Subarachnoid Hemorrhage and Delayed Cerebral Ischemia: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Henry W. Sanicola
,
Caleb E. Stewart
,
Patrick Luther
,
Kevin Yabut
,
Bharat Guthikonda
,
J. Dedrick Jordan
,
J. Steven Alexander

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke resulting from the rupture of an arterial vessel within the brain. Unlike other stroke types, SAH affects both young adults (mid-40s) and the geriatric population. Patients with SAH often experience significant neurological deficits, leading to a substantial societal burden in terms of lost potential years of life. 

  • AHA
  • subarachnoid hemorrhage
  • cerebral vasospasm
  • delayed cerebral ischemia

1. Early Brain Injury and Acute Ischemia (0–3 Days)

1.1. Glycocalyx

The glycocalyx is an important layer lining the internal wall of blood vessels as it can attenuate BBB permeability and is a vasculoprotective [1] barrier between the circulating blood and the endothelium facing the lumen [2][3]. The glycocalyx consists predominantly of proteoglycan and a glycoprotein backbone with glycosaminoglycan connections [1]. It is under constant remodeling due to hemodynamic changes, enzymatic degradation, and shear stress [2]. Interestingly, SAH can disrupt the glycocalyx, often associated with the upregulation of inflammatory cytokine production, reduced nitric oxide production, and neurovascular uncoupling [4].
aSAH can trigger upregulation of pro-inflammatory cytokines (e.g., TNF-alpha, IL-1, IL-6), which can in turn initiate cytokine-induced breakdown of the glycocalyx, leading to endothelium and adhesion molecule (i.e., VCAM, ICAM) dysfunction [4][5][6][7]. While glycocalyx degradation can expose the endothelium to pro-inflammatory cytokine-mediated damage, it also reduces endothelial nitric oxide [4].
During SAH, glycocalyx degradation occurs from the increased expression of inflammatory markers (e.g., IL-1, IL-6, TNF-alpha), atrial natriuretic peptides, and vascular shear stress [3]. Following disruption of the glycocalyx, endothelial NO production is disrupted, leading to vascular smooth muscle cell-mediated vasoconstriction [8]. Additionally, glycocalyx’s breakdown exposes its molecular backbone, which contains the molecules glypican and heparin sulfate, both of which serve to increase neutrophil migration and adhesion and potentiate platelet activation [9][10]. These compounding factors lead to further vascular compromise.

1.2. Endothelial Dysfunction and Neuroinflammation

Endothelial dysfunction in aSAH is characterized by the loss of NO production, unregulated coagulation (via coagulation cascade dysfunction), and enhanced permeability due to glycocalyx impairment [11][12]. Loss of the glycocalyx promotes coagulation since anticoagulant molecules (e.g., anti-thrombin, tissue factor inhibitor pathway, and vWF) are decreased to prevent platelet adhesion and aggregation [4]. aSAH-mediated damage to the endothelium can also decrease prostacyclin release, which prevents platelet adhesion [4]. Furthermore, TNF-α stimulates exposed endothelium to upregulate P-selectin and increase platelet–leukocyte–endothelial cell interactions [13][14].

1.3. Neuroinflammation

aSAH can lead to infiltration of neutrophils at the site of injury, along with systemic neutrophilia via enhanced IL-6 [15]. This process precipitates neutrophil recruitment to the brain between 12 and 48 h following aSAH [16]. Additionally, microglia activation and monocyte recruitment readily occur within the first 48 h of aSAH to promote neuroinflammation [16]. Neutrophil accumulation on endothelial membranes increases oxidative stress (via myeloperoxidase) and lipid peroxidation, resulting in endothelium damage [15][17][18][19]. Toll-like receptor 4 (TLR4) is enhanced in the activated microglia and macrophages, resulting in the secretion of TNF [20]. Free heme from RBC hemolysis forms reactive oxygen species, resulting in upregulation of metalloproteinase-9 (MMP-9) and breakdown of the vascular basement membrane [21].

1.4. Astrocytes

Naïve astrocyte activation occurs during SAH, transforming the cells into the A1 neurotoxic phenotype [22][23]. The A1 phenotype is characterized by upregulation of glial fibrillary acidic protein (GFAP), S100 calcium binding protein B (S100B), and C3, H2-D1, and serping1 cell markers [24]. A1 astrocytes are a form of reactive astrocyte, promoting cell death by releasing proinflammatory cytokines [23]. A2 astrocytes are another phenotypic variant in reactive astrocytes that play a neuroprotective role, in contrast to the dominant A1 neurotoxic phenotype found in SAH [25][26][27][28]. Reactive astrocytes (RAs) display a spectrum of pro- and anti-inflammatory profiles, rather than the simple A1 and A2 phenotypes based on genetic sequencing [29]. Overall, the pro-inflammatory RAs found in SAH exhibit strong neurotoxicity—forming fewer synapses and killing neurons with detached axons [30][31]. Activated astrocytes also undergo morphological changes after SAH, such as end feet swelling and protrusions compressing the capillary lumen [32].

1.5. Glymphatic System

The glymphatic system (GS) is a fluid exchange and drainage system supported by glial cells [33]. The GS includes the entire peripheral vascular system and consists of periarterial cerebrospinal fluid inlets and perivenous interstitial fluid (ISF) outlets [33]. Astrocytic end plates mediate the transport of metabolites via aquaporin-4 (AQP4) channels [34]. This transport system was confirmed with the use of fluorescent tracers administered into the brain parenchyma, which showed deposition in the meningeal lymphatic vessels and ultimately the deep cervical lymph nodes (dCLNs) [35]. Overall, the glymphatic system facilitates transport and clearance of metabolic waste under normal physiologic conditions [36], while during SAH, the glymphatic system is involved in the clearance of neurotoxic solutes, pro-inflammatory cytokines, and erythrocytes [33][37].
After the initial SAH event, blood and its metabolites rapidly leak into the PVS. Blood in the PVS diffuses into the perivascular parenchyma via the GS, leading to a cascade of glial activation, neurotoxicity, and widespread microcirculatory dysfunction in the brain [38]. A recent study performed by Chen et al. found that meningeal lymphatics drained extravasated erythrocytes into the cerebral spinal fluid [37]. Following experimental ablation of meningeal lymphatics via the injection of Visudyne, there was a measurable decline in RBCs found in the cervical nymph nodes [37]. Additionally, following meningeal ablation, neuroinflammation and neurologic deficits were increased in a rodent model. Persistent malfunction of glymphatic and meningeal drainage was observed in an SAH mouse model by Pu et al. [39]. Decreased tracer was observed in the SAH mice compared to controls in meningeal lymphatic vessels and dcLNs [39], suggesting that SAH impairs the ability of meningeal lymphatic vessels to drain cellular debris, immune cells, and inflammatory mediators [40][41]. Additionally, glial cells lining the glymphatic regions become activated in SAH mice, as determined by increased levels of IL-1β, IL-6, and TNF-α expression [39]. This process results in AQP4 upregulation surrounding the arteries, while the AQP4 expression remains the same at the drainage sites around the veins [42]. Consequently, impaired PVS and ISF flow reduces metabolite and hemorrhagic clearance, leading to intermediate injury via immune cell accumulation [43], BBB dysfunction [44], neuronal apoptosis [39], vasculitis [38], cerebral edema [45], and acute hydrocephalus [46].

1.6. SAH and the Intramural Periarterial Drainage (IPAD)

In addition to the glymphatic system, there is another drainage system called the intramural periarterial drainage (IPAD), which has been described as functioning in parallel with the glymphatic system. This system can also be affected during subarachnoid hemorrhage (SAH). Interstitial fluid (ISF), which is the fluid found between brain cells, can drain from the brain along the basement membranes of arteries through the IPAD pathway. Disruptions in the IPAD pathway can lead to problems with proteostasis in the brain, such as in cerebral amyloid angiopathy or Alzheimer’s disease. A study by Sun et al. [47] examined disturbances in the IPAD pathway after SAH in rats. In that study, the authors injected dyes of different sizes into the cisterna magna, a fluid-filled compartment at the back of the brain in the posterior cranial fossa. The cisterna magna is one of the subarachnoid spaces, which is filled with cerebrospinal fluid (CSF) and surrounds the brain and spinal cord. Sun’s group observed that these dyes entered the brain through periarterial channels and were cleared through the basement membranes of the brain’s associated capillaries. Interestingly, different molecular weight tracers showed different patterns of clearance. SAH significantly disrupted the IPAD pathway, causing enlargement of spaces around the blood vessels where ISF clearance was reduced. This effect was related to endothelial cell death, activation of astrocytes (a type of brain cell), increased levels of matrix metalloproteinase-9, and loss of type IV collagen in the basement membrane. Consequently, experimental SAH in rats has been found to significantly disrupt the IPAD pathway, which could have important clinical implications for SAH.

2. Intermediate Injury (3–5 Days)

2.1. BBB Dysfunction

A hallmark of SAH is BBB degradation [48] in the form of endothelial and pericyte dysfunction [49]. Extracellular matrix proteins are also degraded following SAH-mediated degradation of endothelial cells [50].
Cytokines are locally released following SAH-mediated neuroinflammation to degrade cell adhesion molecules (i.e., ICAM-VCAM). Moreover, SAH-mediated neuroinflammation can cause a leaky BBB, which has been shown to decrease tight junction proteins such as ZO-1, occludin, and JAMa.
Pericytes are also important regulators in response to the change in cerebral blood flow with respect to local neuronal activity [51][52][53]. Pericytes also regulate and maintain the BBB by supporting tight junctional proteins [54]. Three to five days after brain injury, glycocalyx breakdown and endothelial dysfunction lead to increased BBB permeability [55]. BBB leakage allows for plasma protein extravasation, such as albumin, activating astrocytes, which in turn disrupt the neurovascular coupling [56]. More importantly, due to increased BBB leakage, extravasation of plasma proteins into the brain parenchyma is a major contributor to brain edema [56][57].
Pericytes amplify the inflammatory response by increasing their expression of microglial markers [58], upregulating periarterial AQP4 anchored in astrocytic end feet [59][60] and enabling extravasation of immune cells [61]. Smooth muscle cells (SMCs) undergo phenotypic transformation and migrate to the subepithelial layer [62]. IL-1β stimulates SMC proliferation in cerebral arteries and arterioles [63] and pericyte invasion of capillary networks, producing basement membrane remodeling [64]. Migration of transformed pericytes and SMCs increases the propensity for vessel spasm [65][66][67]. EC apoptosis starts around 24 h following SAH [68].
Astrocytes also modulate local vasoconstriction and vasodilation by releasing vasoactive compounds that stimulate 20-hydroxyeicosa-tetraenoic acid (20-HETE) production in pericytes [69], Intracellular Ca2+ concentrations in pericytes are also regulated by astrocytes promoting contraction [51][70]. Upregulation of AQP4 in astrocytes accelerates the formation of cytotoxic brain edema, leading to intracellular water accumulation [71][72]. Early in SAH, cellular edema in astrocytes produces an influx of ionic and vasogenic edema, leading to parenchymal edema [57]. Ionic edema develops when osmotic forces in the vasculature propel plasma through the vessel wall into the CNS [57]. The trans-endothelial Na+ gradient increases across the endothelium, leading to Na+ accumulation in the brain parenchyma [73]. This effect is magnified with early-onset CSF hypersecretion by the choroid plexi during SAH [74][75] and declining ISF efflux [76]. The large increase in parenchymal influx from extravasation and hydrocephalus exceeds the clearance rate provided by the glymphatic system. Tight junction breakdown and EC dysfunction contribute to vasogenic edema (e.g., extravasation of plasma proteins) [57]. Increased BBB permeability, cell death, and microvascular spasm and decreased ISF waste clearance escalate shifts in ion and water balance [57][77][78]. This process leads to neurovascular uncoupling, resulting in increased neuron susceptibility to terminal injury from cortical spreading depolarizations [79], excitotoxicity [80], neuronal apoptosis [43], and secondary brain injury [81].

2.2. Neurovascular Uncoupling

The neurovascular unit (NVU) is comprised of the BBB (e.g., ECs, pericytes, SMCs, astrocytes) and its communication with neurons and microglia [82]. The NVU serves to modulate pressure to local regions under normal physiologic conditions, such as regions that process reading, arithmetic, languages, etc. The NVU can also respond to pathophysiologic stimuli, such as seizures or CSD. The neurovascular unit is coupled when the local blood supply matches neuronal demand via modulation of vascular diameter [83]. The cellular interactions in the NVU dynamically regulate this activity [84]. Glutamate released from neurons stimulates nearby astrocytes and pericytes, generating vasoactive molecules [85]. The concentration of vasoconstrictor and vasodilator mediators determines the tone of the surrounding vasculature, modulating CBF [85]. In this model, neurons are “pacemakers” within the NVU model in that they regulate CBF [84]. For example, administration of catecholamines (e.g., dopamine, norepinephrine, and epinephrine) to neurons modifies EC tight junction protein production, thus changing BBB permeability [86]. All components in the NVU may modulate BBB maintenance [87]. Similarly, these components all coordinate to tightly control the CNS ionic microenvironment and ensure optimal neuronal functioning [88]. These processes include having specialized functions for neurotransmitters, maintaining low protein concentrations, preventing CNS exposure to neurotoxins, and limiting inflammatory processes [88]. The main function of astrocytes in the NVU is to regulate nutrient exchange by changing the tight junction density [89][90][91].
BBB breakdown following SAH disrupts the NVU, leading to neuronal hyperexcitability [92]. Neuroinflammation occurring in the CNS decreases the seizure threshold due to rapid changes in glutamate and γ-aminobutyric acid (GABA) receptor phosphorylation and channelopathies [93][94]. In rodent and pig models, BBB breakdown synchronized neuronal activity and increased seizure activity [95][96]. Albumin extravasation contributes to neuronal excitotoxicity by disrupting astrocytic K+ buffering capacity [92]. Albumin injection in naïve rats downregulated astrocytic Kir4.1 channels, leading to transient spiking activity [97]. These findings support neuroinflammation and albumin influx as drivers of neuronal network hyperexcitability [89].
During the intermediate phase (3–5 days post-SAH) neurovascular coupling is compromised following BBB dysfunction [98]. The brain tissue is particularly vulnerable during this period (3–5 days post-hemorrhage); cerebral vasospasm (CVS) is likely to occur during this period and further exacerbate damage to the brain parenchyma [99]. Neurovascular uncoupling occurs when there is a mismatch between blood supply and neuronal demand [4]. Uncoupling is exacerbated by neuronal hyperexcitability (e.g., increased metabolic activity), dysregulated vascular contractility, and decreased metabolic waste clearance, thus reducing the neuronal energy supply, leading to apoptosis [100]. The glymphatic system continues to deteriorate as SAH progresses, with loss of gap junctions (GJ) connecting neighboring astrocytes [101][102]. GJ loss limits neurotransmitter uptake, ion buffering, and glucose distribution for stable neuronal activity [103][104][105].

3. Delayed Injury (5–14 Days)

Loss of astrocytic GJs contributes to astroglial network compromise and subsequent astrocytic apoptosis [106][107]. However, loss of the astrocytic GJ loss diminishes the spread of Ca2+ waves, preventing synchronized activity between neurons and vascular SMCs [108]. Concurrently, disconnection between neurons and the supporting astroglial network hinders the neuronal energy supply [109]. In the setting of hypoglycemia or periods of neuronal hyperactivity, astrocytes monopolize the energy supply [110][111]. This cellular strategy provides another energy source (e.g., astrocyte–neuron lactate shuttle) for neurons during periods of excessive energy demand [112]. In SAH, astrocytic apoptosis is favored to precede neuronal apoptosis [107].
The deregulated neuronal activity of astrocytes depletes the neuronal energy supply and disrupts Na+–K+ pumps, which maintain ion homeostasis [113]. The means for neuronal ATP production are also impaired without the supporting astroglial network [113]. Injured neurons incur further injury from reactive Ca2+ influx, leading to large amounts of glutamate release, triggering local depolarizations [114]. Cortical spreading depolarizations (CSDs) consist of recurrent waves of neuronal and glial depolarizations that propagate widely from the onset zone [115]. CSDs begin under hypoxic conditions, strained energy supplies (e.g., glucose), and exposure to oxyhemoglobin following SAH [116][117]. CSDs peak at days 5–7 following aneurysmal SAH [118]. Changes in the neuronal microenvironment lead to massive glutamate release, loss of membrane potential, and CSD throughout the brain parenchyma [119]. If injured neurons cannot restore membrane potentials using Na–K+ pumps, the associated neurons and astrocytes swell and distort the dendritic connections [120]. CSDs eventually evolve into epileptiform discharges or pathologic changes in electrical potentials, silencing brain electrical activity [121]. Epileptiform discharges transmit greater disturbances in ion homeostasis between the intracellular and extracellular environments, resulting in neuronal swelling and glutamate receptor upregulation [121][122]. Underlying epileptiform discharges are neurons stuck in field potentials that are less than the inactivation threshold for channels generating action potentials [116]. Thus, neurons fire at high frequencies, producing moderately sustained depolarizations and less hyperpolarization [116][123].

Cellular Changes

When metabolic demand exceeds the energy supply provided by the neurovascular unit (e.g., glucose delivery, cerebral blood flow), neuronal ischemia and apoptosis occur [124]. Within minutes, neuronal necrosis surpasses apoptosis as the primary form of cell death within the brain’s parenchyma [125]. The neuroinflammatory response is caused by an increase in neuroinflammatory signaling agents, such as IL-6, PAF, T-cells, and macrophages. The cytokines/chemokines involved are p53, Fas/FasL, tumor necrosis factor receptor, caspase 9 and apoptosis inducing factor [126]. These cytokines and chemokines lead to increased cell death of the brain’s parenchyma [127].
During the late or delayed stage (5–14 days post-SAH), CSDs peak in their occurrence. These peaks are associated with loss of neurovascular autoregulation. This loss is due to deranged NO/NOS signaling following changes to eNOS, nNOS, and iNOS [128]. During this phase, RBCs begin to break down/lyse within the subarachnoid spaces and increase oxyhemoglobin and ferritin concentrations within the brain parenchyma, causing further cerebral vasospasm [129].
The mass effect within the cranial vault physically displaces the brain parenchyma. The displaced parenchyma moves from a higher-pressure region (adjacent to the growing hematoma) to lower-pressure/resistance region(s) (e.g., lumens [openings] within the cranial vault). This process is problematic since, within the cranial vault, these openings are occupied by critical structures (e.g., brainstem, cranial nerves, vertebral arteries and veins) [130]. The brainstem controls functions such as respiration, blood pressure regulation, and other autonomic functions required for life. Compression of the brainstem leads to the loss of these critical autonomic functions [131][132][133][134].
Initially described by Ecker and Riemenschneider in 1951 [135], the association of CVS following SAH has been well documented. However, the exact mechanisms of CVS following SAH have been contested within the recent literature [136]. Previously, the accepted model of CVS, as described by Allcock and Drake [137], was that it occurred in the setting of focal ischemia experienced by the brain parenchyma during SAH and with a peak occurrence at 5–14 days post-initial hemorrhagic event [138]. Additionally, there exists a positive correlation between hemorrhage volume (HV) and the severity of CVS; this correlation has been recognized for its clinical utility and is used as the basis for the Fisher scale [139]. Recently, an ongoing clinical trial examined deferoxamine (i-Def), an iron chelating agent that sequesters the iron component of red blood cells. When i-Def was introduced into the brain’s parenchyma during a hemorrhagic event, initial results from second-phase clinical trials [140] were promising for reducing stroke sequalae [141]. If HV was less than 10 mL, the iatrogenic complications can outweigh any benefit that otherwise would be conferred by i-Def [142].
The link between cerebral vasospasm following the accumulation of blood degradation byproducts has been well established for several decades and was described by Toda and Ohta [143]. Recently, it has been shown that a potent inflammatory marker, oxyhemoglobin, is implicated in CVS, replacing the previously targeted methemoglobin and bilirubin as inflammatory markers [144][145]. The exact mechanism by which these substances induce CVS is still not well understood, although several features have been described. When injected intrathecally, oxyhemoglobin has been shown to induce CVS [136]. The mechanisms by which this outcome occurs is through the modification of normal expression of eicosanoids; oxyhemoglobin will increase the production of PGE2 and decrease PGI2 levels. Both eicosanoids are important in maintaining vascular tonicity. When oxyhemoglobin contacts methemoglobin, it spontaneously releases superoxide, which in turn causes lipid peroxidation, as well as vasoconstriction [136].
Additional substances released into the brain parenchyma during structural compromise of the vessel wall come from the spillage of intervascular wall components (intracellular enzymes and proteins) [146] that are cytotoxic to surrounding CNS tissue. Within minutes, there are gross anatomical and cellular changes to the CNS vasculature, e.g., mechanical/physical compression of neighboring/adjacent vessels, occluding their internal lumen(s), as well as compression of CNS tissue [147][148]. Regarding the cellular changes, notable is the disruption to chemosignaling agents (vasodilators/vasoconstrictors). These signaling agents under normal physiologic conditions are kept in a delicate balance to maintain the CNS vessels’ ability to autoregulate their tone [149].
Following the loss of cerebrovascular autoregulation, ICP equalizes to diastolic blood pressure (DBP) [148]. Given that DBP is several fold greater than normal CNS pressures (80–100 mm Hg and 7–15 mm Hg, respectively), the pressure differential can cause lateral displacement and subsequent compression of CNS tissue [150].
Ultimately, the compounding anatomical and cellular changes further contribute to a loss of micronutrients (perfusion) to local tissues and lack of clearance of toxic metabolic byproducts [148][151]. Within minutes of changes to perfusion, the cell’s ionic transmembrane gradient, which is crucial for normal neuro-signaling, becomes deranged [152]. This outcome follows the failure of adenosine triphosphatase’s ability to maintain the gradient in hypoxic conditions and thus its reliance on relatively ineffective anerobic pathways.
Following SAH, arterial vasospasm can occur, independently impairing perfusion (excluding non-spasmodic causes, e.g., clots, rupture of an atherosclerotic plaque, or embolus). Traditionally, this outcome has been detected by means of transcranial ultrasound (TCD) performed at the patient’s bedside approximately 2–3 days post-initial insult [153][154]. TCD is performed when vasospasm is suspected [155]. Currently, clinicians rely upon alterations in mentation or focal neurologic changes to escalate to imaging modalities for affected patients. In practice, these include shifts in the patient’s level of consciousness (neurobehavioral changes) or any new-onset focal neurologic defects [156]. However, this process can be challenging in patients who are intubated and/or comatose, especially for junior clinicians [157].

This entry is adapted from the peer-reviewed paper 10.3390/pathophysiology30030032

References

  1. Reitsma, S.; Slaaf, D.W.; Vink, H.; van Zandvoort, M.A.; oude Egbrink, M.G. The Endothelial Glycocalyx: Composition, Functions, and Visualization. Pflugers Arch. 2007, 454, 345–359.
  2. Cosgun, Z.C.; Fels, B.; Kusche-Vihrog, K. Nanomechanics of the Endothelial Glycocalyx: From Structure to Function. Am. J. Pathol. 2020, 190, 732–741.
  3. Schott, U.; Solomon, C.; Fries, D.; Bentzer, P. The Endothelial Glycocalyx and Its Disruption, Protection and Regeneration: A Narrative Review. Scand. J. Trauma. Resusc. Emerg. Med. 2016, 24, 48.
  4. Schenck, H.; Netti, E.; Teernstra, O.; De Ridder, I.; Dings, J.; Niemela, M.; Temel, Y.; Hoogland, G.; Haeren, R. The Role of the Glycocalyx in the Pathophysiology of Subarachnoid Hemorrhage-Induced Delayed Cerebral Ischemia. Front. Cell Dev. Biol. 2021, 9, 731641.
  5. Schneider, U.C.; Xu, R.; Vajkoczy, P. Inflammatory Events Following Subarachnoid Hemorrhage (SAH). Curr. Neuropharmacol. 2018, 16, 1385–1395.
  6. Mastorakos, P.; McGavern, D. The Anatomy and Immunology of Vasculature in the Central Nervous System. Sci. Immunol. 2019, 4, eaav0492.
  7. Choi, S.J.; Lillicrap, D. A Sticky Proposition: The Endothelial Glycocalyx and von Willebrand Factor. J. Thromb. Haemost. 2020, 18, 781–785.
  8. Blatter, L.A.; Wier, W.G. Nitric Oxide Decreases i in Vascular Smooth Muscle by Inhibition of the Calcium Current. Cell Calcium 1994, 15, 122–131.
  9. Battinelli, E.; Willoughby, S.R.; Foxall, T.; Valeri, C.R.; Loscalzo, J. Induction of Platelet Formation from Megakaryocytoid Cells by Nitric Oxide. Proc. Natl. Acad. Sci. USA 2001, 98, 14458–14463.
  10. Freitas, A.; Alves-Filho, J.C.; Secco, D.D.; Neto, A.F.; Ferreira, S.H.; Barja-Fidalgo, C.; Cunha, F.Q. Heme Oxygenase/Carbon Monoxide-Biliverdin Pathway down Regulates Neutrophil Rolling, Adhesion and Migration in Acute Inflammation. Br. J. Pharmacol. 2006, 149, 345–354.
  11. Friedrich, V.; Flores, R.; Muller, A.; Sehba, F.A. Escape of Intraluminal Platelets into Brain Parenchyma after Subarachnoid Hemorrhage. Neuroscience 2010, 165, 968–975.
  12. Iuliano, B.A.; Pluta, R.M.; Jung, C.; Oldfield, E.H. Endothelial Dysfunction in a Primate Model of Cerebral Vasospasm. J. Neurosurg. 2004, 100, 287–294.
  13. Gotsch, U.; Jager, U.; Dominis, M.; Vestweber, D. Expression of P-Selectin on Endothelial Cells Is Upregulated by LPS and TNF-Alpha in Vivo. Cell Adhes. Commun. 1994, 2, 7–14.
  14. Ishikawa, M.; Kusaka, G.; Yamaguchi, N.; Sekizuka, E.; Nakadate, H.; Minamitani, H.; Shinoda, S.; Watanabe, E. Platelet and Leukocyte Adhesion in the Microvasculature at the Cerebral Surface Immediately after Subarachnoid Hemorrhage. Neurosurgery 2009, 64, 546–553, discussion 553–554.
  15. Fumoto, T.; Naraoka, M.; Katagai, T.; Li, Y.; Shimamura, N.; Ohkuma, H. The Role of Oxidative Stress in Microvascular Disturbances after Experimental Subarachnoid Hemorrhage. Transl. Stroke Res. 2019, 10, 684–694.
  16. Gris, T.; Laplante, P.; Thebault, P.; Cayrol, R.; Najjar, A.; Joannette-Pilon, B.; Brillant-Marquis, F.; Magro, E.; English, S.W.; Lapointe, R.; et al. Innate Immunity Activation in the Early Brain Injury Period Following Subarachnoid Hemorrhage. J. Neuroinflam. 2019, 16, 253.
  17. Sen, O.; Caner, H.; Aydin, M.V.; Ozen, O.; Atalay, B.; Altinors, N.; Bavbek, M. The Effect of Mexiletine on the Level of Lipid Peroxidation and Apoptosis of Endothelium Following Experimental Subarachnoid Hemorrhage. Neurol. Res. 2006, 28, 859–863.
  18. Sabri, M.; Jeon, H.; Ai, J.; Tariq, A.; Shang, X.; Chen, G.; Macdonald, R.L. Anterior Circulation Mouse Model of Subarachnoid Hemorrhage. Brain Res. 2009, 1295, 179–185.
  19. Coulibaly, A.P.; Pezuk, P.; Varghese, P.; Gartman, W.; Triebwasser, D.; Kulas, J.A.; Liu, L.; Syed, M.; Tvrdik, P.; Ferris, H.; et al. Neutrophil Enzyme Myeloperoxidase Modulates Neuronal Response in a Model of Subarachnoid Hemorrhage by Venous Injury. Stroke 2021, 52, 3374–3384.
  20. Kwon, M.S.; Woo, S.K.; Kurland, D.B.; Yoon, S.H.; Palmer, A.F.; Banerjee, U.; Iqbal, S.; Ivanova, S.; Gerzanich, V.; Simard, J.M. Methemoglobin Is an Endogenous Toll-like Receptor 4 Ligand-Relevance to Subarachnoid Hemorrhage. Int. J. Mol. Sci. 2015, 16, 5028–5046.
  21. Seo, K.W.; Lee, S.J.; Kim, Y.H.; Bae, J.U.; Park, S.Y.; Bae, S.S.; Kim, C.D. Mechanical Stretch Increases MMP-2 Production in Vascular Smooth Muscle Cells via Activation of PDGFR-Beta/Akt Signaling Pathway. PLoS ONE 2013, 8, e70437.
  22. Ma, M.; Li, H.; Wu, J.; Zhang, Y.; Shen, H.; Li, X.; Wang, Z.; Chen, G. Roles of Prokineticin 2 in Subarachnoid Hemorrhage-Induced Early Brain Injury via Regulation of Phenotype Polarization in Astrocytes. Mol. Neurobiol. 2020, 57, 3744–3758.
  23. Zhang, L.; Guo, K.; Zhou, J.; Zhang, X.; Yin, S.; Peng, J.; Liao, Y.; Jiang, Y. Ponesimod Protects against Neuronal Death by Suppressing the Activation of A1 Astrocytes in Early Brain Injury after Experimental Subarachnoid Hemorrhage. J. Neurochem. 2021, 158, 880–897.
  24. Zamanian, J.L.; Xu, L.; Foo, L.C.; Nouri, N.; Zhou, L.; Giffard, R.G.; Barres, B.A. Genomic Analysis of Reactive Astrogliosis. J. Neurosci. 2012, 32, 6391–6410.
  25. Fei, X.; Dou, Y.N.; Wang, L.; Wu, X.; Huan, Y.; Wu, S.; He, X.; Lv, W.; Wei, J.; Fei, Z. Homer1 Promotes the Conversion of A1 Astrocytes to A2 Astrocytes and Improves the Recovery of Transgenic Mice after Intracerebral Hemorrhage. J. Neuroinflam. 2022, 19, 67.
  26. Hou, J.; Bi, H.; Ge, Q.; Teng, H.; Wan, G.; Yu, B.; Jiang, Q.; Gu, X. Heterogeneity Analysis of Astrocytes Following Spinal Cord Injury at Single-Cell Resolution. FASEB J. 2022, 36, e22442.
  27. Luchena, C.; Zuazo-Ibarra, J.; Valero, J.; Matute, C.; Alberdi, E.; Capetillo-Zarate, E. A Neuron, Microglia, and Astrocyte Triple Co-Culture Model to Study Alzheimer’s Disease. Front. Aging Neurosci. 2022, 14, 844534.
  28. Wang, L.; Wu, L.; Duan, Y.; Xu, S.; Yang, Y.; Yin, J.; Lang, Y.; Gao, Z.; Wu, C.; Lv, Z.; et al. Phenotype Shifting in Astrocytes Account for Benefits of Intra-Arterial Selective Cooling Infusion in Hypertensive Rats of Ischemic Stroke. Neurotherapeutics 2022, 19, 386–398.
  29. Yu, G.; Zhang, Y.; Ning, B. Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy. Front. Cell Neurosci. 2021, 15, 792764.
  30. Liddelow, S.A.; Barres, B.A. Reactive Astrocytes: Production, Function, and Therapeutic Potential. Immunity 2017, 46, 957–967.
  31. Lai, N.; Wu, D.; Liang, T.; Pan, P.; Yuan, G.; Li, X.; Li, H.; Shen, H.; Wang, Z.; Chen, G. Systemic Exosomal MiR-193b-3p Delivery Attenuates Neuroinflammation in Early Brain Injury after Subarachnoid Hemorrhage in Mice. J. Neuroinflam. 2020, 17, 74.
  32. Anzabi, M.; Ardalan, M.; Iversen, N.K.; Rafati, A.H.; Hansen, B.; Ostergaard, L. Hippocampal Atrophy Following Subarachnoid Hemorrhage Correlates with Disruption of Astrocyte Morphology and Capillary Coverage by AQP4. Front. Cell Neurosci. 2018, 12, 19.
  33. Lv, T.; Zhao, B.; Hu, Q.; Zhang, X. The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment. Front. Aging Neurosci. 2021, 13, 689098.
  34. Benveniste, H.; Liu, X.; Koundal, S.; Sanggaard, S.; Lee, H.; Wardlaw, J. The Glymphatic System and Waste Clearance with Brain Aging: A Review. Gerontology 2019, 65, 106–119.
  35. Louveau, A.; Smirnov, I.; Keyes, T.J.; Eccles, J.D.; Rouhani, S.J.; Peske, J.D.; Derecki, N.C.; Castle, D.; Mandell, J.W.; Lee, K.S.; et al. Structural and Functional Features of Central Nervous System Lymphatic Vessels. Nature 2015, 523, 337–341.
  36. Wichmann, T.O.; Damkier, H.H.; Pedersen, M. A Brief Overview of the Cerebrospinal Fluid System and Its Implications for Brain and Spinal Cord Diseases. Front. Hum. Neurosci. 2021, 15, 737217.
  37. Chen, J.; Wang, L.; Xu, H.; Xing, L.; Zhuang, Z.; Zheng, Y.; Li, X.; Wang, C.; Chen, S.; Guo, Z.; et al. Meningeal Lymphatics Clear Erythrocytes That Arise from Subarachnoid Hemorrhage. Nat. Commun. 2020, 11, 3159.
  38. Luo, C.; Yao, X.; Li, J.; He, B.; Liu, Q.; Ren, H.; Liang, F.; Li, M.; Lin, H.; Peng, J.; et al. Paravascular Pathways Contribute to Vasculitis and Neuroinflammation after Subarachnoid Hemorrhage Independently of Glymphatic Control. Cell Death Dis. 2016, 7, e2160.
  39. Pu, T.; Zou, W.; Feng, W.; Zhang, Y.; Wang, L.; Wang, H.; Xiao, M. Persistent Malfunction of Glymphatic and Meningeal Lymphatic Drainage in a Mouse Model of Subarachnoid Hemorrhage. Exp. Neurobiol. 2019, 28, 104–118.
  40. Bolte, A.C.; Dutta, A.B.; Hurt, M.E.; Smirnov, I.; Kovacs, M.A.; McKee, C.A.; Ennerfelt, H.E.; Shapiro, D.; Nguyen, B.H.; Frost, E.L.; et al. Meningeal Lymphatic Dysfunction Exacerbates Traumatic Brain Injury Pathogenesis. Nat. Commun. 2020, 11, 4524.
  41. Louveau, A.; Herz, J.; Alme, M.N.; Salvador, A.F.; Dong, M.Q.; Viar, K.E.; Herod, S.G.; Knopp, J.; Setliff, J.C.; Lupi, A.L.; et al. CNS Lymphatic Drainage and Neuroinflammation Are Regulated by Meningeal Lymphatic Vasculature. Nat. Neurosci. 2018, 21, 1380–1391.
  42. Liu, E.; Peng, X.; Ma, H.; Zhang, Y.; Yang, X.; Zhang, Y.; Sun, L.; Yan, J. The Involvement of Aquaporin-4 in the Interstitial Fluid Drainage Impairment Following Subarachnoid Hemorrhage. Front. Aging Neurosci. 2020, 12, 611494.
  43. El Amki, M.; Dubois, M.; Lefevre-Scelles, A.; Magne, N.; Roussel, M.; Clavier, T.; Guichet, P.O.; Gerardin, E.; Compere, V.; Castel, H. Long-Lasting Cerebral Vasospasm, Microthrombosis, Apoptosis and Paravascular Alterations Associated with Neurological Deficits in a Mouse Model of Subarachnoid Hemorrhage. Mol. Neurobiol. 2018, 55, 2763–2779.
  44. Li, Y.; Li, M.; Yang, L.; Qin, W.; Yang, S.; Yuan, J.; Jiang, T.; Hu, W. The Relationship between Blood-Brain Barrier Permeability and Enlarged Perivascular Spaces: A Cross-Sectional Study. Clin. Interv. Aging 2019, 14, 871–878.
  45. Badaut, J.; Brunet, J.F.; Grollimund, L.; Hamou, M.F.; Magistretti, P.J.; Villemure, J.G.; Regli, L. Aquaporin 1 and Aquaporin 4 Expression in Human Brain after Subarachnoid Hemorrhage and in Peritumoral Tissue. Acta Neurochir. Suppl. 2003, 86, 495–498.
  46. Bloch, O.; Papadopoulos, M.C.; Manley, G.T.; Verkman, A.S. Aquaporin-4 Gene Deletion in Mice Increases Focal Edema Associated with Staphylococcal Brain Abscess. J. Neurochem. 2005, 95, 254–262.
  47. Sun, Y.; Liu, E.; Pei, Y.; Yao, Q.; Ma, H.; Mu, Y.; Wang, Y.; Zhang, Y.; Yang, X.; Wang, X.; et al. The Impairment of Intramural Periarterial Drainage in Brain after Subarachnoid Hemorrhage. Acta Neuropathol. Commun. 2022, 10, 187.
  48. Chen, S.; Xu, P.; Fang, Y.; Lenahan, C. The Updated Role of the Blood Brain Barrier in Subarachnoid Hemorrhage: From Basic and Clinical Studies. Curr. Neuropharmacol. 2020, 18, 1266–1278.
  49. Chen, Y.; Li, Q.; Tang, J.; Feng, H.; Zhang, J.H. The Evolving Roles of Pericyte in Early Brain Injury after Subarachnoid Hemorrhage. Brain Res. 2015, 1623, 110–122.
  50. George, N.; Geller, H.M. Extracellular Matrix and Traumatic Brain Injury. J. Neurosci. Res. 2018, 96, 573–588.
  51. Mishra, A.; Reynolds, J.P.; Chen, Y.; Gourine, A.V.; Rusakov, D.A.; Attwell, D. Astrocytes Mediate Neurovascular Signaling to Capillary Pericytes but Not to Arterioles. Nat. Neurosci. 2016, 19, 1619–1627.
  52. Kisler, K.; Nelson, A.R.; Rege, S.V.; Ramanathan, A.; Wang, Y.; Ahuja, A.; Lazic, D.; Tsai, P.S.; Zhao, Z.; Zhou, Y.; et al. Pericyte Degeneration Leads to Neurovascular Uncoupling and Limits Oxygen Supply to Brain. Nat. Neurosci. 2017, 20, 406–416.
  53. Cai, C.; Fordsmann, J.C.; Jensen, S.H.; Gesslein, B.; Lonstrup, M.; Hald, B.O.; Zambach, S.A.; Brodin, B.; Lauritzen, M.J. Stimulation-Induced Increases in Cerebral Blood Flow and Local Capillary Vasoconstriction Depend on Conducted Vascular Responses. Proc. Natl. Acad. Sci. USA 2018, 115, E5796–E5804.
  54. Sengillo, J.D.; Winkler, E.A.; Walker, C.T.; Sullivan, J.S.; Johnson, M.; Zlokovic, B.V. Deficiency in Mural Vascular Cells Coincides with Blood-Brain Barrier Disruption in Alzheimer’s Disease. Brain Pathol. 2013, 23, 303–310.
  55. Zhu, J.; Li, X.; Yin, J.; Hu, Y.; Gu, Y.; Pan, S. Glycocalyx Degradation Leads to Blood-Brain Barrier Dysfunction and Brain Edema after Asphyxia Cardiac Arrest in Rats. J. Cereb. Blood Flow. Metab. 2018, 38, 1979–1992.
  56. Friedman, A.; Kaufer, D.; Heinemann, U. Blood-Brain Barrier Breakdown-Inducing Astrocytic Transformation: Novel Targets for the Prevention of Epilepsy. Epilepsy Res. 2009, 85, 142–149.
  57. Stokum, J.A.; Gerzanich, V.; Simard, J.M. Molecular Pathophysiology of Cerebral Edema. J. Cereb. Blood Flow. Metab. 2016, 36, 513–538.
  58. Ozen, I.; Deierborg, T.; Miharada, K.; Padel, T.; Englund, E.; Genove, G.; Paul, G. Brain Pericytes Acquire a Microglial Phenotype after Stroke. Acta Neuropathol. 2014, 128, 381–396.
  59. Anderova, M.; Benesova, J.; Mikesova, M.; Dzamba, D.; Honsa, P.; Kriska, J.; Butenko, O.; Novosadova, V.; Valihrach, L.; Kubista, M.; et al. Altered Astrocytic Swelling in the Cortex of Alpha-Syntrophin-Negative GFAP/EGFP Mice. PLoS ONE 2014, 9, e113444.
  60. Gundersen, G.A.; Vindedal, G.F.; Skare, O.; Nagelhus, E.A. Evidence That Pericytes Regulate Aquaporin-4 Polarization in Mouse Cortical Astrocytes. Brain Struct. Funct. 2014, 219, 2181–2186.
  61. Wang, S.; Cao, C.; Chen, Z.; Bankaitis, V.; Tzima, E.; Sheibani, N.; Burridge, K. Pericytes Regulate Vascular Basement Membrane Remodeling and Govern Neutrophil Extravasation during Inflammation. PLoS ONE 2012, 7, e45499.
  62. Shimamura, N.; Ohkuma, H. Phenotypic Transformation of Smooth Muscle in Vasospasm after Aneurysmal Subarachnoid Hemorrhage. Transl. Stroke Res. 2014, 5, 357–364.
  63. Forsyth, E.A.; Aly, H.M.; Neville, R.F.; Sidawy, A.N. Proliferation and Extracellular Matrix Production by Human Infragenicular Smooth Muscle Cells in Response to Interleukin-1 Beta. J. Vasc. Surg. 1997, 26, 1002–1007, discussion 1007–1008.
  64. Kemp, S.S.; Aguera, K.N.; Cha, B.; Davis, G.E. Defining Endothelial Cell-Derived Factors That Promote Pericyte Recruitment and Capillary Network Assembly. Arter. Thromb. Vasc. Biol. 2020, 40, 2632–2648.
  65. Orlich, M.M.; Dieguez-Hurtado, R.; Muehlfriedel, R.; Sothilingam, V.; Wolburg, H.; Oender, C.E.; Woelffing, P.; Betsholtz, C.; Gaengel, K.; Seeliger, M.; et al. Mural Cell SRF Controls Pericyte Migration, Vessel Patterning and Blood Flow. Circ. Res. 2022, 131, 308–327.
  66. Zhang, J.H. Vascular Neural Network in Subarachnoid Hemorrhage. Transl. Stroke Res. 2014, 5, 423–428.
  67. Zhang, Z.; Zhao, G.; Liu, L.; He, J.; Darwazeh, R.; Liu, H.; Chen, H.; Zhou, C.; Guo, Z.; Sun, X. Bexarotene Exerts Protective Effects Through Modulation of the Cerebral Vascular Smooth Muscle Cell Phenotypic Transformation by Regulating PPARgamma/FLAP/LTB(4) After Subarachnoid Hemorrhage in Rats. Cell Transpl. 2019, 28, 1161–1172.
  68. Friedrich, V.; Flores, R.; Sehba, F.A. Cell Death Starts Early after Subarachnoid Hemorrhage. Neurosci. Lett. 2012, 512, 6–11.
  69. Metea, M.R.; Newman, E.A. Glial Cells Dilate and Constrict Blood Vessels: A Mechanism of Neurovascular Coupling. J. Neurosci. 2006, 26, 2862–2870.
  70. Sweeney, M.D.; Ayyadurai, S.; Zlokovic, B.V. Pericytes of the Neurovascular Unit: Key Functions and Signaling Pathways. Nat. Neurosci. 2016, 19, 771–783.
  71. Tait, M.J.; Saadoun, S.; Bell, B.A.; Papadopoulos, M.C. Water Movements in the Brain: Role of Aquaporins. Trends Neurosci. 2008, 31, 37–43.
  72. Zhou, Z.; Zhan, J.; Cai, Q.; Xu, F.; Chai, R.; Lam, K.; Luan, Z.; Zhou, G.; Tsang, S.; Kipp, M.; et al. The Water Transport System in Astrocytes-Aquaporins. Cells 2022, 11, 2564.
  73. Lo, W.D.; Betz, A.L.; Schielke, G.P.; Hoff, J.T. Transport of Sodium from Blood to Brain in Ischemic Brain Edema. Stroke 1987, 18, 150–157.
  74. Karimy, J.K.; Zhang, J.; Kurland, D.B.; Theriault, B.C.; Duran, D.; Stokum, J.A.; Furey, C.G.; Zhou, X.; Mansuri, M.S.; Montejo, J.; et al. Inflammation-Dependent Cerebrospinal Fluid Hypersecretion by the Choroid Plexus Epithelium in Posthemorrhagic Hydrocephalus. Nat. Med. 2017, 23, 997–1003.
  75. Li, Q.; Ding, Y.; Krafft, P.; Wan, W.; Yan, F.; Wu, G.; Zhang, Y.; Zhan, Q.; Zhang, J.H. Targeting Germinal Matrix Hemorrhage-Induced Overexpression of Sodium-Coupled Bicarbonate Exchanger Reduces Posthemorrhagic Hydrocephalus Formation in Neonatal Rats. J. Am. Heart Assoc. 2018, 7, e007192.
  76. Thrane, A.S.; Rangroo Thrane, V.; Nedergaard, M. Drowning Stars: Reassessing the Role of Astrocytes in Brain Edema. Trends Neurosci. 2014, 37, 620–628.
  77. Simard, M.; Nedergaard, M. The Neurobiology of Glia in the Context of Water and Ion Homeostasis. Neuroscience 2004, 129, 877–896.
  78. Wang, Y.F.; Parpura, V. Astroglial Modulation of Hydromineral Balance and Cerebral Edema. Front. Mol. Neurosci. 2018, 11, 204.
  79. Winkler, M.K.; Chassidim, Y.; Lublinsky, S.; Revankar, G.S.; Major, S.; Kang, E.J.; Oliveira-Ferreira, A.I.; Woitzik, J.; Sandow, N.; Scheel, M.; et al. Impaired Neurovascular Coupling to Ictal Epileptic Activity and Spreading Depolarization in a Patient with Subarachnoid Hemorrhage: Possible Link to Blood-Brain Barrier Dysfunction. Epilepsia 2012, 53 (Suppl. S6), 22–30.
  80. Santiago, M.F.; Veliskova, J.; Patel, N.K.; Lutz, S.E.; Caille, D.; Charollais, A.; Meda, P.; Scemes, E. Targeting Pannexin1 Improves Seizure Outcome. PLoS ONE 2011, 6, e25178.
  81. Atangana, E.; Schneider, U.C.; Blecharz, K.; Magrini, S.; Wagner, J.; Nieminen-Kelha, M.; Kremenetskaia, I.; Heppner, F.L.; Engelhardt, B.; Vajkoczy, P. Intravascular Inflammation Triggers Intracerebral Activated Microglia and Contributes to Secondary Brain Injury After Experimental Subarachnoid Hemorrhage (ESAH). Transl. Stroke Res. 2017, 8, 144–156.
  82. Bell, A.H.; Miller, S.L.; Castillo-Melendez, M.; Malhotra, A. The Neurovascular Unit: Effects of Brain Insults During the Perinatal Period. Front. Neurosci. 2019, 13, 1452.
  83. Carmignoto, G.; Gomez-Gonzalo, M. The Contribution of Astrocyte Signalling to Neurovascular Coupling. Brain Res. Rev. 2010, 63, 138–148.
  84. Muoio, V.; Persson, P.B.; Sendeski, M.M. The Neurovascular Unit—Concept Review. Acta Physiol. 2014, 210, 790–798.
  85. Hendrikx, D.; Smits, A.; Lavanga, M.; De Wel, O.; Thewissen, L.; Jansen, K.; Caicedo, A.; Van Huffel, S.; Naulaers, G. Measurement of Neurovascular Coupling in Neonates. Front. Physiol. 2019, 10, 65.
  86. Ittner, C.; Burek, M.; Stork, S.; Nagai, M.; Forster, C.Y. Increased Catecholamine Levels and Inflammatory Mediators Alter Barrier Properties of Brain Microvascular Endothelial Cells in Vitro. Front. Cardiovasc. Med. 2020, 7, 73.
  87. Solar, P.; Zamani, A.; Lakatosova, K.; Joukal, M. The Blood-Brain Barrier and the Neurovascular Unit in Subarachnoid Hemorrhage: Molecular Events and Potential Treatments. Fluids Barriers CNS 2022, 19, 29.
  88. Varatharaj, A.; Galea, I. The Blood-Brain Barrier in Systemic Inflammation. Brain Behav. Immun. 2017, 60, 1–12.
  89. Kim, S.Y.; Buckwalter, M.; Soreq, H.; Vezzani, A.; Kaufer, D. Blood-Brain Barrier Dysfunction-Induced Inflammatory Signaling in Brain Pathology and Epileptogenesis. Epilepsia 2012, 53 (Suppl. S6), 37–44.
  90. Dehouck, M.P.; Meresse, S.; Delorme, P.; Fruchart, J.C.; Cecchelli, R. An Easier, Reproducible, and Mass-Production Method to Study the Blood-Brain Barrier in Vitro. J. Neurochem. 1990, 54, 1798–1801.
  91. Haseloff, R.F.; Blasig, I.E.; Bauer, H.C.; Bauer, H. In Search of the Astrocytic Factor(s) Modulating Blood-Brain Barrier Functions in Brain Capillary Endothelial Cells In Vitro. Cell Mol. Neurobiol. 2005, 25, 25–39.
  92. David, Y.; Cacheaux, L.P.; Ivens, S.; Lapilover, E.; Heinemann, U.; Kaufer, D.; Friedman, A. Astrocytic Dysfunction in Epileptogenesis: Consequence of Altered Potassium and Glutamate Homeostasis? J. Neurosci. 2009, 29, 10588–10599.
  93. Viviani, B.; Gardoni, F.; Marinovich, M. Cytokines and Neuronal Ion Channels in Health and Disease. Int. Rev. Neurobiol. 2007, 82, 247–263.
  94. Vezzani, A.; Friedman, A. Brain Inflammation as a Biomarker in Epilepsy. Biomark. Med. 2011, 5, 607–614.
  95. Fieschi, C.; Lenzi, G.L.; Zanette, E.; Orzi, F.; Passero, S. Effects on EEG of the Osmotic Opening of the Blood-Brain Barrier in Rats. Life Sci. 1980, 27, 239–243.
  96. van Vliet, E.A.; da Costa Araujo, S.; Redeker, S.; van Schaik, R.; Aronica, E.; Gorter, J.A. Blood-Brain Barrier Leakage May Lead to Progression of Temporal Lobe Epilepsy. Brain 2007, 130 Pt 2, 521–534.
  97. Frigerio, F.; Frasca, A.; Weissberg, I.; Parrella, S.; Friedman, A.; Vezzani, A.; Noe, F.M. Long-Lasting pro-Ictogenic Effects Induced in Vivo by Rat Brain Exposure to Serum Albumin in the Absence of Concomitant Pathology. Epilepsia 2012, 53, 1887–1897.
  98. Scholler, K.; Trinkl, A.; Klopotowski, M.; Thal, S.C.; Plesnila, N.; Trabold, R.; Hamann, G.F.; Schmid-Elsaesser, R.; Zausinger, S. Characterization of Microvascular Basal Lamina Damage and Blood-Brain Barrier Dysfunction Following Subarachnoid Hemorrhage in Rats. Brain Res. 2007, 1142, 237–246.
  99. Ciurea, A.V.; Palade, C.; Voinescu, D.; Nica, D.A. Subarachnoid Hemorrhage and Cerebral Vasospasm—Literature Review. J. Med. Life 2013, 6, 120–125.
  100. Verhoog, Q.P.; Holtman, L.; Aronica, E.; van Vliet, E.A. Astrocytes as Guardians of Neuronal Excitability: Mechanisms Underlying Epileptogenesis. Front. Neurol. 2020, 11, 591690.
  101. Schwartz, T.H. Neurovascular Coupling and Epilepsy: Hemodynamic Markers for Localizing and Predicting Seizure Onset. Epilepsy Curr. 2007, 7, 91–94.
  102. Wong, M. Astrocyte Networks and Epilepsy: When Stars Collide. Epilepsy Curr. 2009, 9, 113–115.
  103. Gavillet, M.; Allaman, I.; Magistretti, P.J. Modulation of Astrocytic Metabolic Phenotype by Proinflammatory Cytokines. Glia 2008, 56, 975–989.
  104. Escartin, C.; Rouach, N. Astroglial Networking Contributes to Neurometabolic Coupling. Front. Neuroenergetics 2013, 5, 4.
  105. Sheldon, A.L.; Robinson, M.B. The Role of Glutamate Transporters in Neurodegenerative Diseases and Potential Opportunities for Intervention. Neurochem. Int. 2007, 51, 333–355.
  106. Oliveira, J.F.; Araque, A. Astrocyte Regulation of Neural Circuit Activity and Network States. Glia 2022, 70, 1455–1466.
  107. Li, R.; Zhao, M.; Yao, D.; Zhou, X.; Lenahan, C.; Wang, L.; Ou, Y.; He, Y. The Role of the Astrocyte in Subarachnoid Hemorrhage and Its Therapeutic Implications. Front. Immunol. 2022, 13, 1008795.
  108. Bazargani, N.; Attwell, D. Astrocyte Calcium Signaling: The Third Wave. Nat. Neurosci. 2016, 19, 182–189.
  109. Belanger, M.; Allaman, I.; Magistretti, P.J. Brain Energy Metabolism: Focus on Astrocyte-Neuron Metabolic Cooperation. Cell Metab. 2011, 14, 724–738.
  110. Brown, A.M.; Ransom, B.R. Astrocyte Glycogen and Brain Energy Metabolism. Glia 2007, 55, 1263–1271.
  111. Suh, S.W.; Bergher, J.P.; Anderson, C.M.; Treadway, J.L.; Fosgerau, K.; Swanson, R.A. Astrocyte Glycogen Sustains Neuronal Activity during Hypoglycemia: Studies with the Glycogen Phosphorylase Inhibitor CP-316,819 (-5-Chloro-N--1H-Indole-2-Carboxamide). J. Pharmacol. Exp. Ther. 2007, 321, 45–50.
  112. Boison, D.; Steinhauser, C. Epilepsy and Astrocyte Energy Metabolism. Glia 2018, 66, 1235–1243.
  113. Amantea, D.; Bagetta, G. Excitatory and Inhibitory Amino Acid Neurotransmitters in Stroke: From Neurotoxicity to Ischemic Tolerance. Curr. Opin. Pharmacol. 2017, 35, 111–119.
  114. Choi, D.W. Excitotoxicity: Still Hammering the Ischemic Brain in 2020. Front. Neurosci. 2020, 14, 579953.
  115. Suzuki, H.; Kanamaru, H.; Kawakita, F.; Asada, R.; Fujimoto, M.; Shiba, M. Cerebrovascular Pathophysiology of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage. Histol. Histopathol. 2021, 36, 143–158.
  116. Dreier, J.P.; Major, S.; Pannek, H.W.; Woitzik, J.; Scheel, M.; Wiesenthal, D.; Martus, P.; Winkler, M.K.; Hartings, J.A.; Fabricius, M.; et al. Spreading Convulsions, Spreading Depolarization and Epileptogenesis in Human Cerebral Cortex. Brain 2012, 135 Pt 1, 259–275.
  117. Ostergaard, L.; Aamand, R.; Karabegovic, S.; Tietze, A.; Blicher, J.U.; Mikkelsen, I.K.; Iversen, N.K.; Secher, N.; Engedal, T.S.; Anzabi, M.; et al. The Role of the Microcirculation in Delayed Cerebral Ischemia and Chronic Degenerative Changes after Subarachnoid Hemorrhage. J. Cereb. Blood Flow. Metab. 2013, 33, 1825–1837.
  118. Bosche, B.; Graf, R.; Ernestus, R.I.; Dohmen, C.; Reithmeier, T.; Brinker, G.; Strong, A.J.; Dreier, J.P.; Woitzik, J.; Members of the Cooperative Study of Brain Injury, D. Recurrent Spreading Depolarizations after Subarachnoid Hemorrhage Decreases Oxygen Availability in Human Cerebral Cortex. Ann. Neurol. 2010, 67, 607–617.
  119. Kramer, D.R.; Fujii, T.; Ohiorhenuan, I.; Liu, C.Y. Cortical Spreading Depolarization: Pathophysiology, Implications, and Future Directions. J. Clin. Neurosci. 2016, 24, 22–27.
  120. Suzuki, H.; Kawakita, F.; Asada, R. Neuroelectric Mechanisms of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage. Int. J. Mol. Sci. 2022, 23, 3102.
  121. Kramer, D.R.; Fujii, T.; Ohiorhenuan, I.; Liu, C.Y. Interplay between Cortical Spreading Depolarization and Seizures. Ster. Funct. Neurosurg. 2017, 95, 1–5.
  122. Haghir, H.; Kovac, S.; Speckmann, E.J.; Zilles, K.; Gorji, A. Patterns of Neurotransmitter Receptor Distributions Following Cortical Spreading Depression. Neuroscience 2009, 163, 1340–1352.
  123. Ghadiri, M.K.; Kozian, M.; Ghaffarian, N.; Stummer, W.; Kazemi, H.; Speckmann, E.J.; Gorji, A. Sequential Changes in Neuronal Activity in Single Neocortical Neurons after Spreading Depression. Cephalalgia 2012, 32, 116–124.
  124. van Lieshout, J.H.; Dibue-Adjei, M.; Cornelius, J.F.; Slotty, P.J.; Schneider, T.; Restin, T.; Boogaarts, H.D.; Steiger, H.J.; Petridis, A.K.; Kamp, M.A. An Introduction to the Pathophysiology of Aneurysmal Subarachnoid Hemorrhage. Neurosurg. Rev. 2018, 41, 917–930.
  125. Hasegawa, Y.; Suzuki, H.; Sozen, T.; Altay, O.; Zhang, J.H. Apoptotic Mechanisms for Neuronal Cells in Early Brain Injury after Subarachnoid Hemorrhage. Acta Neurochir. Suppl. 2011, 110 Pt 1, 43–48.
  126. Cahill, J.; Calvert, J.W.; Solaroglu, I.; Zhang, J.H. Vasospasm and P53-Induced Apoptosis in an Experimental Model of Subarachnoid Hemorrhage. Stroke 2006, 37, 1868–1874.
  127. Cahill, J.; Calvert, J.W.; Zhang, J.H. Mechanisms of Early Brain Injury after Subarachnoid Hemorrhage. J. Cereb. Blood Flow. Metab. 2006, 26, 1341–1353.
  128. Siuta, M.; Zuckerman, S.L.; Mocco, J. Nitric Oxide in Cerebral Vasospasm: Theories, Measurement, and Treatment. Neurol. Res. Int. 2013, 2013, 972417.
  129. Claassen, J.; Bernardini, G.L.; Kreiter, K.; Bates, J.; Du, Y.E.; Copeland, D.; Connolly, E.S.; Mayer, S.A. Effect of Cisternal and Ventricular Blood on Risk of Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: The Fisher Scale Revisited. Stroke 2001, 32, 2012–2020.
  130. Green, D.M.; Burns, J.D.; DeFusco, C.M. ICU Management of Aneurysmal Subarachnoid Hemorrhage. J. Intensive Care Med. 2013, 28, 341–354.
  131. Takahashi, C.; Hinson, H.E.; Baguley, I.J. Autonomic Dysfunction Syndromes after Acute Brain Injury. Handb. Clin. Neurol. 2015, 128, 539–551.
  132. Khalid, F.; Yang, G.L.; McGuire, J.L.; Robson, M.J.; Foreman, B.; Ngwenya, L.B.; Lorenz, J.N. Autonomic Dysfunction Following Traumatic Brain Injury: Translational Insights. Neurosurg. Focus. 2019, 47, E8.
  133. Borutta, M.C.; Gerner, S.T.; Moeser, P.; Hoelter, P.; Engelhorn, T.; Doerfler, A.; Huttner, H.B.; Schwab, S.; Kuramatsu, J.B.; Koehn, J. Correlation between Clinical Severity and Extent of Autonomic Cardiovascular Impairment in the Acute Phase of Subarachnoid Hemorrhage. J. Neurol. 2022, 269, 5541–5552.
  134. Manea, M.M.; Comsa, M.; Minca, A.; Dragos, D.; Popa, C. Brain-Heart Axis--Review Article. J. Med. Life 2015, 8, 266–271.
  135. Ecker, A.; Riemenschneider, P.A. Arteriographic Demonstration of Spasm of the Intracranial Arteries, with Special Reference to Saccular Arterial Aneurysms. J. Neurosurg. 1951, 8, 660–667.
  136. Budohoski, K.P.; Guilfoyle, M.; Helmy, A.; Huuskonen, T.; Czosnyka, M.; Kirollos, R.; Menon, D.K.; Pickard, J.D.; Kirkpatrick, P.J. The Pathophysiology and Treatment of Delayed Cerebral Ischaemia Following Subarachnoid Haemorrhage. J. Neurol. Neurosurg. Psychiatry 2014, 85, 1343–1353.
  137. Allcock, J.M.; Drake, C.G. Postoperative Angiography in Cases of Ruptured Intracranial Aneurysm. J. Neurosurg. 1963, 20, 752–759.
  138. Harders, A.; Gilsbach, J. Transcranial Doppler Sonography and Its Application in Extracranial-Intracranial Bypass Surgery. Neurol. Res. 1985, 7, 129–141.
  139. Lindvall, P.; Runnerstam, M.; Birgander, R.; Koskinen, L.O. The Fisher Grading Correlated to Outcome in Patients with Subarachnoid Haemorrhage. Br. J. Neurosurg. 2009, 23, 188–192.
  140. Deferoxamine In the Treatment of Aneurysmal Subarachnoid Hemorrhage (aSAH)—Full Text View—ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ct2/show/NCT04566991 (accessed on 27 June 2023).
  141. Selim, M.; Foster, L.D.; Moy, C.S.; Xi, G.; Hill, M.D.; Morgenstern, L.B.; Greenberg, S.M.; James, M.L.; Singh, V.; Clark, W.M.; et al. Deferoxamine Mesylate in Patients with Intracerebral Haemorrhage (i-DEF): A Multicentre, Randomised, Placebo-Controlled, Double-Blind Phase 2 Trial. Lancet Neurol. 2019, 18, 428–438.
  142. Wei, C.; Wang, J.; Foster, L.D.; Yeatts, S.D.; Moy, C.; Mocco, J.; Selim, M.; i-DEF Investigators. Effect of Deferoxamine on Outcome According to Baseline Hematoma Volume: A Post Hoc Analysis of the i-DEF Trial. Stroke 2022, 53, 1149–1156.
  143. Toda, N.; Shimizu, K.; Ohta, T. Mechanism of Cerebral Arterial Contraction Induced by Blood Constituents. J. Neurosurg. 1980, 53, 312–322.
  144. Toda, N. Mechanisms of Contracting Action of Oxyhemoglobin in Isolated Monkey and Dog Cerebral Arteries. Am. J. Physiol. 1990, 258 Pt 2, H57–H63.
  145. Macdonald, R.L.; Weir, B.K.; Grace, M.G.; Martin, T.P.; Doi, M.; Cook, D.A. Morphometric Analysis of Monkey Cerebral Arteries Exposed in Vivo to Whole Blood, Oxyhemoglobin, Methemoglobin, and Bilirubin. Blood Vessels 1991, 28, 498–510.
  146. Wang, J.; Tsirka, S.E. Neuroprotection by Inhibition of Matrix Metalloproteinases in a Mouse Model of Intracerebral Haemorrhage. Brain 2005, 128 Pt 7, 1622–1633.
  147. Hayman, L.A.; Pagani, J.J.; Kirkpatrick, J.B.; Hinck, V.C. Pathophysiology of Acute Intracerebral and Subarachnoid Hemorrhage: Applications to MR Imaging. AJR Am. J. Roentgenol. 1989, 153, 135–139.
  148. Xi, G.; Keep, R.F.; Hoff, J.T. Mechanisms of Brain Injury after Intracerebral Haemorrhage. Lancet Neurol. 2006, 5, 53–63.
  149. Pluta, R.M.; Hansen-Schwartz, J.; Dreier, J.; Vajkoczy, P.; Macdonald, R.L.; Nishizawa, S.; Kasuya, H.; Wellman, G.; Keller, E.; Zauner, A.; et al. Cerebral Vasospasm Following Subarachnoid Hemorrhage: Time for a New World of Thought. Neurol. Res. 2009, 31, 151–158.
  150. Zazulia, A.R.; Diringer, M.N.; Derdeyn, C.P.; Powers, W.J. Progression of Mass Effect after Intracerebral Hemorrhage. Stroke 1999, 30, 1167–1173.
  151. Dang, G.; Yang, Y.; Wu, G.; Hua, Y.; Keep, R.F.; Xi, G. Early Erythrolysis in the Hematoma After Experimental Intracerebral Hemorrhage. Transl. Stroke Res. 2017, 8, 174–182.
  152. Koeppen, A.H.; Dickson, A.C.; McEvoy, J.A. The Cellular Reactions to Experimental Intracerebral Hemorrhage. J. Neurol. Sci. 1995, 134, 102–112.
  153. Samagh, N.; Bhagat, H.; Jangra, K. Monitoring Cerebral Vasospasm: How Much Can We Rely on Transcranial Doppler. J. Anaesthesiol. Clin. Pharmacol. 2019, 35, 12–18.
  154. Newell, D.W.; Winn, H.R. Transcranial Doppler in Cerebral Vasospasm. Neurosurg. Clin. N. Am. 1990, 1, 319–328.
  155. Mascia, L.; Del Sorbo, L. Diagnosis and Management of Vasospasm. F1000 Med. Rep. 2009, 1, 33.
  156. Jeon, H.; Ai, J.; Sabri, M.; Tariq, A.; Shang, X.; Chen, G.; Macdonald, R.L. Neurological and Neurobehavioral Assessment of Experimental Subarachnoid Hemorrhage. BMC Neurosci. 2009, 10, 103.
  157. Zakaria, Z.; Abdullah, M.M.; Halim, S.A.; Ghani, A.R.I.; Idris, Z.; Abdullah, J.M. The Neurological Exam of a Comatose Patient: An Essential Practical Guide. Malays. J. Med. Sci. 2020, 27, 108–123.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback