Pathophysiological Mechanisms and Potential Therapeutic Targets in Intracerebral Hemorrhage

Shao, Zhiwei; Tu, Sheng; Shao, Anwen

doi:10.3389/fphar.2019.01079

Cited by 95 publications

(68 citation statements)

References 85 publications

(113 reference statements)

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“…Oxidative stress and neuronal apoptosis are the main pathological changes after ICH [ 3 , 5 ]. Oxidative stress has been identified as a response to various harmful stimuli and produces excessive amounts of ROS, which reflects an imbalance between the ROS and the biological ability to scavenge ROS [ 28 , 29 ]. After ICH, the hemoglobin/haem is released from the lysed red blood cells.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Melanocortin-1 Receptor by NDP-MSH Attenuates Oxidative Stress and Neuronal Apoptosis through PI3K/Akt/Nrf2 Pathway after Intracerebral Hemorrhage in Mice

Luo

et al. 2020

Oxidative Medicine and Cellular Longevity

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Oxidative stress and neuronal apoptosis play crucial roles in secondary brain injury (SBI) after intracerebral hemorrhage (ICH). Recently, Nle4-D-Phe7-α-melanocyte-stimulating hormone (NDP-MSH), a synthetic agonist of the melanocortin-1 receptor (Mc1r), has been proved to inhibit neuroinflammatory in several diseases. This study is aimed at exploring if NDP-MSH could reduce oxidative stress and neuronal apoptosis following ICH, as well as the potential mechanism. A mouse ICH model was induced by autologous blood injection. NDP-MSH was intraperitoneally injected at 1 h after ICH. Mc1r siRNA and PI3K inhibitor LY294002 were administrated to inhibit the expression of Mc1r and phosphorylation of PI3K, respectively. Neurological test, brain water content, enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), immunofluorescence, and Western blot analysis were utilized in this study. The results exhibited that Mc1r was mainly expressed in neurons, and its level in the ipsilateral hemisphere was significantly elevated after ICH. NDP-MSH treatment significantly attenuated the neurological deficits and brain water content 24 hours after ICH, which was accompanied by the inhibition of oxidative stress and neuronal apoptosis. The administration of NDP-MSH after ICH significantly promoted the expression of Mc1r, p-PI3K, p-Akt, and p-Nrf2, followed by an increase of Bcl-2 and reduction of cleaved caspase-3. Conversely, downregulating the expression of Mc1r and phosphorylation of PI3K aggravated the neurological deficits and brain edema at 24 hours after ICH, meanwhile, the effect of NDP-MSH on the expression of Mc1r, p-PI3K, p-Akt, p-Nrf2, Bcl-2, and cleaved caspase 3 was also abolished. In conclusion, our data suggest that the activation of Mc1r by NDP-MSH ameliorates oxidative stress and neuronal apoptosis through the PI3K/Akt/Nrf2 signaling pathway after ICH in mice.

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Section: Discussionmentioning

confidence: 99%

Activation of the Melanocortin-1 Receptor by NDP-MSH Attenuates Oxidative Stress and Neuronal Apoptosis through PI3K/Akt/Nrf2 Pathway after Intracerebral Hemorrhage in Mice

Luo

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Hematoma expansion as well as activation of inflammatory pathways lead to further tissue damage, edema, and penumbral hypoperfusion. 35,36 Acute blood pressure lowering is recommended to prevent further hematoma growth; however, the prognosis after ICH is poor, with a 1-month mortality of 40%. 37,38 Notably, clinical examination alone cannot reliably differentiate between AIS and ICH in putative stroke patients, making neuroimaging mandatory before treatment initiation.…”

Section: Strokementioning

confidence: 99%

Fibrinolysis and Remote Ischemic Conditioning: Mechanisms and Treatment Perspectives in Stroke

Krag

Blauenfeldt

2021

Semin Thromb Hemost

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Stroke is a leading cause of death and disability. Intravenous thrombolysis and mechanical thrombectomy have greatly improved outcomes in acute ischemic stroke (AIS). However, only a minority of patients receive reperfusion therapies, highlighting the need for novel neuroprotective therapies. Remote ischemic conditioning (RIC), consisting of brief, intermittent extremity occlusion and reperfusion induced with an inflatable cuff, is a potential neuroprotective therapy in acute stroke. The objective of this narrative review is to describe the effect of RIC on endogenous fibrinolysis and, from this perspective, investigate the potential of RIC in the prevention and treatment of stroke. A systematic literature search was performed in PubMed, and human studies in English were included. Seven studies had investigated the effect of RIC on fibrinolysis in humans. Long-term daily administration of RIC increased endogenous fibrinolysis, whereas a single RIC treatment did not acutely influence endogenous fibrinolysis. Fifteen studies had investigated the effect of RIC as a neuroprotective therapy in the prevention and treatment of stroke. Long-term RIC administration proved effective in reducing new cerebral vascular lesions in patients with established cerebrovascular disease. In patients with acute stroke, RIC was safe and feasible, though its clinical efficacy as a neuroprotectant is yet unproven. In conclusion, a single RIC treatment does not affect fibrinolysis in the acute phase, whereas long-term RIC administration may increase endogenous fibrinolysis. Increased endogenous fibrinolysis is unlikely to be the mediator of the acute neuroprotective effect of RIC in stroke patients, whereas it may partly explain the reduced stroke recurrence associated with long-term RIC treatment.

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“…Despite GM has been traditionally considered to have lower tolerability to infarction in ischemic stroke patients [ 60 , 61 , 62 ], WM is found injured in most strokes, and there are studies reporting the high sensitivity to ischemia of the latter, possibly due to its reduced collateral blood supply [ 22 , 37 ]. In addition, differential expression of relevant receptors (e.g., glutamate receptors of NMDA or AMPA subtype, or hemoglobin receptors) in the specific cell types of GM (e.g., neurons) or WM (e.g., OLs) has an impact on their differential susceptibility to excitotoxicity in ischemic stroke [ 25 , 45 , 63 , 64 , 65 , 66 , 67 ] or to cytotoxicity by hemoglobin or heme iron molecules in hemorrhagic stroke [ 68 , 69 , 70 ].…”

Section: Importance Of White Matter Injury In Strokementioning

confidence: 99%

Relevance of Porcine Stroke Models to Bridge the Gap from Pre-Clinical Findings to Clinical Implementation

Melià-Sorolla

Castaño

DeGregorio-Rocasolano

et al. 2020

IJMS

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In the search of animal stroke models providing translational advantages for biomedical research, pigs are large mammals with interesting brain characteristics and wide social acceptance. Compared to rodents, pigs have human-like highly gyrencephalic brains. In addition, increasingly through phylogeny, animals have more sophisticated white matter connectivity; thus, ratios of white-to-gray matter in humans and pigs are higher than in rodents. Swine models provide the opportunity to study the effect of stroke with emphasis on white matter damage and neuroanatomical changes in connectivity, and their pathophysiological correlate. In addition, the subarachnoid space surrounding the swine brain resembles that of humans. This allows the accumulation of blood and clots in subarachnoid hemorrhage models mimicking the clinical condition. The clot accumulation has been reported to mediate pathological mechanisms known to contribute to infarct progression and final damage in stroke patients. Importantly, swine allows trustworthy tracking of brain damage evolution using the same non-invasive multimodal imaging sequences used in the clinical practice. Moreover, several models of comorbidities and pathologies usually found in stroke patients have recently been established in swine. We review here ischemic and hemorrhagic stroke models reported so far in pigs. The advantages and limitations of each model are also discussed.

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Pathophysiological Mechanisms and Potential Therapeutic Targets in Intracerebral Hemorrhage

Cited by 95 publications

References 85 publications

Activation of the Melanocortin-1 Receptor by NDP-MSH Attenuates Oxidative Stress and Neuronal Apoptosis through PI3K/Akt/Nrf2 Pathway after Intracerebral Hemorrhage in Mice

Activation of the Melanocortin-1 Receptor by NDP-MSH Attenuates Oxidative Stress and Neuronal Apoptosis through PI3K/Akt/Nrf2 Pathway after Intracerebral Hemorrhage in Mice

Fibrinolysis and Remote Ischemic Conditioning: Mechanisms and Treatment Perspectives in Stroke

Relevance of Porcine Stroke Models to Bridge the Gap from Pre-Clinical Findings to Clinical Implementation

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