Detrimental role of the EP1 prostanoid receptor in blood-brain barrier damage following experimental ischemic stroke

Frankowski, Jan C.; DeMars, Kelly M.; Ahmad, Abdullah Shafique; Hawkins, Kimberly E.; Yang, Changjun; Leclerc, Jenna L; Doré, Sylvain; Candelario‐Jalil, Eduardo

doi:10.1038/srep17956

Cited by 57 publications

(64 citation statements)

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“…Focal cerebral ischemia was done by tMCAO using the intraluminal filament method as previously described by our group (Candelario‐Jalil, Gonzalez‐Falcon, Garcia‐Cabrera, Leon, & Fiebich, 2007; Frankowski et al., 2015; Hawkins et al., 2014). Briefly, non‐fasted rats were anesthetized with isoflurane (4% for induction and 2% for maintenance) in medical‐grade oxygen.…”

Section: Methodsmentioning

confidence: 99%

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Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery

et al. 2017

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BackgroundResolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A4 (LXA 4) is an anti‐inflammatory, pro‐resolution lipid mediator that reduces neuroinflammation in stroke. Since LXA 4 is rapidly inactivated, potent analogs have been synthesized, including BML‐111. We hypothesized that post‐ischemic, intravenous treatment with BML‐111 for 1 week would provide neuroprotection and reduce neurobehavioral deficits at 4 weeks after ischemic stroke in rats. Additionally, we investigated the potential protective mechanisms of BML‐111 on the post‐stroke molecular and cellular profile.MethodsA total of 133 male Sprague‐Dawley rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) and BML‐111 administration was started at the time of reperfusion. Two methods of week‐long BML‐111 intravenous administration were tested: continuous infusion via ALZET ® osmotic pumps (1.25 and 3.75 μg μl−1 hr−1), or freshly prepared daily single injections (0.3, 1, and 3 mg/kg). We report for the first time on the stability of BML‐111 and characterized an optimal dose and a dosing schedule for the administration of BML‐111.ResultsOne week of BML‐111 intravenous injections did not reduce infarct size or improve behavioral deficits 4 weeks after ischemic stroke. However, post‐ischemic treatment with BML‐111 did elicit early protective effects as demonstrated by a significant reduction in infarct volume and improved sensorimotor function at 1 week after stroke. This protection was associated with reduced pro‐inflammatory cytokine and chemokine levels, decreased M1 CD40+ macrophages, and increased alternatively activated, anti‐inflammatory M2 microglia/macrophage cell populations in the post‐ischemic brain.ConclusionThese data suggest that targeting the endogenous LXA 4 pathway could be a promising therapeutic strategy for the treatment of ischemic stroke. More work is necessary to determine whether a different dosing regimen or more stable LXA 4 analogs could confer long‐term protection.

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Section: Methodsmentioning

confidence: 99%

“…Double immunofluorescence was performed as previously described in our lab (Frankowski et al., 2015). Rats ( n = 5, BML‐111 at 1 mg/kg; n = 7, vehicle group) were perfused with PBS followed by 4% PFA.…”

Section: Methodsmentioning

confidence: 99%

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery

et al. 2017

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“…These results from ischemia models suggest that the EP1 receptor might contribute to PGE 2 -mediated neurotoxicity. In addition, EP1 receptor activation plays an important role in the BBB impairment following ischemic strokes [49]. A recent study revealed that global ablation of EP1 receptor reduces seizure threshold, neuronal damage and proinflammatory responses in hippocampus after kainate injection in mice [50].…”

Section: Prostaglandin Receptor Antagonistsmentioning

confidence: 99%

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

Dey

Jiang

et al. 2016

Trends in Pharmacological Sciences

165

122

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As a crucial component of brain innate immunity, neuroinflammation initially contributes to neuronal tissue repair and maintenance. However, chronic inflammatory processes within the brain and associated blood-brain barrier impairment often cause neurotoxicity and hyperexcitability. Mounting evidence points to a mutual facilitation between inflammation and epilepsy, suggesting that blocking the undesired inflammatory signaling within the brain might provide novel strategies to treat seizures and epilepsy. Neuroinflammation is primarily characterized by the upregulation of proinflammatory mediators in epileptogenic foci, among which, cyclooxygenase-2/prostaglandin E2, interleukin-1β, transforming growth factor-β, toll-like receptor 4, high-mobility group box 1, and tumor necrosis factor-α have been extensively studied. Small molecules that specifically target these key proinflammatory perpetrators have been evaluated for antiepileptic and antiepileptogenic effects in animal models. These important preclinical studies provide new insights into the regulation of inflammation in epileptic brains and guide drug discovery efforts aimed at developing novel anti-inflammatory therapies for seizures and epilepsy.

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“…This report proves an important link between neuroinflammation and BBB breakdown via MMPs. EP1 as a therapeutic target should be considered [152]. Further considerable mechanisms play role in the neuroinflammation in case of mixed and vascular dementia [248].…”

Section: Neuroinflammationmentioning

confidence: 99%

Hemorrhagic transformation of ischemic stroke

J¹,

Hortobágyi²

2017

Vascul Dis Ther

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The better understanding of the diverse mechanisms leading to the hemorrhagic transformation of an ischemic stroke is the crucial point in the prevention of this altogether common phenomenon. The different individual risk factors include the anatomical variability of collateral blood supply, age, genetics, body weight, etiology of the occlusion, side of the occluded vessel, renal status, stroke severity, history of high serum glucose or hypertension and hypertension or hyperglycemia at the onset of the stroke, ferritin level, INR, antiplatelet usage or the platelet count etc. All these might contribute to the process of hemorrhagic transformation. These risk factors have been identified by retrospective epidemiological studies and are useful to identify patients who are at high risk for hemorrhagic conversion and help the decision between conservative, thrombolytic or more advanced treatments such as thrombectomy. The modulations of potential molecular targets participating in the process seem to be promising in animal models, but human trials are lacking the breakthrough success so far, both in extending the time frame of the thrombolysis and in replacing the recombinant tissue plasminogen activator (rtPA) as thrombolytic agent.So far, the careful preselection of patients eligible for thrombolytic therapy is the best way to prevent hemorrhagic transformation. The intensive research in the field revealing small but important molecular details are continuously contributing to the better understanding of hemorrhagic transformation with the intention of finding new agents that co-administrated to the rtPA or completely replacing that could decrease the risk of secondary bleeding.The aim of this review is to give comprehensive insight into the process of hemorrhagic transformation of ischemic stroke, starting with basic overview of the penumbra concept and the collateral supply followed by discussion of the recanalisation-reperfusion-hemorrhagic transformation process after vessel occlusion also highlighting the importance of timing and ratio of recanalisation spontaneously and in case of thrombolytic agent administration. We overview the risk factors of hemorrhagic transformation, which may be helpful to physicians to identify high risk patients before rtPA administration. The last part of the work is dealing with future therapeutic possibilities based on the so far revealed molecular mechanisms of hemorrhagic transformation. With the aim to assess the rate and influencing factors on the recanalisation and reperfusion rate 381 patients with large-vessel occlusion was investigated. The patient group involved ones treated with rtPA or treated conservatively. Partial or complete recanalisation was achieved in 121 out of 210 (58%) patients after intravenous rtPA administration. The recanalisation success was more likely if the patient had atrial fibrillation [4] -maybe because cardioembolic clots consists more fibrin and are more likely to reopen by plasmin proteolysis than thrombosis of an atherosclerotic plaq...

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Detrimental role of the EP1 prostanoid receptor in blood-brain barrier damage following experimental ischemic stroke

Cited by 57 publications

References 64 publications

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

Hemorrhagic transformation of ischemic stroke

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Detrimental role of the EP1 prostanoid receptor in blood-brain barrier damage following experimental ischemic stroke

Cited by 57 publications

References 64 publications

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

Hemorrhagic transformation of ischemic stroke

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Product

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Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery