Intracerebral Hemorrhage: Advances in Preclinical Studies

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (15 June 2022) | Viewed by 15187

Special Issue Editor

Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Interests: intracerebral hemorrhage; cerebral edema; neuroinflammation; oxidative stress; neurodegeneration; excitotoxicity; blood components; neurotoxicity; neurological deficits; blood–brain barrier damage; infiltrating macrophages; glial activation
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Special Issue Information

Dear Colleagues,

Intracerebral hemorrhage (ICH) is a major public health problem and severe subtype of stroke characterized by cerebral bleeding. In comparison to other stroke subtypes, ICH is associated with the highest mortality and morbidity rates. Additionally, the incidence of ICH is expected to increase due to aging and the increasing use of anticoagulants. To date, there is no effective treatment for ICH, making it the deadliest subtype of stroke.

ICH results in severe brain injury, which is categorized into primary and secondary brain damage. The primary brain damage is mainly attributed to the mass effect of the hematoma, whereas the mechanisms of the secondary brain damage include, but are not limited to, neuroinflammation, oxidative stress, apoptosis, and excitotoxicity. The secondary brain injury, which persists for a longer period, contributes to long-term neurological deficits and is considered a viable target for therapeutic intervention. However, given the complex pathophysiology of ICH, further elucidation of the brain injury mechanisms is imperative for the identification of novel molecular targets for therapeutic intervention.

Herein, we attempt to provide an update on ICH by inviting reviews, research articles, and short communications for the Special Issue entitled “Intracerebral Hemorrhage: Advances in Preclinical Studies”.

We look forward to your contributions.

Dr. Sangeetha Sukumari-Ramesh
Guest Editor

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Keywords

  • Neuroinflammation
  • Oxidative stress
  • Neurodegeneration
  • Neurological deficits
  • Blood–brain barrier damage

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Published Papers (6 papers)

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Research

12 pages, 1382 KiB  
Article
Chronic Nicotine Exposure Increases Hematoma Expansion following Collagenase-Induced Intracerebral Hemorrhage in Rats
by Ashish K. Rehni, Sunjoo Cho, Zhexuan Zhang, Weizhao Zhao, Ami P. Raval, Miguel A. Perez-Pinzon and Kunjan R. Dave
Biomolecules 2022, 12(5), 621; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12050621 - 21 Apr 2022
Cited by 2 | Viewed by 3846
Abstract
Spontaneous intracerebral hemorrhage (sICH) is a deadly stroke subtype, and tobacco use increases sICH risk. However epidemiological studies show that, there are no confirmatory studies showing the effect of tobacco use on sICH outcome. Therefore, we evaluated the effect of chronic nicotine exposure [...] Read more.
Spontaneous intracerebral hemorrhage (sICH) is a deadly stroke subtype, and tobacco use increases sICH risk. However epidemiological studies show that, there are no confirmatory studies showing the effect of tobacco use on sICH outcome. Therefore, we evaluated the effect of chronic nicotine exposure (as a surrogate for tobacco use) on outcomes following sICH. Young male and female rats were randomly assigned to either nicotine (4.5 mg/kg b.w. per day) or vehicle (saline) treatment (2–3 weeks) groups. sICH was induced by injecting collagenase into the right striatum. Neurological score and hematoma volume were determined 24 h post-sICH. The hematoma volumes in nicotine-treated male and female rats were significantly higher by 42% and 48% when compared to vehicle-treated male and female rats, respectively. Neurological deficits measured in terms of neurological score for the nicotine-treated male and female groups were significantly higher when compared to the respective vehicle-treated male and female groups. Our results show that chronic nicotine exposure increases hematoma volume post-sICH in rats of both sexes. Identifying the mechanism of nicotine-dependent increase in hematoma growth post-sICH will be crucial to understanding the detrimental effect of tobacco use on the severity of bleeding following intracerebral hemorrhage. Full article
(This article belongs to the Special Issue Intracerebral Hemorrhage: Advances in Preclinical Studies)
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11 pages, 2129 KiB  
Article
Comparing Protection of Remote Limb with Resveratrol Preconditioning following Rodent Subarachnoid Hemorrhage
by Sebastian Koch, Giselle De La Rua, Donnae Farquharson, Isabel Saul, Miguel Perez-Pinzon and Kunjan Dave
Biomolecules 2022, 12(4), 568; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12040568 - 12 Apr 2022
Cited by 1 | Viewed by 1561
Abstract
Background: Preventing delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) remains an important therapeutic target. Preconditioning stimulates multiple endogenous protective mechanisms and may be a suitable treatment for DCI following SAH. We here compare remote limb conditioning with resveratrol conditioning in a clinically [...] Read more.
Background: Preventing delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) remains an important therapeutic target. Preconditioning stimulates multiple endogenous protective mechanisms and may be a suitable treatment for DCI following SAH. We here compare remote limb conditioning with resveratrol conditioning in a clinically relevant SAH model. Methods: We produced a SAH in 39 male Sprague Dawley rats using a single injection model. Animals were randomized to four groups: repetitive limb conditioning with a blood pressure cuff, sham conditioning, intraperitoneal resveratrol (10 mg/kg) or intraperitoneal vehicle administered at 24, 48 and 72 h after SAH. On day 4 neurological and behavioral scores were obtained, and animals were euthanized. The cross-sectional area of the basilar artery was measured at the vertebrobasilar junction, and at the mid and distal segments. Hippocampal cells were counted in both hemispheres and normalized per mm length. We compared true limb preconditioning with sham conditioning and resveratrol with vehicle preconditioning. Results: The cross-sectional area of the mid-basilar artery in the true limb preconditioning group was significantly larger by 43% (p = 0.03) when compared with the sham preconditioning group. No differences in the cross-sectional area were found in the resveratrol-treated group when compared to the vehicle-treated group. We found no differences in the neuro score, behavioral score, and in mean hippocampal neuron counts between the groups. Conclusion: We found beneficial vascular effects of remote limb preconditioning on SAH-induced basilar artery vasoconstriction. Our findings support further studies of limb preconditioning as a potential treatment after SAH. Full article
(This article belongs to the Special Issue Intracerebral Hemorrhage: Advances in Preclinical Studies)
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12 pages, 1580 KiB  
Article
The Influence of Oxidative Stress on Neurological Outcomes in Spontaneous Intracerebral Hemorrhage
by Julia Masomi-Bornwasser, Elena Kurz, Christina Frenz, Jan Schmitt, Dominik M. A. Wesp, Jochem König, Johannes Lotz, Florian Ringel, Thomas Kerz, Harald Krenzlin and Naureen Keric
Biomolecules 2021, 11(11), 1615; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11111615 - 01 Nov 2021
Cited by 9 | Viewed by 1785
Abstract
Spontaneous intracerebral hemorrhage (ICH) causes, besides the primary brain injury, a secondary brain injury (SBI), which is induced, amongst other things, by oxidative stress (OS) and inflammation, determining the patient’s outcome. This study aims to assess the impact of OS in plasma and [...] Read more.
Spontaneous intracerebral hemorrhage (ICH) causes, besides the primary brain injury, a secondary brain injury (SBI), which is induced, amongst other things, by oxidative stress (OS) and inflammation, determining the patient’s outcome. This study aims to assess the impact of OS in plasma and cerebrospinal fluid (CSF) on clinical outcomes in patients with ICH. A total of 19 ICH (volume > 30 cc) patients and 29 control patients were included. From day one until seven, blood and CSF samples were obtained, and ICH volume was calculated. OS markers, like malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione-sulfhydryl (GSH), and the total antioxidant status (TAS) were measured. Clinical data on treatment and outcome were determined. Patients with mRS ≤ 4 showed significantly elevated SOD and GSH-Px levels in plasma compared to patients with poor CO (p = 0.004; p = 0.002). Initial increased TAS in plasma and increased MDA in CSF were linked to an unfavorable outcome after six months (p = 0.06, r = 0.45; p = 0.05, r = 0.44). A higher ICH volume was associated with a worse outcome at week six (p = 0.04, r = 0.47). OS plays a significant role in SBI. Larger ICHs, elevated MDA in CSF, and TAS in plasma were associated with a detrimental outcome, whereas higher plasma-SOD and -GSH-Px were associated with a favorable outcome. Full article
(This article belongs to the Special Issue Intracerebral Hemorrhage: Advances in Preclinical Studies)
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14 pages, 3601 KiB  
Article
Nebulization of Low-Dose S-Nitrosoglutathione in Diabetic Stroke Enhances Benefits of Reperfusion and Prevents Post-Thrombolysis Hemorrhage
by Syed Kashif Zaidi, Farid Ahmed, Heba Alkhatabi, Md Nasrul Hoda and Muhammad Al-Qahtani
Biomolecules 2021, 11(11), 1587; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11111587 - 27 Oct 2021
Cited by 2 | Viewed by 2328
Abstract
The COVID-19 pandemic has escalated the occurrence of hypoxia including thrombotic stroke worldwide, for which nitric oxide (NO) therapy seems very promising and translatable. Therefore, various modes/routes of NO-delivery are now being tested in different clinical trials for safer, faster, and more effective [...] Read more.
The COVID-19 pandemic has escalated the occurrence of hypoxia including thrombotic stroke worldwide, for which nitric oxide (NO) therapy seems very promising and translatable. Therefore, various modes/routes of NO-delivery are now being tested in different clinical trials for safer, faster, and more effective interventions against ischemic insults. Intravenous (IV) infusion of S-Nitrosoglutathione (GSNO), the major endogenous molecular pool of NO, has been reported to protect against mechanical cerebral ischemia-reperfusion (IR); however, it has been never tested in any kind of “clinically” relevant thromboembolic stroke models with or without comorbidities and in combination with the thrombolytic reperfusion therapy. Moreover, “IV-effects” of higher dose of GSNO following IR-injury have been contradicted to augment stroke injury. Herein, we tested the hypothesis that nebulization of low-dose GSNO will not alter blood pressure (BP) and will mitigate stroke injury in diabetic mice via enhanced cerebral blood flow (CBF) and brain tissue oxygenation (PbtO2). GSNO-nebulization (200 μg/kgbwt) did not alter BP, but augmented the restoration of CBF, improved behavioral outcomes and reduced stroke injury. Moreover, GSNO-nebulization increased early reoxygenation of brain tissue/PbtO2 as measured at 6.5 h post-stroke following thrombolytic reperfusion, and enervated unwanted effects of late thrombolysis in diabetic stroke. We conclude that the GSNO-nebulization is safe and effective for enhancing collateral microvascular perfusion in the early hours following stroke. Hence, nebulized-GSNO therapy has the potential to be developed and translated into an affordable field therapy against ischemic events including strokes, particularly in developing countries with limited healthcare infrastructure. Full article
(This article belongs to the Special Issue Intracerebral Hemorrhage: Advances in Preclinical Studies)
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10 pages, 1918 KiB  
Article
White Matter Survival within and around the Hematoma: Quantification by MRI in Patients with Intracerebral Hemorrhage
by Nemanja Novakovic, Joseph R. Linzey, Thomas L. Chenevert, Joseph J. Gemmete, Jonathan P. Troost, Guohua Xi, Richard F. Keep, Aditya S. Pandey and Neeraj Chaudhary
Biomolecules 2021, 11(6), 910; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060910 - 18 Jun 2021
Cited by 7 | Viewed by 2394
Abstract
White matter (WM) injury and survival after intracerebral hemorrhage (ICH) has received insufficient attention. WM disruption surrounding the hematoma has been documented in animal models with histology, but rarely in human ICH with noninvasive means, like magnetic resonance imaging (MRI). A few human [...] Read more.
White matter (WM) injury and survival after intracerebral hemorrhage (ICH) has received insufficient attention. WM disruption surrounding the hematoma has been documented in animal models with histology, but rarely in human ICH with noninvasive means, like magnetic resonance imaging (MRI). A few human MRI studies have investigated changes in long WM tracts after ICH remote from the hematoma, like the corticospinal tract, but have not attempted to obtain an unbiased quantification of WM changes within and around the hematoma over time. This study attempts such quantification from 3 to 30 days post ictus. Thirteen patients with mild to moderate ICH underwent diffusion tensor imaging (DTI) MRI at 3, 14, and 30 days. Fractional anisotropy (FA) maps were used to calculate the volume of tissue with FA > 0.5, both within the hematoma (lesion) and in the perilesional tissue. At day 3, the percentages of both lesional and perilesional tissue with an FA > 0.5 were significantly less than contralateral, unaffected, anatomically identical tissue. This perilesional contralateral difference persisted at day 14, but there was no significant difference at day 30. The loss of perilesional tissue with FA > 0.5 increased with increasing hematoma size at day 3 and day 14. All patients had some tissue within the lesion with FA > 0.5 at all time points. This did not decrease with duration after ictus, suggesting the persistence of white matter within the hematoma/lesion. These results outline an approach to quantify WM injury, both within and surrounding the hematoma, after mild to moderate ICH using DTI MRI. This may be important for monitoring treatment strategies, such as hematoma evacuation, and assessing efficacy noninvasively. Full article
(This article belongs to the Special Issue Intracerebral Hemorrhage: Advances in Preclinical Studies)
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11 pages, 6998 KiB  
Article
Hydrocephalus Induced by Intraventricular Peroxiredoxin-2: The Role of Macrophages in the Choroid Plexus
by Ting Chen, Xiaoxiao Tan, Fan Xia, Ya Hua, Richard F. Keep and Guohua Xi
Biomolecules 2021, 11(5), 654; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11050654 - 29 Apr 2021
Cited by 11 | Viewed by 2350
Abstract
The choroid plexus (CP) is the primary source of cerebrospinal fluid in the central nervous system. Recent evidence indicates that inflammatory pathways at the CP may be involved in hydrocephalus development. Peroxiredoxin 2 (Prx2) is a major component of red blood cells. Extracellular [...] Read more.
The choroid plexus (CP) is the primary source of cerebrospinal fluid in the central nervous system. Recent evidence indicates that inflammatory pathways at the CP may be involved in hydrocephalus development. Peroxiredoxin 2 (Prx2) is a major component of red blood cells. Extracellular Prx2 is proinflammatory, and its release after red blood cell lysis may contribute to hydrocephalus after intraventricular hemorrhage. This study aimed to identify alterations in CP macrophages and dendritic cells following intracerebroventricular Prx2 injection and investigate the relationship between macrophages/dendritic cells and hydrocephalus. There were two parts to this study. In the first part, adult male Sprague–Dawley rats received an intracerebroventricular injection of Prx2 or saline. In the second part, Prx2 was co-injected with clodronate liposomes or control liposomes. All animals were euthanized at 24 h after magnetic resonance imaging. Immunohistochemistry was used to evaluate macrophages in CP, magnetic resonance imaging to quantify hydrocephalus, and histology to assess ventricular wall damage. The intracerebroventricular injection of Prx2 not only increased the OX-6 positive cells, but it also altered their location in the CP and immunophenotype. Co-injecting clodronate liposomes with Prx2 decreased the number of macrophages and simultaneously attenuated Prx2-induced hydrocephalus and ventricular wall damage. These results suggest that CP macrophages play an essential role in CP inflammation-induced hydrocephalus. These macrophages may be a potential therapeutic target in post-hemorrhagic hydrocephalus. Full article
(This article belongs to the Special Issue Intracerebral Hemorrhage: Advances in Preclinical Studies)
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