ accumulation. MiR-26a-5p negatively regulated DYRK1A via targeting its 3’UTR. In vivo, increased miR-26a-5p down-regulated Aβ40, Aβ42, p-APP and p-Tau levels in AD mice through decreasing DYRK1A. Meanwhile, the swimming path and the latency time, to reach the platform, was shorten after enhancing miR-26a-5p expression. Conclusion: Overexpression of miR-26a-5p could repress Tau phosphorylation and Aβ accumulation via down-regulating DYRK1A level in AD mice.

Background: Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. Objective: The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Methods: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Results: Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. Conclusion: This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.

Objective: Ischemia-reperfusion (I/R) injury is a pathological feature of ischemic stroke. This study investigated the regulatory role of miR-485-5p in I/R injury. Methods: SH-SY5Y cells were induced with oxygen and glucose deprivation/reoxygenation (OGD/R) to mimic I/R injury in vitro. Cells were transfected with designated constructs (miR-485- 5p mimics, miR-485-5p inhibitor, lentiviral vectors overexpressing Rac1 or their corresponding controls). Cell viability was evaluated using the MTT assay. The concentrations of lactate dehydrogenase, malondialdehyde, and reactive oxygen species were detected to indicate the degree of oxidative stress. Flow cytometry and caspase-3 activity assay were used for apoptosis assessment. Dual-luciferase reporter assay was performed to confirm that Rac family small GTPase 1 (Rac1) was a downstream gene of miR-485-5p. Results: OGD/R resulted in decreased cell viability, elevated oxidative stress, increased apoptosis, and downregulated miR-485-5p expression in SH-SY5Y cells. MiR-485-5p upregulation alleviated I/R injury, evidenced by improved cell viability, decreased oxidative markers, and reduced apoptotic rate. OGD/R increased the levels of Rac1 and neurogenic locus notch homolog protein 2 (Notch2) signaling-related proteins in cells with normal miR-485-5p expression, whereas miR- 485-5p overexpression successfully suppressed OGD/R-induced upregulation of these proteins. Furthermore, the delivery of vectors overexpressing Rac1 in miR-485-5p mimics-transfected cells reversed the protective effect of miR-485-5p in cells with OGD/R-induced injury. Conclusion: This study showed that miR-485-5p protected cells following I/R injury via targeting Rac1/Notch2 signaling suggest that targeted upregulation of miR-485-5p might be a promising therapeutic option for the protection against I/R injury.

Background: Paclitaxel treatment is a major cause of chemotherapy-induced peripheral neuropathy. The sodium channel Nav1.7 plays a critical role in pain perception. However, whether Nav1.7 in the dorsal root ganglion (DRG) is involved in paclitaxel-induced peripheral neuropathy remains unclear. Thus, our study aimed to evaluate whether Nav1.7 participates in the pathogenesis of paclitaxel-induced neuropathy. Methods: Paclitaxel-induced peripheral neuropathy was generated by intraperitoneal administration of paclitaxel on four alternate days. Results: The results showed that DRG mRNA and protein expression levels of Nav1.7 were upregulated between days 7 and 21 after the administration of paclitaxel. Besides, paclitaxel upregulated extracellular signal-regulated kinase (ERK1/2) phosphorylation in DRG. Intrathecal injection of U0126 (a MEK inhibitor) blocking ERK1/2 phosphorylation blunted up-regulation of Nav1.7 in the DRG and correspondingly attenuated hyperalgesia. Conclusion: These results indicated that the sodium channel Nav1.7 in the DRG exerted an important function in paclitaxel-induced neuropathy, which was associated with ERK phosphorylation in neurons.

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

Background: Cerebral ischemia causes a strong inflammatory response. Neumentix is a dietary supplement containing 14.9% rosmarinic acid and 29.9% total phenolic content, which has been proved to be beneficial against inflammatory response. Therefore, Neumentix’s effect on anti-inflammatory and blood brain barrier (BBB) disruption in transient middle cerebral artery occlusion (tMCAO) model mice is investigated in this study. Methods: After the pretreatment of vehicle or Neumentix 134 mg/kg/d, intraperitoneal injection (i.p.) (containing rosmarinic acid 20 mg/kg/d) for 14 days, mice were subjected to tMCAO for 60 min and kept receiving vehicle or Neumentix daily 5 days afterward. Results: Neumentix treatment ameliorated neurobehavioral impairment in the corner test (5d after tMCAO, **P<0.01), reduced infarct volume (#P<0.05), suppressed expression of ionized calciumbinding adapter molecule-1 (Iba-1), tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) (###P<0.001), and improved the integrity of BBB (§P<0.05) at 5 days after tMCAO. Conclusion: The present study provided an evidence of Neumentix’s anti-inflammatory and neuroprotection effect against BBB disruption on experimental tMCAO model mice, suggesting that Neumentix could be a potential therapeutic agent for stroke.

Background: Neutrophil to lymphocyte ratio (NLR) on admission was reported to be a predictor of pneumonia after stroke. The aim of this study was to investigate the association between the temporal change of NLR and post-stroke infection and whether infection modified the effect of NLR on the outcome. Methods: We enrolled patients with acute ischemic stroke within 24 h after onset. The blood was collected on admission, day 1, 3, 7 after admission to detect white blood cells (WBC), neutrophils, and lymphocytes. Primary outcomes included pneumonia, urinary tract infection (UTI), other infection, and the secondary outcome was 3-month death. Results: Of 798 stroke patients, 299 (37.66%) developed infection with 240 (30.23%) pneumonia, 78 (9.82%) UTI, and 9 (1.13%) other infection. The median time of infection occurrence was 48 h (interquartile range 27-74 h) after onset. NLR reached to the peak at 36 h. For all outcomes, NLR at 36 h after stroke had the highest predictive value than WBC, neutrophil, lymphocyte. NLR was independently associated with the presence of any infection (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.05-1.17), pneumonia (OR 1.12, 95%CI 1.05-1.19), but not UTI (OR 0.95, 95%CI 0.89-1.01). Adding infection or the interaction term did not substantially change the OR of NLR predicting 3-month death (OR 1.09, 95%CI 1.01, 1.17). Conclusion: Increased NLR around 36 h after stroke was a predictor of infection in patients with acute ischemic stroke. The increased NLR value was associated with a higher risk of 3-month death, which was independent of poststroke infection.

Background: Hemiplegia is a common symptom after acute cerebral infarction. Objective: This study aimed to explore the influence factors of gait performance and investigate whether donepezil could improve gait performance in patients with an acute cerebral infarction. Methods: A total of 107 patients who experienced unilateral paresis after an acute cerebral infarction incident were enrolled in this prospectively observational study. Participants underwent a 3- month assessment. At the study's conclusion, patients were divided into 2 groups-those who received donepezil daily (observation Group) and those who did not (Control Group). Results: There was a significant difference (t=3.269, P=0.001) of Wisconsin Gait Scale (WGS) score between single site infarction (27.11±6.65) and multiple sites infarction (31.54±6.42). For gender, smoking, drinking, hypertension, hyperlipidemia and diabetes, there was no difference in WGS scores between subgroups (P>0.05), respectively. The patient's admission National Institute of Health Stroke Scale(NIHSS) score had a strongly positive correlation with WGS score (r=0.850, P<0.001). Besides, age (r=0.218, P=0.024), glycosylated hemoglobin (r=0.274, P=0.004), MMSE (r=-0.261, P=0.007) and Montreal Cognitive Assessment (MoCA) (r=-0.272, P=0.005) had a weak correlation with WGS scores. Multivariate analysis showed age (95% CI: 0.042~0.188, P=0.002), admission NIHSS score (95% CI: 2.405~3.137, P<0.001) and multiple sites infarction (95% CI: 0.044~2.983, P=0.044) were independent risk factors of WGS scores. WGS scores of both observation and control groups gradually decreased after admission (P<0.001). At 3 months after admission, WGS score of the observation group was significantly lower than the control group (t=2.468, P=0.015). There were no significant differences between observation and control group at admission and 1 month after admission (P>0.05) and WGS scores of both single site and multiple sites infarction gradually decreased at one month and three months after admission (P<0.001), while there was no significant difference between two groups (P>0.05). Conclusion: Admission NIHSS score, age and multiple sites infarction were independent risk factors of WGS score. Donepezil could improve gait performance in patients with acute cerebral infarction.

Background: The pathogenic mechanisms involved in a disastrous scenario, following epidural steroid injections (ESI), remain unclarified. Intra-arterial injection of steroids with needlepenetrating vascular injury would be the culprit, as particulate medicine elicits a brain or spinal cord stroke-like attack. Methods: On the other hand, the limited experimental approaches simulating an accidental steroid intra-arterial injection for ESI conflicted in their results: hemorrhage vs. ischemia. Results: This article dissects the potential pathogenic mechanisms at a neurovascular unit. Noticeably, a schematic representation provides an explanation of how emboli formed by particulate steroids elicit either hemorrhagic, or ischemic lesion. Conclusion: In addition, the development of a rat model with intravertebral artery steroid injection is a proposal to address the unmet need in evaluating steroids and vascular injury in ESI.

Memory retrieval is mediated by discharges of acetylcholine, glutamate, gammaaminobutyric acid, norepinephrine, and serotonin/5-hydroxytryptamine circuits. These projections and memory interact through engram circuits, neurobiological traces of memory. Increased excitability in engram circuits of the medial prefrontal cortex and hippocampus results in remote and recent memory retrievals, respectively. However, due to degenerated neurotransmitter projections, the excitability state of engram circuits is decreased in the patient with dementia; and thus, acquired- memory cannot be retrieved by natural cues. Here, we suggest that artificial neuropharmacological stimulations of the acquired-memory with an excitation potential higher than a natural cue can excite engram circuits in the medial prefrontal cortex, which results in the retrieval of lost memories in dementia. The neuropharmacological foundations of engram cell-mediated memory retrieval strategy in severe dementia, in line with this has also been explained. We particularly highlighted the close interactions between periaqueductal gray, locus coeruleus, raphe nuclei, and medial prefrontal cortex and basolateral amygdala as treatment targets for memory loss. Furthermore, the engram circuits projecting raphe nuclei, locus coeruleus, and pontomesencephalic tegmentum complex could be significant targets of memory editing and memory formation in the absence of experience, and a well-defined study of the neural events underlying the interaction of brain stem and memory will be relevant for such developments. We anticipate our perspective to be a starting point for more sophisticated in vivo models for neuropharmacological modulations of memory retrieval in Alzheimer’s dementia.

The prevalence of diabetes mellitus (DM) continues to increase throughout the world. In the United States (US) alone, approximately ten percent of the population is diagnosed with DM and another thirty-five percent of the population is considered to have prediabetes. Yet, current treatments for DM are limited and can fail to block the progression of multi-organ failure over time. Wnt1 inducible signaling pathway protein 1 (WISP1), also known as CCN4, is a matricellular protein that offers exceptional promise to address underlying disease progression and develop innovative therapies for DM. WISP1 holds an intricate relationship with other primary pathways of metabolism that include protein kinase B (Akt), mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and mammalian forkhead transcription factors (FoxOs). WISP1 is an exciting prospect to foster vascular as well as neuronal cellular protection and regeneration, control cellular senescence, block oxidative stress injury, and maintain glucose homeostasis. However, under some scenarios WISP1 can promote tumorigenesis, lead to obesity progression with adipocyte hyperplasia, foster fibrotic hepatic disease, and lead to dysregulated inflammation with the progression of DM. Given these considerations, it is imperative to further elucidate the complex relationship WISP1 holds with other vital metabolic pathways to successfully develop WISP1 as a clinically effective target for DM and metabolic disorders.

Multiple viral pathogens can pose a significant health risk to individuals. As a recent example, the β-coronavirus family virion, SARS-CoV-2, has quickly evolved as a pandemic leading to coronavirus disease 2019 (COVID-19) and has been declared by the World Health Organization as a Public Health Emergency of International Concern. To date, no definitive treatment or vaccine application exists for COVID-19. Although new investigations seek to repurpose existing antiviral treatments for COVID-19, innovative treatment strategies not normally considered to have antiviral capabilities may be critical to address this global concern. One such avenue that may prove to be exceedingly fruitful and offer exciting potential as new antiviral therapy involves the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), and AMP activated protein kinase (AMPK). Recent work has shown that mTOR pathways in conjunction with AMPK may offer valuable targets to control cell injury, oxidative stress, mitochondrial dysfunction, and the onset of hyperinflammation, a significant disability associated with COVID-19. Furthermore, pathways that can activate mTOR may be necessary for anti-hepatitis C activity, reduction of influenza A virus replication, and vital for type-1 interferon responses with influenza vaccination. Yet, important considerations for the development of safe and effective antiviral therapy with mTOR pathways exist. Under some conditions, mTOR can act as a double edge sword and participate in virion replication and virion release from cells. Future work with mTOR as a potential antiviral target is highly warranted and with a greater understanding of this novel pathway, new treatments against several viral pathogens may successfully emerge.

Dr. Xiufeng Ye and Dr. Guangfu Chen are both co-corresponding authors. Accordingly, please make the following two corrections to the paper: 1) Add * to the author Xiufeng Ye. 2) *Address correspondence to Dr. Chen guangfu, [email protected] or Dr. Xiufeng Ye, szrosexiu@ 126.com, Shenzhen Second People’s Hospital, 3002, Sungang West Road, Shenzhen 518035, China.