Blood -brain barrier disruption was less under isoflurane than pentobarbital anesthesia via a PI3K/Akt pathway in early cerebral ischemia

Z., Oak; Mellender, Scott J.; Kiss, Geza; Liu, Xia; Weiss, Harvey R.

doi:10.1016/j.brainresbull.2017.02.007

Cited by 19 publications

(10 citation statements)

References 31 publications

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“…TNF signaling impacts the expression of junction-associated proteins in a BBB cell model [24]. In addition, the activity in PI3K-Akt pathway has recently shown to be important for BBB integrity in both mouse and rat [58,59], and the WNT signaling pathway has previously been indicated in governing BBB formation [17,24]. In our studies, the expression of BCRP and P-gp were upregulated in coculture.…”

Section: Discussionsupporting

confidence: 55%

Barrier Properties and Transcriptome Expression in Human iPSC-Derived Models of the Blood–Brain Barrier

Delsing

Dönnes²,

Sánchez

et al. 2018

Stem Cells

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Cell-based models of the blood-brain barrier (BBB) are important for increasing the knowledge of BBB formation, degradation and brain exposure of drug substances. Human models are preferred over animal models because of interspecies differences in BBB structure and function. However, access to human primary BBB tissue is limited and has shown degeneration of BBB functions in vitro. Human induced pluripotent stem cells (iPSCs) can be used to generate relevant cell types to model the BBB with human tissue. We generated a human iPSC-derived model of the BBB that includes endothelial cells in coculture with pericytes, astrocytes and neurons. Evaluation of barrier properties showed that the endothelial cells in our coculture model have high transendothelial electrical resistance, functional efflux and ability to discriminate between CNS permeable and non-permeable substances. Whole genome expression profiling revealed transcriptional changes that occur in coculture, including upregulation of tight junction proteins, such as claudins and neurotransmitter transporters. Pathway analysis implicated changes in the WNT, TNF, and PI3K-Akt pathways upon coculture. Our data suggest that coculture of iPSC-derived endothelial cells promotes barrier formation on a functional and transcriptional level. The information about gene expression changes in coculture can be used to further improve iPSC-derived BBB models through selective pathway manipulation. Stem Cells 2018.

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Section: Discussionsupporting

confidence: 55%

Barrier Properties and Transcriptome Expression in Human iPSC-Derived Models of the Blood–Brain Barrier

Delsing

Dönnes²,

Sánchez

et al. 2018

Stem Cells

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“…Short-duration treatments with isoflurane during or shortly after SE in the kainate or paraoxon models of epileptogenesis attenuated BBB breakdown, glial activation, and neuroinflammation, reduced neuronal damage, abolished epileptiform activity, and reduced the incidence of late epilepsy. 96 The vasoprotective effect of isoflurane has also been shown in rodent models of stroke [97][98][99] and in subarachnoid hemorrhage. 100 Thus, preclinical data suggest isoflurane as a promising antiepileptogenic, vasoprotective, and neuroprotective agent in specific patient populations, including SE and severe traumatic or ischemic brain injuries that require general anesthesia.…”

Section: Isofluranementioning

confidence: 98%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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“…As warfarin has a half-life between 20 and 60 h, we expected that warfarin had a pharmacologically active anticoagulant effect starting several hours after dosing (initially with decreasing factor VII levels) until euthanasia at 24 h later. Route of administration was selected to minimize stress and negate the need for anesthetics, both of which could influence BBB integrity [ 38 , 39 ]. A non-lethal dosage was selected to produce a clinically relevant increase in bleeding time (i.e., international normalized ratio 2–3× longer than normal).…”

Section: Experiments 3: Testing For Late Bleeding After Ich Onsetmentioning

confidence: 99%

Prolonged Blood-Brain Barrier Injury Occurs After Experimental Intracerebral Hemorrhage and Is Not Acutely Associated with Additional Bleeding

Nadeau

Dietrich

Wilkinson

et al. 2018

Transl. Stroke Res.

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Intracerebral hemorrhage (ICH) causes blood-brain barrier (BBB) damage along with altered element levels in the brain. BBB permeability was quantified at 3, 7, and 14 days with Evans Blue dye after collagenase-induced ICH in rat. At peak permeability (day 3), a gadolinium (Gd)-based contrast agent was injected to further characterize BBB disruption, and X-ray fluorescence imaging (XFI) was used to map Gd, Fe, Cl, and other elements. XFI revealed that Ca, Cl, Gd, and Fe concentrations were significantly elevated, whereas K was significantly decreased. Therefore, using Gd-XFI, we co-determined BBB dysfunction with alterations in the metallome, including those that contribute to cell death and functional outcome. Warfarin was administered 3 days post-ICH to investigate whether additional or new bleeding occurs during peak BBB dysfunction, and hematoma volume was assessed on day 4. Warfarin administration prolonged bleeding time after a peripheral cut-induced bleed, but warfarin did not worsen hematoma volume. Accordingly, extensive BBB leakage occurred after ICH, but did not appear to affect total hematoma size.

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Blood -brain barrier disruption was less under isoflurane than pentobarbital anesthesia via a PI3K/Akt pathway in early cerebral ischemia

Cited by 19 publications

References 31 publications

Barrier Properties and Transcriptome Expression in Human iPSC-Derived Models of the Blood–Brain Barrier

Barrier Properties and Transcriptome Expression in Human iPSC-Derived Models of the Blood–Brain Barrier

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Prolonged Blood-Brain Barrier Injury Occurs After Experimental Intracerebral Hemorrhage and Is Not Acutely Associated with Additional Bleeding

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