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Background: Hydrocephalus is a severe complication of intracerebral hemorrhage with ventricular extension (ICH-IVH) and causes cerebrospinal fluid (CSF) accumulation. The choroid plexus epithelium plays an important role in CSF secretion and constitutes the blood-CSF barrier within the brain-immune system interface. Although the NLRP3 inflammasome, as a key component of the innate immune system, promotes neuroinflammation, its role in the pathogenesis of hydrocephalus after hemorrhage has not been investigated. Therefore, this study aimed to investigate the potential mechanism of NLRP3 in hydrocephalus to discover a potential marker for targeted therapy., Methods: A rat model of hydrocephalus after ICH-IVH was developed through autologous blood infusion in wild-type and Nlrp3 -/- rats. By studying the features and processes of the model, we investigated the relationship between the NLRP3 inflammasome and CSF hypersecretion in the choroid plexus., Results: The ICH-IVH model rats showed ventricular dilation accompanied by CSF hypersecretion for 3 days. Based on the choroid plexus RNA-seq and proteomics results, we found that an inflammatory response was activated. The NLRP3 inflammasome was investigated, and the expression levels of NLRP3 inflammasome components reached a peak at 3 days after ICH-IVH. Inhibition of NLRP3 by an MCC950 inflammasome inhibitor or Nlrp3 knockout decreased CSF secretion and ventricular dilation and attenuated neurological deficits after ICH-IVH. The mechanism underlying the neuroprotective effects of NLRP3 inhibition involved decreased phosphorylation of NKCC1, which is a major protein that regulates CSF secretion by altering Na + - and K + -coupled water transport, via MCC950 or Nlrp3 knockout. In combination with the in vitro experiments, this experiment confirmed the involvement of the NLRP3/p-NKCC1 pathway and Na + and K + flux., Conclusions: This study demonstrates that NKCC1 phosphorylation in the choroid plexus epithelium promotes NLRP3 inflammasome-mediated CSF hypersecretion and that NLRP3 plays an important role in the pathogenesis of hydrocephalus after hemorrhage. These findings provide a new therapeutic strategy for treating hydrocephalus., (© 2022. The Author(s).)

Urokinase-type plasminogen activator (uPA) was demonstrated to alleviate kaolin-induced communicating hydrocephalus via inhibiting subarachnoid space fibrosis, but the exact mechanism remains elusive. Thus, this study was designed to investigate if hepatocyte growth factor (HGF), which plays a vital role in uPA-triggered inhibiting of fibrosis in multiple systems, is involved in this process in hydrocephalus. There were 2 parts in this study. First, hydrocephalus was induced in rats by basal cistern injection of kaolin. Then rats were treated with saline or uPA and brain tissue and CSF were collected for Western blot and enzyme-linked immuno sorbent assay (ELISA) four days later. Second, kaolin-induced hydrocephalus rats were treated with saline, uPA, uPA + PHA665752 (antagonist of HGF) or PHA665752. Some animals received MRI four weeks later and brains were used for immunofluorescence. The others were euthanized four days later for ELISA. Both levels of total and activated HGF in the CSF was increased after uPA injections, but related mRNA expression of HGF showed no statistical significance when compared with the control group. Further, the effects of uPA that alleviating ventricular enlargement, subarachnoid fibrosis and reactive astrocytosis were partially reversed by PHA665752. Moreover, PHA665752 partially abolished uPA-induced reduction of transforming growth factor- β1(TGF- β1) level in CSF. Our data suggest that uPA effectively inhibited subarachnoid fibrosis and restricted the development of communicating hydrocephalus in rats in part by promoting HGF release and activation, which may further regulate the TGF-β1 expression in CSF., Competing Interests: Declaration of Competing Interest All authors indicate no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We previously found that hematoma worsens hydrocephalus after intraventricular hemorrhage (IVH) via increasing iron deposition and aggravating ependymal cilia injury; therefore, promoting hematoma absorption may be a promising strategy for IVH. Recently, some investigations imply that simvastatin has the ability of accelerating hematoma absorption. Thus, this study was designed to examine the efficacy of simvastatin for IVH in rats. Intracerebral hemorrhage with ventricular extension was induced in adult male Sprague-Dawley rats after autologous blood injection. Simvastatin or vehicle was administered orally at 1 day after IVH and then daily for 1 week. MRI studies were performed to measure the volumes of intracranial hematoma and lateral ventricle at days 1, 3, 7, 14, and 28 after IVH. Motor and neurocognitive functions were assessed at days 1 to 7 and 23 to 28, respectively. Iron deposition, iron-related protein expression, ependymal damage, and histology were detected at day 28. Expression of CD36 scavenger receptor (facilitating phagocytosis) was examined at day 3 after IVH using western blotting and immunofluorescence. Simvastatin significantly increased hematoma absorption ratio, reduced ventricular volume, and attenuated neurological dysfunction post-IVH. In addition, less iron accumulation and more cilia survival was observed in the simvastatin group when compared with the control. What's more, higher expression of CD36 was detected around the hematoma after simvastatin administration. Simvastatin significantly enhanced brain hematoma absorption, alleviated hydrocephalus, and improved neurological recovery after experimental IVH, which may in part by upregulating CD36 expression. Our data suggest that early simvastatin use may be a novel therapy for IVH patients.

Post-hemorrhagic hydrocephalus (PHH), also referred to as progressive ventricular dilatation, is caused by disturbances in cerebrospinal fluid (CSF) flow or absorption following hemorrhage in the brain. As one of the most serious complications of neonatal/adult intraventricular hemorrhage (IVH), subarachnoid hemorrhage (SAH), and traumatic brain injury (TBI), PHH is associated with increased morbidity and disability of these events. Common sequelae of PHH include neurocognitive impairment, motor dysfunction, and growth impairment. Non-surgical measures to reduce increased intracranial pressure (ICP) in PHH have shown little success and most patients will ultimately require surgical management, such as external ventricular drainage and shunting which mostly by inserting a CSF drainage shunt. Unfortunately, shunt complications are common and the optimum time for intervention is unclear. To date, there remains no comprehensive strategy for PHH management and it becomes imperative that to explore new therapeutic targets and methods for PHH. Over past decades, increasing evidence have indicated that hemorrhage-derived blood and subsequent metabolic products may play a key role in the development of IVH-, SAH- and TBI-associated PHH. Several intervention strategies have recently been evaluated and cross-referenced. In this review, we summarized and discussed the common aspects of hydrocephalus following IVH, SAH and TBI, relevant experimental animal models, clinical translation of in vivo experiments, and potential preventive and therapeutic targets for PHH., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Fibrosis of the subarachnoid space (SAS) after infection, inflammation, or hemorrhage can impair cerebrospinal fluid absorption and circulation, causing diffuse ventricular dilatation. In the present study, we tested the hypothesis that urokinase (also known as urokinase-type plasminogen activator [uPA]), a fibrinolytic agent, attenuates fibrosis and ventriculomegaly in a rat model of kaolin-induced communicating hydrocephalus and thus may have potential as a therapy for these conditions. Thirty microliters of sterile 25% kaolin suspension was injected into the basal cisterns of adult Sprague-Dawley rats to induce hydrocephalus, and 2 intraventricular injections of either uPA or vehicle (saline) were administered immediately and 3 days thereafter. Ventricular volumes were measured by magnetic resonance imaging (MRI) on days 3, 14, and 28 after kaolin injection. Fibrosis and reactive astrogliosis were evaluated on day 28 by immunofluorescence and Western blotting. Neurocognitive features were tested using the Morris water maze from days 23 to 28. MRI analysis demonstrated that kaolin administration successfully induced hydrocephalus in rats and that uPA treatment significantly attenuated ventricular enlargement. In addition, uPA inhibited the deposition of laminin and fibronectin, extracellular matrix molecules, in the SAS, attenuated gliosis, and improved learning and memory in kaolin-treated rats. Therefore, we concluded that uPA prevents the development of kaolin-induced communicating hydrocephalus by preventing the development of subarachnoid fibrosis and by eliciting improvements in neurocognition. The results of this study indicate that uPA may be a novel clinical therapy for communicating hydrocephalus., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Fibrosis in ventricular system has a role in hydrocephalus following intraventricular hemorrhage (IVH). The cannabinoid receptor 2 (CB2) has been reported to participate in alleviating the fibrosis process of many diseases. However, its role in fibrosis after IVH was unclear so far, and we hypothesized that CB2 activation has potential to attenuate hydrocephalus after IVH via restricting fibrosis. So the present study was designed to investigate this hypothesis in a modified rat IVH model. Autologous non-anticoagulative blood injection model was induced to mimic ventricular extension of hemorrhage in adult Sprague-Dawley rats. Rats were randomized to receive JWH-133(CB2 agonist), SR144528 (CB2 antagonist) or saline. The lateral ventricular volumes, fibrosis in the subarachnoid space and ventricular wall, transforming growth factor-β 1(TGF-β1) in cerebrospinal fluid and brain tissue, and animal neurological scores were measured to evaluate the effects of CB2 in hydrocephalus following IVH. CB2 agonist JWH-133 significantly decreased the lateral ventricular volumes, improved the associated neurological deficits, down-regulated TGF-β1 expression, and alleviated fibrosis in the subarachnoid space and ventricular wall after IVH. All of these effects were reversed by SR144528. In conclusion, CB2 may have anti-fibrogenic effects after IVH. CB2 agonist suppressed fibrosis of ventricular system and alleviated hydrocephalus following IVH, which is partly mediated by inhibiting TGF-β1., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective To investigate the effect of astrocyte-microglia crosstalk mediated by complement C3/C3aR signaling on hydrocephalus after germinal matrix hemorrhage (GMH) in newborn rats. Methods GMH was induced in post-natal day 7 SD rats by collagenase Ⅶ-S injection into the ganglionic eminence. We detected the changes in the expression of periventricular C3 and C3aR over time after GMH, and observed the effect of intraperitoneal injection of C3aRA (a selective C3aR antagonist) on hydrocephalus using magnetic resonance imaging (MRI). The learning and memory functions of the rats were tested after the treatment using Morris water maze test, and the expression of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and aquaporin 4 in the brain tissues were detected using Western blotting at different time points after GMH. Results The neonatal rats with GMH showed significantly up-regulated expression of C3 and C3aR around the cerebral ventricles and increased expression of IL-1β, IL-6, TNF-α and TGF-β1 in the brain, presenting also with obvious lateral ventricle dilation, compression of the cortex and hippocampus, and impairment of the learning and memory functions. Treatment of the rats with C3aRA obviously decreased C3 and C3aR expression, alleviated hydrocephalus, improved the neurological deficits, and reduced the expression of the inflammatory factors in the brain. GMH caused obvious ectopic expression of aquaporins 4 and increased its expression level on the astrocytes, and C3aRA treatment significantly improved the abnormal expression of aquaporins 4. Conclusion GMH causes the astrocytes to up-regulate and release C3, which binds to C3aR on the microglia to promote inflammation and aggravate hydrocephalus. The ectopic expression of aquaporin 4 in astrocytes may play an important role in the occurrence of hydrocephalus following GMH. rats newborn

• Tolvaptan attenuated brain edema after intracerebral hemorrhage. • Tolvaptan alleviated neurological deficits after intracerebral hemorrhage. • Tolvaptan prevented blood brain barrier destruction after intracerebral hemorrhage. Arginine-vasopressin (AVP) is believed to be positively correlated with the brain edema formation, but the underlying mechanism is still unclear. In this study, we explored the role of the V2 receptors antagonist tolvaptan on brain edema following intracerebral hemorrhage (ICH) with a rat model. Animals were randomly given tolvaptan or vehicle through oral gavage at 12 h, 36 h, and 60 h after ICH surgery. Brain swelling (%), brain water content(BWC), neurological scores, Evans blue fluorescence and blood-brain barrier (BBB) tight junction proteins were measured to evaluate the effect of tolvaptan in ICH. We found that tolvaptan alleviated the brain swelling (%), decreased the BWC growth, and attenuated the neurological deficits after ICH (p < 0.05, vs vehicle). What's more, tolvaptan increased the expression of ZO-1 and occludin (p < 0.05, vs vehicle), which might be attributed to the down-regulated effects of tolvaptan on MMP-9. These results provided evidence supporting the use of tolvaptan for ICH-induced brain edema. Large animal experiments are required to further explore the efficacy and mechanism of tolvaptan in ICH treatment. [ABSTRACT FROM AUTHOR]