A novel model for brain iron uptake: introducing the concept of regulation

Neurologic disorders such as Alzheimer''s, Parkinson''s disease, and Restless Legs Syndrome involve a loss of brain iron homeostasis. Moreover, iron deficiency is the most prevalent nutritional concern worldwide with many associated cognitive and neural ramifications. Therefore, understanding the mechanisms by which iron enters the brain and how those processes are regulated addresses significant global health issues. The existing paradigm assumes that the endothelial cells (ECs) forming the blood–brain barrier (BBB) serve as a simple conduit for transport of transferrin-bound iron. This concept is a significant oversimplification, at minimum failing to account for the iron needs of the ECs. Using an in vivo model of brain iron deficiency, the Belgrade rat, we show the distribution of transferrin receptors in brain microvasculature is altered in luminal, intracellular, and abluminal membranes dependent on brain iron status. We used a cell culture model of the BBB to show the presence of factors that influence iron release in non-human primate cerebrospinal fluid and conditioned media from astrocytes; specifically apo-transferrin and hepcidin were found to increase and decrease iron release, respectively. These data have been integrated into an interactive model where BBB ECs are central in the regulation of cerebral iron metabolism.     

颅内血肿微创抽吸术对脑出血患者血脑屏障指数及血清髓鞘碱性蛋白的影响

目的　观察颅内血肿抽吸术对高血压脑出血患者血脑屏障 (BBB)功能的影响。方法　观察脑出血病人常规治疗组 2 5例和常规治疗 颅内血肿清除术组 2 5例 ,对照分析BBB指数和血清髓鞘碱性蛋白 (MBP)的变化 ,并分别与正常对照组对比。结果　血肿清除术组BBB指数明显低于常规治疗组 (P <0 0 5 ) ,而此 2组病人BBB指数均高于正常对照组 (P <0 0 5 ) ;血肿清除术组血清MBP浓度明显低于常规治疗组 (P <0 0 1) ,而此 2组病人MBP均高于正常对照组 (P <0 0 1)。结论　脑出血增加血脑屏障的通透性 ,使BBB指数和血清中MBP含量增高 ,颅内血肿清除术可以减轻细胞毒性对血脑屏障的损伤 ,从而减轻脑水肿。     

缺血性卒中的神经血管单元保护研究进展

为深入了解局部脑缺血/再灌注的病理生理过程中神经血管单元各个成分的病理反应,本文对相关文献作一综述。神经血管单元是由微血管、神经胶质细胞及其突起、神经元、细胞外基质组成的概念性框架,强调血脑屏障的概念和功能可加深对神经血管单元的理解。缺血/再灌注可损伤神经血管单元的各个成分,在缺血/再灌注的各阶段对神经血管单元的各成分实施多途径的全面保护,可进一步改善缺血性卒中的治疗效果。     

Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

Locus coeruleus (LC) is the main noradrenergic (NA) nucleus of the central nervous system. LC degenerates early during Alzheimer's disease (AD) and NA loss might concur to AD pathogenesis. Aside from neurons, LC terminals provide dense innervation of brain intraparenchymal arterioles/capillaries, and NA modulates astrocyte functions. The term neurovascular unit (NVU) defines the strict anatomical/functional interaction occurring between neurons, glial cells, and brain vessels. NVU plays a fundamental role in coupling the energy demand of activated brain regions with regional cerebral blood flow, it includes the blood–brain barrier (BBB), plays an active role in neuroinflammation, and participates also to the glymphatic system. NVU alteration is involved in AD pathophysiology through several mechanisms, mainly related to a relative oligoemia in activated brain regions and impairment of structural and functional BBB integrity, which contributes also to the intracerebral accumulation of insoluble amyloid. We review the existing data on the morphological features of LC-NA innervation of the NVU, as well as its contribution to neurovascular coupling and BBB proper functioning. After introducing the main experimental data linking LC with AD, which have repeatedly shown a key role of neuroinflammation and increased amyloid plaque formation, we discuss the potential mechanisms by which the loss of NVU modulation by LC might contribute to AD pathogenesis. Surprisingly, thus far not so many studies have tested directly these mechanisms in models of AD in which LC has been lesioned experimentally. Clarifying the interaction of LC with NVU in AD pathogenesis may disclose potential therapeutic targets for AD.     

Model of the transient neurovascular response based on prompt arterial dilation

Brief neural stimulation results in a stereotypical pattern of vascular and metabolic response that is the basis for popular brain-imaging methods such as functional magnetic resonance imagine. However, the mechanisms of transient oxygen transport and its coupling to cerebral blood flow (CBF) and oxygen metabolism (CMRO₂) are poorly understood. Recent experiments show that brief stimulation produces prompt arterial vasodilation rather than venous vasodilation. This work provides a neurovascular response model for brief stimulation based on transient arterial effects using one-dimensional convection–diffusion transport. Hemoglobin oxygen dissociation is included to enable predictions of absolute oxygen concentrations. Arterial CBF response is modeled using a lumped linear flow model, and CMRO₂ response is modeled using a gamma function. Using six parameters, the model successfully fit 161/166 measured extravascular oxygen time courses obtained for brief visual stimulation in cat cerebral cortex. Results show how CBF and CMRO₂ responses compete to produce the observed features of the hemodynamic response: initial dip, hyperoxic peak, undershoot, and ringing. Predicted CBF and CMRO₂ response amplitudes are consistent with experimental measurements. This model provides a powerful framework to quantitatively interpret oxygen transport in the brain; in particular, its intravascular oxygen concentration predictions provide a new model for fMRI responses.     

重型脑室出血患者血脑屏障与神经功能相关性研究

目的探讨重型脑室出血患者术前和术后血脑屏障（BBB）改变对神经功能的影响。方法观察重型脑室出血患者常规治疗组（B组）、脑室引流组（C组）和脑室引流并脑脊液置换组（D组）各16例，对照分析其BBB指数和S100蛋白的变化，并分别与正常对照组（A组，10例）作对比。同时，记录B、C和D组患者临床神经功能缺损程度，并分别在治疗前、治疗1个月后评分。结果A组的BBB指数及血清S100蛋白浓度明显低于B、C和D组，B组的BBB指数、血清S100蛋白浓度和临床神经功能缺损程度评分明显高于C、D组，其差异具有显著性意义（P〈0．05）；而C、D组的BBB指数、S100蛋白浓度和临床神经功能缺损程度评分没有明显差别，其差异无显著性意义（P〉0．05）。结论脑室出血会增加BBB的通透性，进而损害患者的神经功能；脑室穿刺引流术并腰穿脑脊液置换术可以降低BBB的通透性，促进患者的临床神经功能恢复，这可能是治疗重型脑室出血的一个机制。     

In vivo 3D morphology of astrocyte–vasculature interactions in the somatosensory cortex: implications for neurovascular coupling

Astrocytes are increasingly believed to play an important role in neurovascular coupling. Recent in vivo studies have shown that intracellular calcium levels in astrocytes correlate with reactivity in adjacent diving arterioles. However, the hemodynamic response to stimulation involves a complex orchestration of vessel dilations and constrictions that spread rapidly over wide distances. In this work, we study the three-dimensional cytoarchitecture of astrocytes and their interrelations with blood vessels down through layer IV of the mouse somatosensory cortex using in vivo two-photon microscopy. Vessels and astrocytes were visualized through intravenous dextran-conjugated fluorescein and cortically applied sulforhodamine 101 (SR101), respectively. In addition to exploring astrocyte density, vascular proximity, and microvascular density, we found that sheathing of subpial vessels by astrocyte processes was continuous along all capillaries, arterioles, and veins, comprising a highly interconnected pathway through which signals could feasibly be relayed over long distances via gap junctions. An inner SR101-positive sheath noted along pial and diving arterioles was determined to be nonastrocytic, and appears to represent selective SR101 staining of arterial endothelial cells. Our findings underscore the intimate relationship between astrocytes and all cortical blood vessels, and suggest that astrocytes could influence neurovascular regulation at a range of sites, including the capillary bed and pial arterioles.     

The 100 most-cited articles about the role of neurovascular unit in stroke 2001–2020: A bibliometric analysis

BackgroundThe neurovascular unit (NVU) is emerging as a potential therapeutic target in neurological conditions, such as stroke, brain injury, Alzheimer''s disease, and Parkinson''s disease; meanwhile, stroke is the second leading cause of death globally. The purpose of the study is to analyze the most influential articles, authors, countries, and topics in the role of NVU in stroke.MethodsThe Web of Science (WoS) database was used for bibliometric analysis using the search terms “Stroke” and “Neurovascular unit” on January 1st, 2021. Data were extracted from the WoS database to identify collaborations between authors, countries, organizations, and keywords using VOSviewer (1.6.16 mac). Two bibliometric indicators, the activity index (AI) and category normalized citation impact (CNCI), were computed. The keywords of bursts were also identified by CiteSpace.ResultsA total of 770 articles were analyzed by VOSviewer. AIs and CNCIs were computed of the eighteen countries according to VOSviewer co‐authorship analysis results. The majority of authors mainly came from the United States and Japan. Romania, Hungary, and Poland have emerged as rising‐star countries. In the 100 most‐cited articles, the number of citations ranged from 1873 to 69, with a total of 15,758 citations. Most articles were published in 2011 and 2012 (n = 13 each), followed by 2009 (n = 11) and 2013, 2014, and 2015 (n = 8 each). Stroke and Journal of Cerebral Blood Flow and Metabolism were the two top journals. EH Lo from Harvard University/ Massachusetts General Hospital was the top first author and corresponding author. Harvard University/Massachusetts General Hospital was the most productive affiliated institution with 15 publications.ConclusionThere has been growing attention and efforts made in the field of stroke and NVU. The merit of the above findings may help to shape the research policy in ischemic stroke both at the country and institutional level.     

Sublamina-specific organization of the blood brain barrier in the mouse olfactory nerve layer

Astrocytes constitute the main glial component of the mammalian blood brain barrier (BBB). However, in the olfactory bulb (OB), the olfactory nerve layer (ONL) is almost devoid of astrocytes, raising the question which glial cells are part of the BBB. We used mice expressing EGFP in astrocytes and tdTomato in olfactory ensheathing cells (OECs), a specialized type of glial cells in the ONL, to unequivocally identify both glial cell types and investigate their contribution to the BBB in the olfactory bulb. OECs were located exclusively in the ONL, while somata of astrocytes were located in deeper layers and extended processes in the inner sublamina of the ONL. These processes surrounded blood vessels and contained aquaporin-4, an astrocytic protein enriched at the BBB. In the outer sublamina of the ONL, in contrast, blood vessels were surrounded by aquaporin-4-negative processes of OECs. Transcardial perfusion of blood vessels with lanthanum and subsequent visualization by electron microscopy showed that blood vessels enwrapped by OECs possessed intact tight junctions. In acute olfactory bulb preparations, injection of fluorescent glucose 6-NBDG into blood vessels resulted in labeling of OECs, indicating glucose transport from the perivascular space into OECs. In addition, Ca²⁺ transients in OECs in the outer sublamina evoked vasoconstriction, whereas Ca²⁺ signaling in OECs of the inner sublamina had no effect on adjacent blood vessels. Our results demonstrate that the BBB in the inner sublamina of the ONL contains astrocytes, while in the outer ONL OECs are part of the BBB.     

Blood-brain barrier to albumin in embryonic new born and adult rats

Summary A study was made on the permeability of cerebral blood vessels to albumin during development. Fluorescent labeled bovine serum albumin was injected into a tail vein of newborn, young and adult rats and into the umbilical artery of embryos from the fifteenth to the twenty-first day of pregnancy. The distribution of the tracer was ascertained by means of fluorescence microscopy. In the brains of the embryos and postnatal rats the fluorescent albumin was strictly confined to the lumen of the blood vessels, while considerable extravascular passage was observed in subcutaneous tissue. The results indicate that in rat embryos the cerebral blood vessels are impermeable to albumin at least as early as the fifteenth day after fertilization.

---

Zusammenfassung Es wurde eine Untersuchung der Permeabilität der Hirngefäße für Albumin im Verlaufe der Entwicklung durchgeführt. Fluorescenz-markiertes Rinder-Serumalbumin wurde in eine Schwanzvene von neugeborenen, jungen und erwachsenen Ratten sowie in die Umbilicalarterie von Embryonen zwischen dem 15. und 21. Schwangerschaftstag injiziert. Die Verteilung der markierten Substanz wurde fluorescenzmikroskopisch nachgewiesen. In den Gehirnen embryonaler und postnataler Ratten war das fluorescenzmarkierte Albumin streng auf das Lumen der Blutgefäße beschränkt, während im subeutanen Gewebe eine erhebliche extravasale Passage nachgewiesen werden konnte. Die Befunde sprechen dafür, daß bei Rattenembryonen die Hirngefäße zumindest ab dem 15. Schwangerschaftstag für Albumin undurchlässig sind.

     

全脑照射后血脑屏障改变对放射性脑损伤的影响

目的 探讨全脑照射后血脑屏障通透性的改变对放射性脑损伤的影响.方法 80只昆明小鼠随机分对照组、5 Gy、15 Gy和30 Gy剂量组,每组20只,分别于照射后1周和4周,各组随机取出10只小鼠采用Morris水迷宫测试其空间记忆能力,行为测试结束后,随机抽取7只测量其脑内伊文思蓝的含量,3只在电镜下观察血脑屏障结构的改变.结果 照射后1周,15 Gy和30 Gy剂量组脑内依文思蓝明显升高;照射后4周,15 Gy剂量组恢复到对照组水平,而30 Gy剂量组仍未见恢复.照射后1周,15 Gy和30 Gy剂量组小鼠第1次穿越平台的时间延长和穿越次数明显减少;照射后4周,15 cy剂量组恢复到对照组水平,而30 Gy剂量组仍未见恢复.电镜结果显示15 Gy剂量组照射后1周血脑屏障基膜周围出现透亮区,照射后4周恢复;30 Gy剂量组照射后1周血脑屏障基膜周围也出现透亮区,而照射后4周除血脑屏障基膜继续透亮区外,尚出现内皮细胞核固缩、神经元凋亡和脱髓鞘等现象.结论 放射后血脑屏障的通透性的改变是放射损伤的结果,可能也是放射后继发性脑损伤的原因.     

Ultrastructural studies of the neurovascular unit reveal enhanced endothelial transcytosis in hyperglycemia-enhanced hemorrhagic transformation after stroke

AimsPre‐existing hyperglycemia (HG) aggravates the breakdown of blood–brain barrier (BBB) and increases the risk of hemorrhagic transformation (HT) after acute ischemic stroke in both animal models and patients. To date, HG‐induced ultrastructural changes of brain microvascular endothelial cells (BMECs) and the mechanisms underlying HG‐enhanced HT after ischemic stroke are poorly understood.MethodsWe used a mouse model of mild brain ischemia/reperfusion to investigate HG‐induced ultrastructural changes of BMECs that contribute to the impairment of BBB integrity after stroke. Adult male mice received systemic glucose administration 15 min before middle cerebral artery occlusion (MCAO) for 20 min. Ultrastructural characteristics of BMECs were evaluated using two‐dimensional and three‐dimensional electron microscopy and quantitatively analyzed.ResultsMice with acute HG had exacerbated BBB disruption and larger brain infarcts compared to mice with normoglycemia (NG) after MCAO and 4 h of reperfusion, as assessed by brain extravasation of the Evans blue dye and microtubule‐associated protein 2 immunostaining. Electron microscopy further revealed that HG mice had more endothelial vesicles in the striatal neurovascular unit than NG mice, which may account for their deterioration of BBB impairment. In contrast with enhanced endothelial transcytosis, paracellular tight junction ultrastructure was not disrupted after this mild ischemia/reperfusion insult or altered upon HG. Consistent with the observed increase of endothelial vesicles, transcytosis‐related proteins caveolin‐1, clathrin, and hypoxia‐inducible factor (HIF)‐1α were upregulated by HG after MCAO and reperfusion.ConclusionOur study provides solid structural evidence to understand the role of endothelial transcytosis in HG‐elicited BBB hyperpermeability. Enhanced transcytosis occurs prior to the physical breakdown of BMECs and is a promising therapeutic target to preserve BBB integrity.     

Beyond barrier functions: Roles of pericytes in homeostasis and regulation of neuroinflammation

Pericytes are contractile cells that extend along the vasculature to mediate key homeostatic functions of endothelial barriers within the body. In the central nervous system (CNS), pericytes are important contributors to the structure and function of the neurovascular unit, which includes endothelial cells, astrocytes and neurons. The understanding of pericytes has been marred by an inability to accurately distinguish pericytes from other stromal cells with similar expression of identifying markers. Evidence is now growing in favor of pericytes being actively involved in both CNS homeostasis and pathology of neurological diseases, including multiple sclerosis, spinal cord injury, and Alzheimer's disease among others. In this review, we discuss the current understanding on the characterization of pericytes, their roles in maintaining the integrity of the blood–brain barrier, and their contributions to neuroinflammation and neurorepair. Owing to its plethora of surface receptors, pericytes respond to inflammatory mediators such as CCL2 (monocyte chemoattractant protein-1) and tumor necrosis factor-α, in turn secreting CCL2, nitric oxide, and several cytokines. Pericytes can therefore act as promoters of both the innate and adaptive arms of the immune system. Much like professional phagocytes, pericytes also have the ability to clear up cellular debris and macromolecular plaques. Moreover, pericytes promote the activities of CNS glia, including in maturation of oligodendrocyte lineage cells for myelination. Conversely, pericytes can impair regenerative processes by contributing to scar formation. A better characterization of CNS pericytes and their functions would bode well for therapeutics aimed at alleviating their undesirable properties and enhancing their benefits.     

曲克芦丁脑蛋白水解物对大脑中动脉栓塞后大鼠神经血管单元的保护作用

目的 验证曲克芦丁脑蛋白水解物对局灶性脑缺血后神经血管单元的保护作用,探讨其保护作用的 机制。 方法 采用大脑中动脉栓塞（middle c erebral a rtery o cclusion,MCAO）制备大鼠局灶性脑缺血模型。 120只雄性SD大鼠,采用随机数字表法分成假手术（SHAM）组（n =40）、MCAO组（n =40）以及MCAO+曲 克芦丁治疗组（n =40）。MCAO+曲克芦丁治疗组于术后立即给予曲克芦丁3 ml/kg,1次/日腹腔注射 3 d。采用改良神经功能缺损评分（modified Neurological Severity Score,mNSS）分别评价栓塞后3 d、7 d、 14 d大鼠的行为改变;栓塞后3 d,采用7.0 T高分辨率磁共振的T2及动脉自旋标记（arterial spin label, ASL）序列评价梗死体积及梗死区血流变化;采用尼氏染色评价神经元存活率及形态学变化;采用 免疫荧光染色技术评价各组内皮细胞、星形胶质细胞及紧密连接标记分子表达的变化;采用蛋白质 印迹法评价各组3-硝基酪氨酸（3-nitrotyrosine,3-NT）、基质金属蛋白酶9（matrix metalloproteinase 9, MMP-9）及诱导型一氧化氮合酶（inducible nitric oxide synthase,iNOS）表达的变化。 结果 MCAO后3 d,MCAO组与SHAM组相比,ASL序列显示梗死区域血流显著减少;尼氏染色结果显示 神经元存活率降低,大量空泡形成,核固缩;免疫荧光显示内皮细胞及紧密连接标记分子减少而星 形胶质细胞增多;蛋白质印迹法结果显示iNOS、3-NT、MMP-9增多。而MCAO+曲克芦丁治疗组与MCAO组 相比,梗死区域血流显著增多,神经元存活率升高,内皮细胞、紧密连接标记分子增多,星形胶质细 胞减少,i NOS、3-NT、MMP-9减少。 结论 曲克芦丁脑蛋白水解物可以通过抑制iNOS和MMP-9的表达,减少3-NT的产生,从而对MCAO后 大鼠神经血管单元起到保护作用。     

Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis

Recent reports suggest that functional or structural defect of vascular components are implicated in amyotrophic lateral sclerosis (ALS) pathology. In the present study, we examined a possible change of the neurovascular unit consisting of endothelium (PCAM-1), tight junction (occludin), and basement membrane (collagen IV) in relation to a possible activation of MMP-9 in ALS patients and ALS model mice. We found that the damage in the neurovascular unit was more prominent in the outer side and preferentially in the anterior horn of ALS model mice. This damage occurred prior to motor neuron degeneration and was accompanied by MMP-9 up-regulation. We also found the dissociation between the PCAM-1-positive endothelium and GFAP-positive astrocyte foot processes in both humans and the animal model of ALS. The present results indicate that perivascular damage precedes the sequential changes of the disease, which are held in common between humans and the animal model of ALS, suggesting that the neurovascular unit is a potential target for therapeutic intervention in ALS.     

Biphasic roles of pentraxin 3 in cerebrovascular function after white matter stroke

Recent clinical studies suggest that pentraxin 3 (PTX3), which is known as an acute-phase protein that is produced rapidly at local sites of inflammation, may be a new biomarker of disease risk for central nervous system disorders, including stroke. However, the effects of PTX3 on cerebrovascular function in the neurovascular unit (NVU) after stroke are mostly unknown, and the basic research regarding the roles of PTX3 in NVU function is still limited. In this reverse translational study, we prepared mouse models of white matter stroke by vasoconstrictor (ET-1 or L-Nio) injection into the corpus callosum region to examine the roles of PTX3 in the pathology of cerebral white matter stroke. PTX3 expression was upregulated in GFAP-positive astrocytes around the affected region in white matter for at least 21 days after vasoconstrictor injection. When PTX3 expression was reduced by PTX3 siRNA, blood-brain barrier (BBB) damage at day 3 after white matter stroke was exacerbated. In contrast, when PTX3 siRNA was administered at day 7 after white matter stroke, compensatory angiogenesis at day 21 was promoted. In vitro cell culture experiments confirmed the inhibitory effect of PTX3 in angiogenesis, that is, recombinant PTX3 suppressed the tube formation of cultured endothelial cells in a Matrigel-based in vitro angiogenesis assay. Taken together, our findings may support a novel concept that astrocyte-derived PTX3 plays biphasic roles in cerebrovascular function after white matter stroke; additionally, it may also provide a proof-of-concept that PTX3 could be a therapeutic target for white matter-related diseases, including stroke.     

Effects of visual contrast on visual evoked potentials and Doppler signal

We studied visually evoked cerebral blood flow responses (VEFR) and visual evoked potentials (VEP) to different visual contrasts and analysed the relationship between them. The records were made from 35 healthy volunteers aged 38.6 +/- 10.1 years. The stimulus was a black-and-white checkerboard with visual contrasts (VC) of 1%, 10% and 100%. The VEFR were measured in the posterior cerebral artery using transcranial Doppler, and the VEP were recorded from the occipital leads. We found the relationship between visual contrast and VEFR (r = 0.79, P < 0.01) as well as between visual contrast and VEP (r = 0.71, P < 0.01). We also found moderate association between the VEP and the VEFR (r = 0.69, P < 0.01). The analysis of the regression slopes between two different age subgroups (P < 0.01) did not show a significant difference (P = 0.020). We concluded that a simultaneous recording of VEFR and VEP to visual contrasts could allow an assessment of neurovascular coupling in humans.     

Therapeutic role of inflammasome inhibitors in neurodegenerative disorders

Neuroinflammation, characterized by the activation of glial cells, is a hallmark in several neurological and neurodegenerative disorders. Inadequate inflammation cannot eliminate the infection of pathogens, while excessive or hyper-reactive inflammation can cause chronic or systemic inflammatory diseases affecting the central nervous system (CNS). In response to a brain injury or pathogen invasion, the pathogen recognition receptors (PRRs) expressed on glial cells are activated via binding to cellular damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). This subsequently leads to the activation of NOD (nucleotide-binding oligomerization domain)-like receptor proteins (NLRs). In neurodegenerative diseases such as HIV-1-associated neurocognitive disorders (HAND), Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), chronic inflammation is a critical contributing factor for disease manifestation including pathogenesis. Emerging evidence points to the involvement of “inflammasomes”, especially the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) complex in the development of these diseases. The activated NLRP3 results in the proteolytic activation of caspase-1 that facilitates the cleavage of pro-IL-1β and the secretion of IL-1β and IL-18 proinflammatory cytokines. Accordingly, these and other seminal findings have led to the development of NLRP-targeting small-molecule therapeutics as possible treatment options for neurodegenerative disorders. In this review, we will discuss the new advances and evidence-based literature concerning the role of inflammasomes in neurodegenerative diseases, its role in the neurological repercussions of CNS chronic infection, and the examples of preclinical or clinically tested NLRP inhibitors as potential strategies for the treatment of chronic neurological diseases.     

In vivo quantification of blood-brain transfer and binding of [125I]HEAT, an alpha 1-adrenoceptor antagonist

The uptake and binding constants of [125I]iodo-2-[beta-(4-hydroxyphenyl)-ethyl-amino-methyl]tetralone ( [125I]HEAT) in rat brain were determined in vivo. The initial clearance of the radioligand from blood to brain, K1, was calculated from the initial uptake of the radioligand; it averaged 0.21 +/- 0.01 (SD) ml g-1 min -1, consistent with an initial extraction of 25% (i.e., one-quarter of the blood flow). The most strongly binding regions included the olfactory bulb, thalamic nuclei, medial geniculate body, and cerebral cortical layers. We identified saturable, specific binding in frontal cortex layers 1, 5a, and 5c (motor region), frontal cortex layers 3+4, ventral thalamic nuclei, medial geniculate body, striatum, cerebellum, and olfactory bulb. Addition of unlabeled ligand depressed binding in all regions to the same low level (partition coefficient) of 0.8 ml g-1. Displacement of [125 I]HEAT binding by unlabeled HEAT yielded a global affinity constant (KDVd) of 34 +/- 8 pmol g-1 and receptor densities (Bmax) that varied from 50 pmol g-1 in cerebellar cortex and caudate nucleus to 200 pmol g-1 in the region of highest specific binding, the medial geniculate body.