Translational Stroke Research最新文献

Subarachnoid hemorrhage (SAH) is a prevalent cerebrovascular disease with significant global mortality and morbidity rates. Despite advancements in pharmacological and surgical approaches, the quality of life for SAH survivors has not shown substantial improvement. Traditionally, vasospasm has been considered a primary contributor to death and disability following SAH, but anti-vasospastic therapies have not demonstrated significant benefits for SAH patients' prognosis. Emerging studies suggest that early brain injury (EBI) may play a crucial role in influencing SAH prognosis. Sirtuins (SIRTs), a group of NAD + -dependent deacylases comprising seven mammalian family members (SIRT1 to SIRT7), have been found to be involved in neural tissue development, plasticity, and aging. They also exhibit vital functions in various central nervous system (CNS) processes, including cognition, pain perception, mood, behavior, sleep, and circadian rhythms. Extensive research has uncovered the multifaceted roles of SIRTs in CNS disorders, offering insights into potential markers for pathological processes and promising therapeutic targets (such as SIRT1 activators and SIRT2 inhibitors). In this article, we provide an overview of recent research progress on the application of SIRTs in subarachnoid hemorrhage and explore their underlying mechanisms of action.

Cerebral small vessel disease (cSVD) refers to the age-dependent pathological processes involving the brain small vessels and leading to vascular cognitive impairment, intracerebral hemorrhage, and acute lacunar ischemic stroke. Despite the significant public health burden of cSVD, disease-specific therapeutics remain unavailable due to the incomplete understanding of the underlying pathophysiological mechanisms. Recent advances in neuroimaging acquisition and processing capabilities as well as findings from cSVD animal models have revealed critical roles of several age-dependent processes in cSVD pathogenesis including arterial stiffness, vascular oxidative stress, low-grade systemic inflammation, gut dysbiosis, and increased salt intake. These factors interact to cause a state of endothelial cell dysfunction impairing cerebral blood flow regulation and breaking the blood brain barrier. Neuroinflammation follows resulting in neuronal injury and cSVD clinical manifestations. Impairment of the cerebral waste clearance through the glymphatic system is another potential process that has been recently highlighted contributing to the cognitive decline. This review details these mechanisms and attempts to explain their complex interactions. In addition, the relevant knowledge gaps in cSVD mechanistic understanding are identified and a systematic approach to future translational and early phase clinical research is proposed in order to reveal new cSVD mechanisms and develop disease-specific therapeutics.

Blood-brain barrier (BBB) disruption is a prominent pathophysiological mechanism in stroke. Transplantation of mesenchymal stem cells (MSCs) preserves BBB integrity following ischemic stroke. Fibroblast growth factor 21 (FGF21) has been shown to be a potent neuroprotective agent that reduces neuroinflammation and protects against BBB leakage. In this study, we assessed the effects of transplantation of MSCs overexpressing FGF21 (MSCs-FGF21) on ischemia-induced neurological deficits and BBB breakdown. MSCs-FGF21 was injected into the rat brain via the intracerebroventricular route 24 h after middle cerebral artery occlusion (MCAO) surgery. The behavioral performance was assessed using modified neurological severity scores and Y-maze tests. BBB disruption was measured using Evans blue staining, IgG extravasation, and brain water content. The levels of tight junction proteins, aquaporin 4, and neuroinflammatory markers were analyzed by western blotting and immunohistochemistry. The activity of matrix metalloproteinase-9 (MMP-9) was determined using gelatin zymography. At day-5 after MCAO surgery, intraventricular injection of MSCs-FGF21 was found to significantly mitigate the neurological deficits and BBB disruption. The MCAO-induced loss of tight junction proteins, including ZO-1, occludin, and claudin-5, and upregulation of the edema inducer, aquaporin 4, were also remarkably inhibited. In addition, brain infarct volume, pro-inflammatory protein expression, and MMP-9 activation were effectively suppressed. These MCAO-induced changes were only marginally improved by treatment with MSCs-mCherry, which did not overexpress FGF21. Overexpression of FGF21 dramatically improved the therapeutic efficacy of MSCs in treating ischemic stroke. Given its multiple benefits and long therapeutic window, MSC-FGF21 therapy may be a promising treatment strategy for ischemic stroke.

Sigma 1 receptors are intracellular chaperone proteins that have been explored as a subacute treatment to enhance post-stroke recovery. We recently identified the antitussive oxeladin as a selective sigma 1 receptor agonist with the ability to stimulate the release of brain-derived neurotrophic factor from neurons in vitro. In this study, we hypothesized that oral oxeladin citrate would stimulate BDNF secretion and improve stroke outcomes when administered to male rats starting 48 h after transient middle cerebral artery occlusion. Oxeladin did not alter blood clotting and crossed the blood brain barrier within 30 min of oral administration. Rats underwent 90 min of transient middle cerebral artery occlusion. Forty-eight hours later rats began receiving daily oxeladin (135 mg/kg) for 11 days. Oxeladin significantly improved neurological function on days 3, 7, and 14 following MCAO. Infarct size was not altered by a single dose, but the final extent of infarct after 14 days was decreased. However, there was no significant reduction in astrogliosis or microgliosis compared to vehicle-treated control rats. In agreement with in vitro studies, oxeladin increased the amount of mature BDNF in the cerebral cortex 2, 6, and 24 h after single oral dose. However, the increase in BDNF did not result in increases in cellular proliferation in the subventricular zone or dentate gyrus when compared to vehicle-treated controls. These results suggest that oxeladin may reduce the extent of infarct expansion in the subacute phase of stroke, although this action does not appear to involve a reduction in inflammation or increased cell proliferation.

Cerebral cavernous malformation (CCM), either sporadic or familial, is a devastating vascular malformation affecting the central nervous system that can present with intracerebral hemorrhage, seizure, and new focal neurologic deficits resulting in substantial morbidity and mortality. To date, there is no effective evidence-based preventive regimen. There have been several preclinical and clinical studies investigating the potential mechanisms and benefits of beta-blockers, especially on propranolol. We aimed to conduct a systematic review on the published literature investigating the use of beta-blockers in the treatment of CCM, including both preclinical and clinical studies between 2008 and 2023 using public databases. A total of 2 preclinical studies and 6 clinical studies met the inclusion/exclusion criteria and were included. Data was extracted and synthesized from 5 clinical studies for meta-analysis. The meta-analysis failed to demonstrate a statistically significant protective effect of beta-blockers in preventing intracerebral hemorrhage or developing focal neurologic deficits in subjects with CCM (overall effect = 0.78 (0.20, 3.11), p = 0.73). Overall, there was a paucity of high quality clinical trials, partially due to limited cases of CCM. Addressing this gap may require collaborative efforts at a national or international level. In this review, we summarized all barriers and opportunities on this topic. Additionally, we proposed establishing an evidence-based approach on the use of beta-blockers in preventing recurrent hemorrhage and focal neurological deficits in patients with CCM.

Clinical studies have investigated the effects of using sodium-glucose co-transporter-2 (SGLT2) inhibitors on the development of new-onset stroke (NOS) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), but the findings are inconsistent. This study aimed to examine the association between the use of SGLT2 inhibitors and NOS risk in patients with T2D and CKD. We conducted a nationwide retrospective cohort study using data from the Taiwan Health Insurance Review and Assessment Service database for the years 2004 to 2019. The primary outcome was the risk of incident stroke, which was estimated using hazard ratios (HRs) and 95% confidence intervals (CIs). We used multiple Cox regression modeling to analyze the association between SGLT2 inhibitor use and the risk of stroke in patients with T2D and CKD. In a cohort of 113,710 patients with T2D and CKD who were using SGLT2 inhibitors and 227,420 patients with T2D and CKD who were not using SGLT2 inhibitors, after applying a 1:2 sex- and age-matching strategy, 2,842 and 7,169 NOS events were recorded, respectively. The event rate per 10,000 person-months was 10.60 (95% CI 10.21 to 11.03) for SGLT2 inhibitor users and 13.71 (13.39-14.03) for non-SGLT2 inhibitor users. After adjusting for the index year, sex, age, comorbidities, and concurrent medication, there was a decreased risk of NOS for SGLT2 inhibitor users (adjusted HR 0.80; 95% CI 0.77-0.84) compared with non-SGLT2 inhibitor users. The sensitivity test for the propensity score 1:1-matched analyses showed similar results (adjusted HR 0.80; 95% CI 0.76-0.84). The type of SGLT2 inhibitor subgroup analysis for incident stroke showed consistent results. We concluded that the use of SGLT2 inhibitors in patients with T2D and CKD was associated with significantly low rates of NOS. The significantly low rates of NOS in patients with T2D and CKD were greater among females and less than 50 years patients.

To evaluate the prognostic value of venous outflow (VO) profiles evaluated on multiphase CTA (mCTA) for the patients with acute ischemic stroke (AIS) after endovascular thrombectomy (EVT). We retrospectively collected 150 patients with AIS who underwent pre-treatment CT perfusion (CTP) evaluation and subsequent EVT from April 2018 to April 2022. Three-phases (peak arterial phase, peak venous phase, late venous phase) CTA was reconstructed from CTP raw data, and VO was evaluated on three-phases CTA, respectively. Favorable VO was regarded as a cortical vein opacification score of 3-6, and unfavorable VO as a score of 0-2. Good outcome was defined as modified Rankin Scale score of 0-2 at 90 days after EVT. Multivariate logistic regression analysis was performed to explore the predictors of good outcome. Prognostic value was assessed and compared using receiver operating characteristic (ROC) curves and Delong test. We found that good outcome was achieved in 85 (56.7%) patients. Among the mCTA-derived VO profiles, only favorable peak venous phase VO was found to be independently associated with good outcome (P < 0.001). After integrating favorable peak venous phase VO with lower post-treatment National Institute of Health Stroke Scale score at 24 hours, successful recanalization and favorable hypoperfusion intensity ratio, the predictive ability for a good outcome was significantly improved than before (area under the ROC curve; 0.947 vs 0.881; P = 0.002). This study supports that favorable peak venous VO profiles on mCTA might be a promising biomarker in predicting the good outcome in patients with AIS after EVT.

In genetic studies of cerebrovascular diseases, the optimal vessels to use as controls remain unclear. Our goal is to compare the transcriptomic profiles among 3 different types of control vessels: superficial temporal artery (STA), middle cerebral arteries (MCA), and arteries from the circle of Willis obtained from autopsies (AU). We examined the transcriptomic profiles of STA, MCA, and AU using RNAseq. We also investigated the effects of using these control groups on the results of the comparisons between aneurysms and the control arteries. Our study showed that when comparing pathological cerebral arteries to control groups, all control groups presented similar responses in the activation of immunological processes, the regulation of intracellular signaling pathways, and extracellular matrix productions, despite their intrinsic biological differences. When compared to STA, AU exhibited upregulation of stress and apoptosis genes, whereas MCA showed upregulation of genes associated with tRNA/rRNA processing. Moreover, our results suggest that the matched case-control study design, which involves control STA samples collected from the same subjects of matched aneurysm samples in our study, can improve the identification of non-inherited disease-associated genes. Given the challenges associated with obtaining fresh intracranial arteries from healthy individuals, our study suggests that using MCA, AU, or paired STA samples as controls are feasible strategies for future large-scale studies investigating cerebral vasculopathies. However, the intrinsic differences of each type of control should be taken into consideration when interpreting the results. With the limitations of each control type, it may be most optimal to use multiple tissues as controls.

Inflammation plays an integral role in the formation, growth, and progression to rupture of unruptured intracranial aneurysms. Aneurysm wall enhancement (AWE) in high-resolution magnetic resonance imaging (HR-MRI) has emerged as a surrogate biomarker of vessel wall inflammation and unruptured intracranial aneurysm instability. We investigated the correlation between anti-inflammatory drug use and three-dimensional AWE of fusiform intracranial aneurysms (FIAs). We retrospectively analyzed consecutive patients with FIAs in our database who underwent 3T HR-MRI at three Chinese centers. FIAs were classified as fusiform-type, dolichoectatic-type, or transitional-type. AWE was objectively defined using the aneurysm-to-pituitary stalk contrast ratio in three-dimensional space by determining the contrast ratio of the average signal intensity in the aneurysmal wall and pituitary stalk on post-contrast T1-weighted images. Data on aneurysm size, morphology, and location, as well as patient demographics and comorbidities, were collected. Univariate and multivariate logistic regression analyses were performed to determine factors independently associated with AWE of FIAs on HR-MRI. In total, 127 FIAs were included. In multivariate analysis, statin use (β = -0.236, P = 0.007) was the only independent factor significantly associated with decreased AWE. In the analysis of three FIA subtypes, the fusiform and transitional types were significantly associated with statin use (r_s = -0.230, P = 0.035; and r_s = -0.551, P = 0.010; respectively). It establishes an incidental correlation between the use of statins daily for ≥ 6 months and decreased AWE of FIAs. The findings also indicate that the pathophysiology may differ among the three FIA subtypes.