Comparative in silico analysis of CNS-active molecules targeting the blood-brain barrier choline transporter for Alzheimer's disease therapy.

This study investigated the blood‒brain barrier (BBB) permeability of the central nervous system (CNS)-active compounds donepezil (DON), methionine (MET), and memantine (MEM) by employing a comprehensive in silico approach. These compounds are of particular interest for Alzheimer's disease (AD) therapy. Rigid-flexible molecular docking simulations indicated favorable binding affinities of all the compounds with BBB-ChT, with DON exhibiting the highest binding affinity (ΔGbind = -10.26 kcal/mol), predominantly mediated by significant hydrophobic interactions. In silico kinetic profiling suggested the stability of the DON/BBB-ChT complex, with ligand release prompted by conformational changes. 3D molecular alignment corroborated a minor conformational shift for DON in its minimal binding energy pose. Predictions indicated that active transport mechanisms notably enhance the brain distribution of donepezil compared to that of MET and MEM. Additionally, DON and MEM exhibited low mutagenic probabilities, while MET was identified as highly mutagenic. Overall, these findings highlight the potential of donepezil for superior BBB penetration, primarily through active transport mechanisms, underscoring the need for further validation through in vitro and in vivo studies for effective AD treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00245-w.

Synergistic Effects of Weight Loss and Catheter Ablation: Can microRNAs Serve as Predictive Biomarkers for the Prevention of Atrial Fibrillation Recurrence?

In atrial fibrillation (AF), multifactorial pathologic atrial alterations are manifested by structural and electrophysiological changes known as atrial remodeling. AF frequently develops in the context of underlying cardiac abnormalities. A critical mechanistic role played by atrial stretch is played by abnormal substrates in a number of conditions that predispose to AF, including obesity, heart failure, hypertension, and sleep apnea. The significant role of overweight and obesity in the development of AF is known; however, the differential effect of overweight, obesity, cardiovascular comorbidities, lifestyle, and other modifiable risk factors on the occurrence and recurrence of AF remains to be determined. Reverse remodeling of the atrial substrate and subsequent reduction in the AF burden by conversion into a typical sinus rhythm has been associated with weight loss through lifestyle changes or surgery. This makes it an essential pillar in the management of AF in obese patients. According to recently published research, microRNAs (miRs) may function as post-transcriptional regulators of genes involved in atrial remodeling, potentially contributing to the pathophysiology of AF. The focus of this review is on their modulation by both weight loss and catheter ablation interventions to counteract atrial remodeling in AF. Our analysis outlines the experimental and clinical evidence supporting the synergistic effects of weight loss and catheter ablation (CA) in reversing atrial electrical and structural remodeling in AF onset and in recurrent post-ablation AF by attenuating pro-thrombotic, pro-inflammatory, pro-fibrotic, arrhythmogenic, and male-sex-associated hypertrophic remodeling pathways. Furthermore, we discuss the promising role of miRs with prognostic potential as predictive biomarkers in guiding approaches to AF recurrence prevention.

Protecting the Brain: Novel Strategies for Preventing Breast Cancer Brain Metastases through Selective Estrogen Receptor ß Agonists and In Vitro Blood-Brain Barrier Models.

Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood-brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor ß (ERß), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17ß-estradiol (E2) and the selective ERß agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative Her2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERß as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications.

Exploratory Review of the Takotsubo Syndrome and the Possible Role of the Psychosocial Stress Response and Inflammaging.

Takotsubo syndrome (TTS) is a cardiomyopathy that clinically presents as a transient and reversible left ventricular wall motion abnormality (LVWMA). Recovery can occur spontaneously within hours or weeks. Studies have shown that it mainly affects older people. In particular, there is a higher prevalence in postmenopausal women. Physical and emotional stress factors are widely discussed and generally recognized triggers. In addition, the hypothalamic-pituitary-adrenal (HPA) axis and the associated glucocorticoid-dependent negative feedback play an important role in the resulting immune response. This review aims to highlight the unstudied aspects of the trigger factors of TTS. The focus is on emotional stress/chronic unpredictable mild stress (CUMS), which is influenced by estrogen concentration and noradrenaline, for example, and can lead to changes in the behavioral, hormonal, and autonomic systems. Age- and gender-specific aspects, as well as psychological effects, must also be considered. We hypothesize that this leads to a stronger corticosteroid response and altered feedback of the HPA axis. This may trigger proinflammatory markers and thus immunosuppression, inflammaging, and sympathetic overactivation, which contributes significantly to the development of TTS. The aim is to highlight the importance of CUMS and psychological triggers as risk factors and to make an exploratory proposal based on the new knowledge. Based on the imbalance between the sympathetic and parasympathetic nervous systems, transcutaneous vagus nerve stimulation (tVNS) is presented as a possible new therapeutic approach.

Afterload reduction after non-invasive vagus nerve stimulation in acute heart failure.

Introduction: While central blood pressure (BP) has been recognized as a major indicator of left ventricular (LV) afterload, the reduction of central pressure decreases LV afterload and may prevent heart failure (HF) decompensation. Non-invasive transcutaneous vagus nerve stimulation (tVNS) was shown to improve cardiac function in HF patients. In this study, the relationship between active tVNS and reduction of central BP was investigated in patients with acute HF (AHF). Methods: The 22 patients hospitalized for AHF after initial stabilization (median 80 yrs, males 60%) were randomly assigned to active or sham group. For 1 h daily over 5 days, low-level transcutaneous electrical stimulation (LLTS) (20 Hz, 1 mA) was performed after attaching an ear clip to the tragus (active group) or the earlobe (sham control group). Before and after stimulation, central aortic systolic pressure (CASP), brachial systolic BP (SBP), diastolic BP (DBP) as well as heart rate (HR) were noninvasively measured. Results: No significant differences in baseline characteristics were observed between the active and sham groups. In the active group, CASP, SBP, DBP, and HR each decreased significantly after stimulation (all p < 0.05), whereas in the sham group, CASP, SBP, DBP, and HR each increased significantly after stimulation (all p < 0.05). All the changes in CASP, SBP, DBP and HR before and after stimulation were also significantly different between active and sham groups (all p < 0.01). There were no device-related side effects. Conclusion: In this study, the left tragus tVNS resulted in an acute afterload reduction in the elderly AHF patients. Non-invasive LLTS may be useful and safe for reducing afterload in AHF. Clinical trial registration: ClinicalTrials.gov, identifier UMIN000044121.

Linking Cerebrovascular Dysfunction to Age-Related Hearing Loss and Alzheimer's Disease-Are Systemic Approaches for Diagnosis and Therapy Required?

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction, cognitive decline, and the accumulation of amyloid ß peptide (Aß) in the brain and tau-related lesions in neurons termed neurofibrillary tangles (NFTs). Aß deposits and NFT formation are the central pathological hallmarks in AD brains, and the majority of AD cases have been shown to exhibit a complex combination of systemic comorbidities. While AD is the foremost common cause of dementia in the elderly, age-related hearing loss (ARHL) is the most predominant sensory deficit in the elderly. During aging, chronic inflammation and resulting endothelial dysfunction have been described and might be key contributors to AD; we discuss an intriguing possible link between inner ear strial microvascular pathology and blood-brain barrier pathology and present ARHL as a potentially modifiable and treatable risk factor for AD development. We present compelling evidence that ARHL might well be seen as an important risk factor in AD development: progressive hearing impairment, leading to social isolation, and its comorbidities, such as frailty, falls, and late-onset depression, link ARHL with cognitive decline and increased risk of dementia, rendering it tempting to speculate that ARHL might be a potential common molecular and pathological trigger for AD. Additionally, one could speculate that amyloid-beta might damage the blood-labyrinth barrier as it does to the blood-brain barrier, leading to ARHL pathology. Finally, there are options for the treatment of ARHL by targeted neurotrophic factor supplementation to the cochlea to improve cognitive outcomes; they can also prevent AD development and AD-related comorbidity in the future.

Case report: SGLT2i, transcutaneous vagus nerve stimulation, and their effects on intrarenal venous flow pattern in HFpEF.

Renal congestion in heart failure (HF) is a predictor of the prognosis of cardiovascular disease. The effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and vagus nerve stimulation (VNS) on renal congestion has not been reported in HF. A 77-year-old man with HF with preserved ejection fraction (HFpEF) was referred to our hospital because of poor response to loop diuretics. Echocardiography showed severe tricuspid regurgitation with dilation of the right atrium. Three months after adding SGLT2i, body weight was lost without worsening of renal function. Left and right doppler-derived intrarenal venous flow (IRVF) has been changed from a monophasic to a discontinuous pattern with a systolic interruption. One month later, he discontinued SGLT2i administration at his own discretion. In order to stabilizing autonomic balance, transcutaneous VNS (tVNS) was performed via left ear tragus. One hour after transcutaneous tVNS, ipsilateral IRVF has been dramatically improved from a fusional biphasic to a discontinuous pattern with a systolic interruption. SGLT2i and tVNS may be associated with renal decongestion in HFpEF.

Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood-Brain Barrier In Vitro and In Vivo.

Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood-brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB's integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100-300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy.

Hemorrhagic Cerebral Insults and Secondary Takotsubo Syndrome: Findings in a Novel In Vitro Model Using Human Blood Samples.

Intracranial hemorrhage results in devastating forms of cerebral damage. Frequently, these results also present with cardiac dysfunction ranging from ECG changes to Takotsubo syndrome (TTS). This suggests that intracranial bleeding due to subarachnoid hemorrhage (SAH) disrupts the neuro-cardiac axis leading to neurogenic stress cardiomyopathy (NSC) of different degrees. Following this notion, SAH and secondary TTS could be directly linked, thus contributing to poor outcomes. We set out to test if blood circulation is the driver of the brain-heart axis by investigating serum samples of TTS patients. We present a novel in vitro model combining SAH and secondary TTS to mimic the effects of blood or serum, respectively, on blood-brain barrier (BBB) integrity using in vitro monolayers of an established murine model. We consistently demonstrated decreased monolayer integrity and confirmed reduced Claudin-5 and Occludin levels by RT-qPCR and Western blot and morphological reorganization of actin filaments in endothelial cells. Both tight junction proteins show a time-dependent reduction. Our findings highlight a faster and more prominent disintegration of BBB in the presence of TTS and support the importance of the bloodstream as a causal link between intracerebral bleeding and cardiac dysfunction. This may represent potential targets for future therapeutic inventions in SAH and TTS.

Isosteviol Sodium (STVNA) Reduces Pro-Inflammatory Cytokine IL-6 and GM-CSF in an In Vitro Murine Stroke Model of the Blood-Brain Barrier (BBB).

Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood-brain barrier (BBB) dysfunction.

The Protective Effects of Neurotrophins and MicroRNA in Diabetic Retinopathy, Nephropathy and Heart Failure via Regulating Endothelial Function.

Diabetes mellitus is a common disease affecting more than 537 million adults worldwide. The microvascular complications that occur during the course of the disease are widespread and affect a variety of organ systems in the body. Diabetic retinopathy is one of the most common long-term complications, which include, amongst others, endothelial dysfunction, and thus, alterations in the blood-retinal barrier (BRB). This particularly restrictive physiological barrier is important for maintaining the neuroretina as a privileged site in the body by controlling the inflow and outflow of fluid, nutrients, metabolic end products, ions, and proteins. In addition, people with diabetic retinopathy (DR) have been shown to be at increased risk for systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. DR is, therefore, considered an independent predictor of heart failure. In the present review, the effects of diabetes on the retina, heart, and kidneys are described. In addition, a putative common microRNA signature in diabetic retinopathy, nephropathy, and heart failure is discussed, which may be used in the future as a biomarker to better monitor disease progression. Finally, the use of miRNA, targeted neurotrophin delivery, and nanoparticles as novel therapeutic strategies is highlighted.

Quantitative Lipidomic Analysis of Takotsubo Syndrome Patients' Serum.

Takotsubo syndrome (TTS), also known as the transient left ventricular apical ballooning syndrome, is in contemporary times known as novel acute cardiac syndrome. It is characterized by transient left ventricular apical akinesis and hyperkinesis of the basal left ventricular portions. Although the precise etiology of TTS is unknown, events like the sudden release of stress hormones, such as the catecholamines and the increased inflammatory status might be plausible causes leading to the cardiovascular pathologies. Recent studies have highlighted that an imbalance in lipid accumulation might promote a deviant immune response as observed in TTS. However, there is no information on comprehensive profiling of serum lipids of TTS patients. Therefore, we investigated a detailed quantitative lipid analysis of TTS patients using ES-MSI. Our results showed significant differences in the majority of lipid species composition in the TTS patients compared to the control group. Furthermore, the computational analyses presented was able to link the altered lipids to the pro-inflammatory cytokines and disseminate possible mechanistic pathways involving TNFα and IL-6. Taken together, our study provides an extensive quantitative lipidome of TTS patients, which may provide a valuable Pre-diagnostic tool. This would facilitate the elucidation of the underlying mechanisms of the disease and to prevent the development of TTS in the future.

Microvascular Barrier Protection by microRNA-183 via FoxO1 Repression: A Pathway Disturbed in Neuropathy and Complex Regional Pain Syndrome.

Blood nerve barrier disruption and edema are common in neuropathic pain as well as in complex regional pain syndrome (CRPS). MicroRNAs (miRNA) are epigenetic multitarget switches controlling neuronal and non-neuronal cells in pain. The miR-183 complex attenuates hyperexcitability in nociceptors, but additional non-neuronal effects via transcription factors could contribute as well. This study explored exosomal miR-183 in CRPS and murine neuropathy, its effect on the microvascular barrier via transcription factor FoxO1 and tight junction protein claudin-5, and its antihyperalgesic potential. Sciatic miR-183 decreased after CCI. Substitution with perineural miR-183 mimic attenuated mechanical hypersensitivity and restored blood nerve barrier function. In vitro, serum from CCI mice und CRPS patients weakened the microvascular barrier of murine cerebellar endothelial cells, increased active FoxO1 and reduced claudin-5, concomitant with a lack of exosomal miR-183 in CRPS patients. Cellular stress also compromised the microvascular barrier which was rescued either by miR-183 mimic via FoxO1 repression or by prior silencing of Foxo1. PERSPECTIVE: Low miR-183 leading to barrier impairment via FoxO1 and subsequent claudin-5 suppression is a new aspect in the pathophysiology of CRPS and neuropathic pain. This pathway might help untangle the wide symptomatic range of CRPS and nurture further research into miRNA mimics or FoxO1 inhibitors.

Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer's Disease.

Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aß) inhibitor tramiprosate to screen the DrugCentral database (n = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aß inhibitors with an improved binding affinity (ΔGbind) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial.

The Conspicuous Link between Ear, Brain and Heart-Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer's Disease and Associated Amyloid Cardiomyopathy?

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid ß peptide (Aß) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aß pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain-ear-heart axis by which Aß and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease.

A mid-ventricular variant of Takotsubo syndrome: was it triggered by insular cortex damage?

Takotsubo syndrome (TTS) is a transient cardiomyopathy that is often associated with cerebrovascular diseases. Earlier studies have supported the concept that the cardiovascular system is regulated by a central autonomic network (CAN) consisting of the insular cortex (IC), anterior cingulate gyrus and amygdala. We report the case of a 79-year-old female diagnosed with a mid-ventricular variant of TTS concomitant with right IC ischaemic stroke. After 12 h of hospitalization, she experienced a sudden collapse. Rapid cardiopulmonary resuscitation resulted in a return of spontaneous circulation. Subsequent left ventriculography revealed akinesis in the mid-portion of the left ventricle with vigorous contraction of the basal and apex segment. Two weeks after admission, cardiac ultrasound showed improved left ventricular contraction. Right IC ischaemia in this patient might have been associated with a dysregulation of the CAN and subsequent increased sympathetic nervous system activity that triggered TTS.

Senescence and associated blood-brain barrier alterations in vitro.

Progressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood-brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within.

Hydroxyethylstarch revisited for acute brain injury treatment.

Infusion of the colloid hydroxyethylstarch has been used for volume substitution to maintain hemodynamics and microcirculation after e.g., severe blood loss. In the last decade it was revealed that hydroxyethylstarch can aggravate acute kidney injury, especially in septic patients. Because of the serious risk for critically ill patients, the administration of hydroxyethylstarch was restricted for clinical use. Animal studies and recently published in vitro experiments showed that hydroxyethylstarch might exert protective effects on the blood-brain barrier. Since the prevention of blood-brain barrier disruption was shown to go along with the reduction of brain damage after several kinds of insults, we revisit the topic hydroxyethylstarch and discuss a possible niche for the application of hydroxyethylstarch in acute brain injury treatment.

The insular cortex as a vestibular area in relation to autonomic function.

The forebrain cerebral network including the insular cortex plays a crucial role in the regulation of the central autonomic nervous system in relation to emotional stress. Numerous studies have recently shown that the insular cortex also has roles as a vestibular area in addition to auditory function. In this review, we summarize the recent literature regarding the relationship between the insular cortex and vestibular function, and we describe our hypothesis that the insular cortex has a pivotal role in vestibular-cardiovascular integration.