Short-term outcomes after selective shunt during carotid endarterectomy: A propensity score matching analysis / Resultados a corto plazo después de shunting selectivo durante la endarterectomía carotídea con anestesia regional: un análisis de propensity score-matching

Introduction and objectives: Carotid cross-clamping during carotid endarterectomy might lead to intraoperative neurologic deficits, increasing stroke/death risk. If deficits are detected, carotid shunting has been recommended to reduce the risk of stroke. However, shunting may sustain a specific chance of embolic events and subsequently incurring harm. Current evidence is still questionable regarding its clear benefit. The aim is to determine whether a policy of selective shunt impacts the complication rate following an endarterectomy. Material and methods: From January 2013 to May 2021, all patients undergoing carotid endarterectomy under regional anesthesia with intraoperative neurologic alteration were retrieved. Patients submitted to selective shunt were compared to a non-shunt group. A 1:1 propensity score matching (PSM) was performed. Differences between the groups and clinical outcomes were calculated, resorting to univariate analysis. Results: Ninety-eight patients were selected, from which 23 were operated on using a shunt. After PSM, 22 non-shunt patients were compared to 22 matched shunted patients. Concerning demographics and comorbidities, both groups were comparable to pre and post-PSM, except for chronic heart failure, which was more prevalent in shunted patients (26.1%, P=0.036) in pre-PSM analysis. Regarding 30-day stroke and score Clavien–Dindo≥2, no significant association was found (P=0.730, P=0.635 and P=0.942, P=0.472, correspondingly, for pre and post-PSM). Conclusions: In this cohort, resorting to shunting did not demonstrate an advantage regarding 30-day stroke or a Clavien–Dindo≥2 rates. Nevertheless, additional more extensive studies are mandatory to achieve precise results concerning the accurate utility of carotid shunting in this subset of patients under regional anesthesia.(AU)

Introducción y objetivos: El pinzamiento carotídeo durante la endarterectomía carotídea podría provocar déficits neurológicos intraoperatorios, lo que aumenta el riesgo de accidente cerebrovascular/muerte. Si se detectan déficits, se ha recomendado la derivación carotídea para reducir el riesgo de accidente cerebrovascular. Sin embargo, la derivación puede sostener una posibilidad específica de eventos embólicos y, posteriormente, provocar daños. La evidencia actual aún es cuestionable con respecto a su claro beneficio. El objetivo es determinar si una política de derivación selectiva afecta la tasa de complicaciones después de una endarterectomía. Material y métodos: Desde enero de 2013 hasta mayo de 2021 se recuperaron todos los pacientes sometidos a endarterectomía carotídea bajo anestesia regional con alteración neurológica intraoperatoria. Los pacientes sometidos a derivación selectiva se compararon con un grupo sin derivación. Se realizó una coincidencia de puntuación de propensión (PSM) 1:1. Se calcularon las diferencias entre los grupos y los resultados clínicos recurriendo al análisis univariado. Resultados: Se seleccionaron 98 pacientes, de los cuales 23 fueron intervenidos mediante derivación. Después de la PSM se compararon 22 pacientes sin derivación con 22 pacientes emparejados con derivación. Con respecto a la demografía y las comorbilidades, ambos grupos fueron comparables a los de antes y después de la PSM, excepto por la insuficiencia cardíaca crónica, que fue más prevalente en los pacientes con derivación (26,1%, p=0,036) en el análisis previo a la PSM. En cuanto al accidente cerebrovascular a los 30 días y la puntuación de Clavien-Dindo≥2, no se encontró asociación significativa (p=0,730, p=0,635 y p=0,942, p=0,472, correspondientemente, para pre y post-PSM). Conclusiones: En esta cohorte recurrir a la derivación no demostró una ventaja con respecto a las tasas de ictus a los 30 días o Clavien-Dindo≥2...(AU)

Enriched Environment Inhibits Neurotoxic Reactive Astrocytes via JAK2-STAT3 to Promote Glutamatergic Synaptogenesis and Cognitive Improvement in Chronic Cerebral Hypoperfusion Rats.

Chronic cerebral hypoperfusion (CCH) is a primary contributor to cognitive decline in the elderly. Enriched environment (EE) is proved to improve cognitive function. However, mechanisms involved remain unclear. The purpose of the study was exploring the mechanisms of EE in alleviating cognitive deficit in rats with CCH. To create a rat model of CCH, 2-vessel occlusion (2-VO) surgery was performed. All rats lived in standard or enriched environments for 4 weeks. Cognitive function was assessed using the novel object recognition test and Morris water maze test. The protein levels of glutamatergic synapses, neurotoxic reactive astrocytes, reactive microglia, and JAK2-STAT3 signaling pathway were measured using Western blot. The mRNA levels of synaptic regulatory factors, C1q, TNF-α, and IL-1α were identified using quantitative PCR. Immunofluorescence was used to detect glutamatergic synapses, neurotoxic reactive astrocytes, and reactive microglia, as well as the expression of p-STAT3 in astrocytes in the hippocampus. The results demonstrated that the EE mitigated cognitive impairment in rats with CCH and enhanced glutamatergic synaptogenesis. EE also inhibited the activation of neurotoxic reactive astrocytes. Moreover, EE downregulated microglial activation, levels of C1q, TNF-α and IL-1α and phosphorylation of JAK2 and STAT3. Our results suggest that inhibition of neurotoxic reactive astrocytes may be one of the mechanisms by which EE promotes glutamatergic synaptogenesis and improves cognitive function in rats with CCH. The downregulation of reactive microglia and JAK2-STAT3 signaling pathway may be involved in this process.

miR-30a-5p mediates ferroptosis of hippocampal neurons in chronic cerebral hypoperfusion-induced cognitive dysfunction by modulating the SIRT1/NRF2 pathway.

OBJECTIVE: Chronic cerebral hypoperfusion (CCH) is a common cause of brain dysfunction. As a microRNA (also known as miRNAs or miRs), miR-30a-5p participates in neuronal damage and relates to ferroptosis. We explored the in vivo and in vitro effects and functional mechanism of miR-30a-5p in CCH-triggered cognitive impairment through the silent information regulator 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. METHODS: After 1 month of CCH modeling through bilateral common carotid artery stenosis, mice were injected with 2µL antagomir (also known as anti-miRNAs) miR-30a-5p, with cognitive function evaluated by Morris water maze and novel object recognition tests. In vitro HT-22 cell oxygen glucose deprivation (OGD) model was established, followed by miR-30a-5p inhibitor and/or si-SIRT1 transfections, with Fe2+ concentration, malonaldehyde (MDA) and glutathione (GSH) contents, reactive oxygen species (ROS), miR-30a-5p and SIRT1 and glutathione peroxidase 4 (GPX4) protein levels, NRF2 nuclear translocation, and miR-30a-5p-SIRT1 targeting relationship assessed. RESULTS: CCH-induced mice showed obvious cognitive impairment, up-regulated miR-30a-5p, and down-regulated SIRT1. Ferroptosis occurred in hippocampal neurons, manifested by elevated Fe2+ concentration and ROS and MDA levels, mitochondrial atrophy, and diminished GSH content. Antagomir miR-30a-5p or miR-30a-5p inhibitor promoted SIRT1 expression and NRF2 nuclear translocation, increased GPX4, cell viability and GSH content, and reduced Fe2+ concentration and ROS and MDA levels. miR-30a-5p negatively regulated SIRT1. In vitro, miR-30a-5p knockout increased NRF2 nuclear translocation by up-regulating SIRT1, inhibiting OGD-induced ferroptosis in HT-22 cells. CONCLUSION: miR-30a-5p induces hippocampal neuronal ferroptosis and exacerbates post-CCH cognitive dysfunction by targeting SIRT1 and reducing NRF2 nuclear translocation.

Deciphering mitochondrial dysfunction: Pathophysiological mechanisms in vascular cognitive impairment.

Vascular cognitive impairment (VCI) encompasses a range of cognitive deficits arising from vascular pathology. The pathophysiological mechanisms underlying VCI remain incompletely understood; however, chronic cerebral hypoperfusion (CCH) is widely acknowledged as a principal pathological contributor. Mitochondria, crucial for cellular energy production and intracellular signaling, can lead to numerous neurological impairments when dysfunctional. Recent evidence indicates that mitochondrial dysfunction-marked by oxidative stress, disturbed calcium homeostasis, compromised mitophagy, and anomalies in mitochondrial dynamics-plays a pivotal role in VCI pathogenesis. This review offers a detailed examination of the latest insights into mitochondrial dysfunction within the VCI context, focusing on both the origins and consequences of compromised mitochondrial health. It aims to lay a robust scientific groundwork for guiding the development and refinement of mitochondrial-targeted interventions for VCI.

Skin mottling score assesses peripheral tissue hypoperfusion in critically ill patients following cardiac surgery.

BACKGROUND: Skin mottling is a common manifestation of peripheral tissue hypoperfusion, and its severity can be described using the skin mottling score (SMS). This study aims to evaluate the value of the SMS in detecting peripheral tissue hypoperfusion in critically ill patients following cardiac surgery. METHODS: Critically ill patients following cardiac surgery with risk factors for tissue hypoperfusion were enrolled (n = 373). Among these overall patients, we further defined a hypotension population (n = 178) and a shock population (n = 51). Hemodynamic and perfusion parameters were recorded. The primary outcome was peripheral hypoperfusion, defined as significant prolonged capillary refill time (CRT, > 3.0 s). The characteristics and hospital mortality of patients with and without skin mottling were compared. The area under receiver operating characteristic curves (AUROC) were used to assess the accuracy of SMS in detecting peripheral hypoperfusion. Besides, the relationships between SMS and conventional hemodynamic and perfusion parameters were investigated, and the factors most associated with the presence of skin mottling were identified. RESULTS: Of the 373-case overall population, 13 (3.5%) patients exhibited skin mottling, with SMS ranging from 1 to 5 (5, 1, 2, 2, and 3 cases, respectively). Patients with mottling had lower mean arterial pressure, higher vasopressor dose, less urine output (UO), higher CRT, lactate levels and hospital mortality (84.6% vs. 12.2%, p < 0.001). The occurrences of skin mottling were higher in hypotension population and shock population, reaching 5.6% and 15.7%, respectively. The AUROC for SMS to identify peripheral hypoperfusion was 0.64, 0.68, and 0.81 in the overall, hypotension, and shock populations, respectively. The optimal SMS threshold was 1, which corresponded to specificities of 98, 97 and 91 and sensitivities of 29, 38 and 67 in the three populations (overall, hypotension and shock). The correlation of UO, lactate, CRT and vasopressor dose with SMS was significant, among them, UO and CRT were identified as two major factors associated with the presence of skin mottling. CONCLUSION: In critically ill patients following cardiac surgery, SMS is a very specific yet less sensitive parameter for detecting peripheral tissue hypoperfusion.

MRI hypoperfusion as a determinant of cognitive impairment in adults with Moyamoya angiopathy.

INTRODUCTION: In Moyamoya angiopathy (MMA), mechanisms underlying cognitive impairment remain debated. We aimed to assess the association of cognitive impairment with the degree and the topography of cerebral hypoperfusion in MMA. METHODS: A retrospective analysis of neuropsychological and perfusion MRI data from adults with MMA was performed. Ischemic and haemorrhagic lesion masks were created to account for cerebral lesions in the analysis of cerebral perfusion. Whole brain volume of hypoperfused parenchyma was outlined on perfusion maps using different Tmax thresholds from 4 to 12 s. Regional analysis produced mean Tmax values at different regions of interest. Analyses compared perfusion ratios in patients with and without cognitive impairment, with multivariable logistic regression analysis to identify predictive factors. RESULTS: Cognitive impairment was found in 20/48 (41.7%) patients. Attention/processing speed and memory were equally impaired (24%) followed by executive domain (23%). After adjustment, especially for lesion volume, hypoperfused parenchyma volume outlined by Tmax > 4 s or Tmax > 5 s thresholds was an independent factor of cognitive impairment (OR for Tmax > 4 s = 1.06 [CI 95% 1.008-1.123]) as well as attention/processing speed (OR for Tmax > 4 s = 1.07 [CI 95% 1.003-1.133]) and executive domains (OR for Tmax > 5 s = 1.08 [CI 95% 1.004-1.158]). Regarding cognitive functions, patients with processing speed and flexibility impairment had higher frontal Tmax compared to other ROIs and to patients with normal test scores. DISCUSSION: Cerebral hypoperfusion emerged as an independent factor of cognitive impairment in MMA particularly in attention/processing speed and executive domains, with a strong contribution of frontal areas. CONCLUSION: Considering this association, revascularization surgery could improve cognitive impairment.

Binary Nano-inhalant Formulation of Icariin Enhances Cognitive Function in Vascular Dementia via BDNF/TrkB Signaling and Anti-inflammatory Effects.

Vascular dementia (VaD) has a serious impact on the patients' quality of life. Icariin (Ica) possesses neuroprotective potential for treating VaD, yet its oral bioavailability and blood-brain barrier (BBB) permeability remain challenges. This research introduced a PEG-PLGA-loaded chitosan hydrogel-based binary formulation tailored for intranasal delivery, enhancing the intracerebral delivery efficacy of neuroprotective agents. The formulation underwent optimization to facilitate BBB crossing, with examinations conducted on its particle size, morphology, drug-loading capacity, in vitro release, and biodistribution. Using the bilateral common carotid artery occlusion (BCCAO) rat model, the therapeutic efficacy of this binary formulation was assessed against chitosan hydrogel and PEG-PLGA nanoparticles loaded with Ica. Post-intranasal administration, enhanced cognitive function was evident in chronic cerebral hypoperfusion (CCH) rats. Further mechanistic evaluations, utilizing immunohistochemistry (IHC), RT-PCR, and ELISA, revealed augmented transcription of synaptic plasticity-associated proteins like SYP and PSD-95, and a marked reduction in hippocampal inflammatory markers such as IL-1ß and TNF-α, highlighting the formulation's promise in alleviating cognitive impairment. The brain-derived neurotrophic factor (BDNF)/tropomyosin related kinase B (TrkB) pathway was activated significantly in the binary formulation compared with the other two. Our study demonstrates that the intranasal application of chitosan hydrogel loaded with Ica-encapsulated PEG-PLGA could effectively deliver Ica into the brain and enhance its neuroprotective effect.

Microglial AT1R Conditional Knockout Ameliorates Hypoperfusive Cognitive Impairment by Reducing Microglial Inflammatory Responses.

Chronic cerebral hypoperfusion (CCH) can cause vascular cognitive impairment and dementia. AT1R, angiotensin II type I receptor, plays a vital role in central nervous system pathologies, but its concrete function in vascular dementia is still unclear. Herein, we investigated the effects of AT1R during CCH by conditional knockout of the microglial AT1R and candesartan treatment. Using the bilateral carotid artery stenosis (BCAS) model, we found that the AT1R is crucial in exacerbating CCH-induced cognitive impairment via regulating microglial activation. The levels of AT1R were increased in the hippocampus and the hippocampal microglia after CCH induction. Microglial AT1R conditional knockout ameliorated cognitive impairment by reducing inflammatory responses and microglial activation, and so did candesartan treatment. However, we observed restoration of cerebral blood flow (CBF) but no significant neuronal loss in the hippocampus at 28 days after BCAS. Finally, we screened three hub genes (Ctss, Fcer1g, Tyrobp) associated with CCH. Our findings indicated that microglial expression of AT1R is critical for regulating neuroinflammation in CCH, and AT1R antagonism may be a feasible and promising method for ameliorating CCH-caused cognitive impairment.

Bilateral watershed infarcts due to hypoperfusion in the context of drug abuse: case report.

BACKGROUND: Watershed infarcts (WIs) are a distinct type of stroke with a varying clinical presentation that affects the border areas between the territories of two cerebral arteries and are typically associated with hemodynamic impairment and internal carotid artery stenosis. However, there is a paucity of data concerning its association with the history of recreational substance and drug abuse. METHODS/CASE REPORT: This case report presents a unique instance of bilateral internal watershed infarcts in a 23-year-old male with a history of polysubstance abuse, including methadone and cocaine. The patient's presentation included confusion, lower limb weakness, and systemic complications such as acute liver injury and myonecrosis, underlying the complexity of the clinical scenario. RESULTS: The investigation revealed no evidence of arterial stenosis or thrombosis, leading to the conclusion that the infarctions were likely precipitated by a total loss of consciousness due to substance abuse-related cerebral hypoperfusion and vasoconstriction. Methadone and cocaine, both implicated in vasoconstriction, lowering the seizure threshold and contributing to QTc prolongation, thus leading to loss of consciousness, were identified as potential triggers for the episode. CONCLUSIONS: In the young adult population, it is important to consider drug abuse as an etiological trigger for watershed infarcts, whereas the multi-system involvement and atypical presentation highlight the need for a comprehensive approach.

Effects of clitorienolactones from Clitoria ternatea root on calcium channel mediating hippocampal long-term potentiation in rats induced chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is a common mechanism of acute brain injury due to impairment of blood flow to the brain. Moreover, a prolonged lack of oxygen supply may result in cerebral infarction or global ischemia, which subsequently causes long-term memory impairment. Research on using Clitoria ternatea root extract for treating long-term memory has been studied extensively. However, the bioactive compound contributing to its neuroprotective effects remains uncertain. In the present study, we investigate the effects of clitorienolactone A (CLA) and B (CLB) from the roots of Clitoria ternatea extract on hippocampal neuroplasticity in rats induced by CCH. CLA and CLB were obtained using column chromatography. The rat model of CCH was induced using two-vessel occlusion surgery (2VO). The 2VO rats were given 10 mg/kg of CLA and CLB orally, followed by hippocampal neuroplasticity recording using in vivo electrophysiological. Rats received CLA and CLB (10 mg/kg) significantly reversed the impairment of long-term potentiation following 2VO surgery. Furthermore, we investigate the effect of CLA and CLB on the calcium channel using the calcium imaging technique. During hypoxia, CLA and CLB sustain the increase in intracellular calcium levels. We next predict the binding interactions of CLA and CLB against NMDA receptors containing GluN2A and GluN2B subunits using in silico molecular docking. Our result found that both CLA and CLB exhibited lower binding affinity against GluN2A and GluN2B subunits. Our findings demonstrated that bioactive compounds from Clitoria ternatea improved long-term memory deficits in the chronic cerebral hypoperfusion rat model via calcium uptake. Hence, CLA and CLB could be potential therapeutic tools for treating cognitive dysfunction.

Acrobatic training prevents motor deficits and neuronal loss in male and female rats following chronic cerebral hypoperfusion.

BACKGROUND: Chronic cerebral hypoperfusion in vascular dementia leads to memory and motor deficits; Physical exercise improves these aspects and promotes neuroprotection. Sexual dimorphism may significantly influence both ischemic and exercise outcomes. AIMS: The aim of this study was to investigate the effects of 2VO (Two-Vessel occlusion) and the acrobatic training on motor function, functional performance, and tissue loss in male and female rats. METHODS: Male and female rats were randomly divided into 4 groups: sham acrobatic, sham sedentary, 2VO acrobatic and 2VO sedentary. After 45 days of 2VO surgery, the animals received 4 weeks of acrobatic training. At the end, open field, beam balance and horizontal ladder tests were performed. Brain samples were taken for histological and morphological evaluation. RESULTS: Spontaneous motor activity in the open field was not affected by 2VO, on the other hand, an impairment in forelimb placement was observed after 2VO and acrobatic training prevented errors and improved hindlimb placement. Neuronal loss was found in the motor cortex and striatum after 2VO, especially in females, which was prevented by acrobatic training. CONCLUSION: Mild motor damage was found in animals after 2VO when refined movement was evaluated, probably associated to neuronal death in the motor cortex and striatum. The acrobatic exercise showed a neuroprotective effect, promoting neuronal survival and attenuating the motor deficit.

Red solid line: Patterns of terminal loss of cerebrovascular reactivity at the bedside.

Introduction: Continuous monitoring of the pressure reactivity index (PRx) provides an estimation of dynamic cerebral autoregulation (CA) at the bedside in traumatic brain injury (TBI) patients. Visualising the time-trend of PRx with a risk bar chart in ICM + software at the bedside allows for better real-time interpretability of the autoregulation status. When PRx>0.3 is sustained for long periods, typically of at least half an hour, the bar shows a pattern called "red solid line" (RSL). RSL was previously described to precede refractory intracranial hypertension and brain death. Research question: We aimed to describe pathophysiological changes in measured signals/parameters during RSL. Material and methods: Observation of time-trends of PRx, intracranial pressure, cerebral perfusion pressure, brain oxygenation and compensatory reserve of TBI patients with RSL. Results: Three pathophysiological patterns were identified: RSL precedes intracranial hypertension, RSL is preceded by intracranial hypertension, or RSL is preceded by brain hypoperfusion. In all cases, RSL was followed by death and the RSL onset was between 1 h and 1 day before the terminal event. Discussion and conclusion: RSL precedes death in intensive care and could represent a marker for terminal clinical deterioration in TBI patients. These findings warrant further investigations in larger cohorts to characterise pathophysiological mechanisms underlying the RSL pattern and whether RSL has a significant relationship with outcome after TBI.

Measurable transitions during seizures in intracranial EEG: A stereoelectroencephalography and SPECT study.

OBJECTIVE: Ictal Single Photon Emission Computed Tomography (SPECT) and stereo-electroencephalography (SEEG) are diagnostic techniques used for the management of patients with drug-resistant focal epilepsies. While hyperperfusion patterns in ictal SPECT studies reveal seizure onset and propagation pathways, the role of ictal hypoperfusion remains poorly understood. The goal of this study was to systematically characterize the spatio-temporal information flow dynamics between differently perfused brain regions using stereo-EEG recordings. METHODS: We identified seizure-free patients after resective epilepsy surgery who had prior ictal SPECT and SEEG investigations. We estimated directional connectivity between the epileptogenic-zone (EZ), non-resected areas of hyperperfusion, hypoperfusion, and baseline perfusion during the interictal, preictal, ictal, and postictal periods. RESULTS: Compared to the background, we noted significant information flow (1) during the preictal period from the EZ to the baseline and hyperperfused regions, (2) during the ictal onset from the EZ to all three regions, and (3) during the period of seizure evolution from the area of hypoperfusion to all three regions. CONCLUSIONS: Hypoperfused brain regions were found to indirectly interact with the EZ during the ictal period. SIGNIFICANCE: Our unique study, combining intracranial electrophysiology and perfusion imaging, presents compelling evidence of dynamic changes in directional connectivity between brain regions during the transition from interictal to ictal states.

Ischaemic Gastropathy: An Under-Recognised cause of Abdominal Pain.

Ischaemic gastropathy is an under-recognised phenomenon with a particularly poor prognosis, where early diagnosis is crucial for successful medical intervention and the prevention of life-threatening complications. We present a case involving a 42-year-old female with no history of vascular insufficiency who developed ischaemic gastropathy following a prolonged stay in the intensive care unit, from septic shock secondary to Escherichia coli bacteraemia due to complicated acute appendicitis. This case underscores the importance of the physician's awareness regarding this rare entity and the necessity to consider it in the differential diagnosis of abdominal pain and haematemesis. Prompt diagnosis and treatment may significantly improve survival outcomes in this less-documented pathology, especially in the younger adult population. LEARNING POINTS: Awareness needs to be increased regarding the consideration of ischaemic gastropathy as a differential diagnosis.A patient without a history of vascular compromise could have a diagnosis of ischaemic gastropathy.This is possibly the first noted case of ischaemic gastropathy occurring after an appendectomy, which is complicated by gram-negative bacteraemia and haemodynamic instability.

Cerebrovascular Dysfunction in Alzheimer's Disease and Transgenic Rodent Models.

Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementia (ADRD) are the primary causes of dementia that has a devastating effect on the quality of life and is a tremendous economic burden on the healthcare system. The accumulation of extracellular beta-amyloid (Aß) plaques and intracellular hyperphosphorylated tau-containing neurofibrillary tangles (NFTs) in the brain are the hallmarks of AD. They are also thought to be the underlying cause of inflammation, neurodegeneration, brain atrophy, and cognitive impairments that accompany AD. The discovery of APP, PS1, and PS2 mutations that increase Aß production in families with early onset familial AD led to the development of numerous transgenic rodent models of AD. These models have provided new insight into the role of Aß in AD; however, they do not fully replicate AD pathology in patients. Familial AD patients with mutations that elevate the production of Aß represent only a small fraction of dementia patients. In contrast, those with late-onset sporadic AD constitute the majority of cases. This observation, along with the failure of previous clinical trials targeting Aß or Tau and the modest success of recent trials using Aß monoclonal antibodies, has led to a reappraisal of the view that Aß accumulation is the sole factor in the pathogenesis of AD. More recent studies have established that cerebral vascular dysfunction is one of the earliest changes seen in AD, and 67% of the candidate genes linked to AD are expressed in the cerebral vasculature. Thus, there is an increasing appreciation of the vascular contribution to AD, and the National Institute on Aging (NIA) and the Alzheimer's Disease Foundation recently prioritized it as a focused research area. This review summarizes the strengths and limitations of the most commonly used transgenic AD animal models and current views about the contribution of Aß accumulation versus cerebrovascular dysfunction in the pathogenesis of AD.

Chuanzhitongluo capsule improves cognitive impairment in mice with chronic cerebral hypoperfusion via the cholinergic anti-inflammatory pathway.

Vascular cognitive impairment (VCI) has become a common disease-causing cognitive deficit in humans, second only to Alzheimer's Disease (AD). Chuanzhitongluo capsule (CZTL) is a Traditional Chinese Medicine (TCM) preparation known for its effective protection against cerebral ischemia. However, its potential to ameliorate VCI remains unclear. This study aimed to investigate the cognitive improvement effects of CZTL in a mouse model of VCI. Chronic cerebral hypoperfusion (CCH) was induced in mice by bilateral common carotid artery stenosis (BCAS) to simulate the pathological changes associated with VCI. Spatial learning and memory abilities were assessed using the Morris Water Maze (MWM). RNA sequencing (RNA-Seq) was employed to identify differentially expressed genes (DEGs) in the hippocampus. Levels of inflammatory factors were measured through enzyme-linked immunosorbent assay (ELISA), while immunofluorescence (IF) determined the expression intensity of target proteins. Western Blot (WB) confirmed the final action pathway. Results indicated that CZTL significantly improved the spatial learning and memory abilities of CCH mice, along with alterations in gene expression profiles in the hippocampus. It also reduced neuroinflammation in the hippocampus and upregulated the choline acetyltransferase (ChAT) and α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR), which are in synaptic plasticity and neuronal development. Moreover, CZTL inhibited the NF-κB signaling pathway. In conclusion, CZTL may alleviate neuroinflammation induced by CCH and improve cognitive impairment in CCH mice by regulating the cholinergic anti-inflammatory pathway (CAIP) involving ChAT/α7nAChR/NF-κB.

Inhibition of Endoplasmic Reticulum Stress Improves Chronic Ischemic Hippocampal Damage Associated with Suppression of IRE1α/TRAF2/ASK1/JNK-Dependent Apoptosis.

Chronic cerebral ischemia is a complex form of stress, of which the most common hemodynamic characteristic is chronic cerebral hypoperfusion (CCH). Lasting endoplasmic reticulum (ER) stress can drive neurological disorders. Targeting ER stress shows potential neuroprotective effects against stroke. However, the role of ER stress in CCH pathological processes and the effects of targeting ER stress on brain ischemia are unclear. Here, a CCH rat model was established by bilateral common carotid artery occlusion. Rats were treated with 4-PBA, URB597, or both for 4 weeks. Neuronal morphological damage was detected using hematoxylin-eosin staining. The expression levels of the ER stress-ASK1 cascade-related proteins GRP78, IRE1α, TRAF2, CHOP, Caspase-12, ASK1, p-ASK1, JNK, and p-JNK were assessed by Western blot. The mRNA levels of TNF-α, IL-1ß, and iNOS were assessed by RT-PCR. For oxygen-glucose deprivation experiments, mouse hippocampal HT22 neurons were used. Apoptosis of the hippocampus and HT22 cells was detected by TUNEL staining and Annexin V-FITC analysis, respectively. CCH evoked ER stress with increased expression of GRP78, IRE1α, TRAF2, CHOP, and Caspase-12. Co-immunoprecipitation experiments confirmed the interaction between TRAF2 and ASK1. ASK1/JNK signaling, inflammatory cytokines, and neuronal apoptosis were enhanced, accompanied by persistent ER stress; these were reversed by 4-PBA and URB597. Furthermore, the ASK1 inhibitor GS4997 and 4-PBA displayed synergistic anti-apoptotic effects in cells with oxygen-glucose deprivation. In summary, ER stress-induced apoptosis in CCH is associated with the IRE1α/TRAF2/ASK1/JNK signaling pathway. Targeting the ER stress-ASK1 cascade could be a novel therapeutic approach for ischemic cerebrovascular diseases.

Xinshubao tablet rescues cognitive dysfunction in a mouse model of vascular dementia: Involvement of neurogenesis and neuroinflammation.

Vascular dementia (VaD) represents a severe cognitive dysfunction syndrome closed linked to cardiovascular function. In the present study, we assessed the potential of Xinshubao tablet (XSB), a traditional Chinese prescription widely used for cardiovascular diseases, to mitigate neuropathological damage in a mouse model of VaD and elucidated the underlying mechanisms. Our findings revealed that oral administration of XSB rescued the cardiac dysfunction resulting from bilateral common carotid artery stenosis (BCAS), improved the cerebral blood flow (CBF) and cognitive function, reduced white matter injury, inhibited excessive microglial and astrocytic activation, stimulated hippocampal neurogenesis, and reduced neural apoptosis in the brains of BCAS mice. Mechanistically, RNA-seq analysis indicated that XSB treatment was significantly associated with neuroinflammation, vasculature development, and synaptic transmission, which were further confirmed by q-PCR assays. Western blot results revealed that XSB treatment hindered the nuclear translocation of nuclear factor-κB (NF-κB), thereby suppressing the NF-κB signaling pathway. These results collectively demonstrated that XSB could ameliorate cognitive dysfunction caused by BCAS through regulating CBF, reducing white matter lesions, suppressing glial activation, promoting neurogenesis, and mitigating neuroinflammation. Notably, the NF-κB signaling pathway emerged as a pivotal player in this mechanism.

Inhibition of Glial Activation and Subsequent Reduction in White Matter Damage through Supplementation with a Combined Extract of Wheat Bran, Citrus Peel, and Jujube in a Rat Model of Vascular Dementia.

Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease. In our previous studies, we showed that wheat bran extract (WBE) reduced white matter damage in a rat VaD model and improved memory in a human clinical trial. However, starch gelatinization made the large-scale preparation of WBE difficult. To simplify the manufacturing process and increase efficacy, we attempted to find a decoction containing an optimum ratio of wheat bran, sliced citrus peel, and sliced jujube (WCJ). To find an optimal ratio, the cell survival of C6 (rat glioma) cultured under hypoxic conditions (1% O2) was measured, and apoptosis was assessed. To confirm the efficacies of the optimized WCJ for VaD, pupillary light reflex, white matter damage, and the activation of astrocytes and microglia were assessed in a rat model of bilateral common carotid artery occlusion (BCCAO) causing chronic hypoperfusion. Using a combination of both searching the literature and cell survival experiments, we chose 6:2:1 as the optimal ratio of wheat bran to sliced citrus peel to sliced jujube to prepare WCJ. We showed that phytic acid contained only in wheat bran can be used as an indicator component for the quality control of WCJ. We observed in vitro that the WCJ treatment improved cell survival by reducing apoptosis through an increase in the Bcl-2/Bax ratio. In the BCCAO experiments, the WCJ-supplemented diet prevented astrocytic and microglial activation, mitigated myelin damage in the corpus callosum and optic tract, and, consequently, improved pupillary light reflex at dosages over 100 mg/kg/day. The results suggest that the consumption of WCJ can prevent VaD by reducing white matter damage, and WCJ can be developed as a safe, herbal medicine to prevent VaD.

Physical and social environmental enrichment alleviate ferroptosis and inflammation with inhibition of TLR4/MyD88/p38MAPK pathway in chronic cerebral hypoperfusion rats.

A typical enriched environment (EE), which combines physical activity and social interaction, has been proven to mitigate cognitive impairment caused by chronic cerebral hypoperfusion (CCH). However, it remains unclear how the different components of EE promote cognitive recovery after CCH. This study stripped out the different components of EE into physical environmental enrichment (PE) and social environmental enrichment (SE), and compared the neuroprotective effects of PE, SE and typical EE (PSE) in CCH. The results of novel object recognition and Morris water maze tests showed that PE, SE, and PSE improved cognitive function in CCH rats. Additionally, Nissl and TUNEL staining revealed that three EEs reduced neuronal loss in the hippocampus. PSE exhibited superior neuroprotective and functional improvement effects compared to PE and SE, while there was no significant difference between PE and SE. Furthermore, three EEs reduced lipid peroxidation in the hippocampus with decreasing the levels of MDA and increasing the activities of SOD and GSH. The expression of SLC7A11 and GPX4 was increased, while the level of p53 was reduced in three EEs. This suggested that three EEs inhibited ferroptosis by maintaining the redox homeostasis in the hippocampus. Three EEs reduced the levels of IL-ß, TNF-α, and IL-6, thereby inhibiting neuroinflammation. Additionally, Western blotting and immunofluorescence results indicated that three EEs also inhibited the TLR4/MyD88/p38MAPK signaling pathway. These findings collectively demonstrated that the three EEs alleviated hippocampal ferroptosis and neuroinflammation in CCH rats, thereby reducing neuronal loss, which might be associated with the inhibition of the TLR4/MyD88/p38MAPK signaling pathway. Moreover, the study results supported that it is only through the combination of physical exercise and social interaction that the optimal neuroprotective effects can be achieved. These findings provided valuable insights for the prevention and treatment of vascular cognitive impairment.