Acute Leakage Patterns of Fluorescent Plasma Flow Markers after Transient Focal Cerebral Ischemia Suggest Large Openings in Blood‐Brain Barrier

Nagaraja, Tavarekere N.; Keenan, Kelly A.; Fenstermacher, Joseph D.; Knight, Robert A.

doi:10.1080/10739680701409811

Cited by 51 publications

(56 citation statements)

References 40 publications

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“…As shown previously, significant opening of the BBB starts only 6 h after ischemia/reperfusion (Nagaraja et al, 2008;Strbian et al, 2008). Therefore, the rapid transfer of nanospheres to the brain cannot be attributed to the increased permeability of the BBB.…”

mentioning

confidence: 86%

A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood–Brain Barrier and Provides Neuroprotection

Aktaş²,

et al. 2009

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Caspases play an important role as mediators of cell death in acute and chronic neurological disorders. Although peptide inhibitors of caspases provide neuroprotection, they have to be administered intracerebroventricularly because they cannot cross the blood-brain barrier (BBB). Herein, we present a nanocarrier system that can transfer chitosan nanospheres loaded with N-benzyloxycarbonylAsp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVD-FMK), a relatively specific caspase-3 inhibitor, across BBB. Caspase-3 was chosen as a pharmacological target because of its central role in cell death. Polyethylene glycol-coated nanospheres were conjugated to an anti-mouse transferrin receptor monoclonal antibody (TfRMAb) that selectively recognizes the TfR type 1 on the cerebral vasculature. We demonstrate with intravital microscopy that this nanomedicine is rapidly transported across the BBB without being measurably taken up by liver and spleen. Pre-or post-treatment (2 h) with intravenously injected Z-DEVD-FMK-loaded nanospheres dose dependently decreased the infarct volume, neurological deficit, and ischemia-induced caspase-3 activity in mice subjected to 2 h of MCA occlusion and 24 h of reperfusion, suggesting that they released an amount of peptide sufficient to inhibit caspase activity. Similarly, nanospheres inhibited physiological caspase-3 activity during development in the neonatal mouse cerebellum on postnatal day 17 after closure of the BBB. Neither nanospheres functionalized with TfRMAb but not loaded with Z-DEVD-FMK nor nanospheres lacking TfRMAb but loaded with Z-DEVD-FMK had any effect on either paradigm, suggesting that inhibition of caspase activity and subsequent neuroprotection were due to efficient penetration of the peptide into brain. Thus, chitosan nanospheres open new and exciting opportunities for brain delivery of biologically active peptides that are useful for the treatment of CNS disorders.

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confidence: 86%

A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood–Brain Barrier and Provides Neuroprotection

Aktaş²,

et al. 2009

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“…The study concluded that the 2000 kDa dextran was too large to pass through the opening of the BBB after 3 h of reperfusion in about 40% of the microvascular networks that were visualized. 120 These studies give insight on the amount and extent of leakage that different dextrans could indicate, in regard to the disruption of particular components of the BBB. The studies indicate that selectivity in choosing a dextran size to assess BBB permeability as a result of neurotrauma is important.…”

Section: Methods Of Detection Of Vascular Changes Post-tbimentioning

confidence: 99%

“…These effects deplete energy and lead to alterations in calcium homeostasis. 120 Excess cytoplasmic calcium is taken up by various calcium buffers of the cell, such as the mitochondria. Calcium intake by mitochondria affects the mitochondrial membrane potential and when its threshold is reached, the excess calcium is pumped back into cell cytoplasm.…”

Section: What Component Of the Cerebral Vasculature Is ''Leaky''?mentioning

confidence: 99%

Effects of concussion on the blood–brain barrier in humans and rodents

Sahyouni

Gutierrez

Gold

et al. 2017

Journal of Concussion

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Traumatic brain injury and the long-term consequences of repeated concussions constitute mounting concerns in the United States, with 5.3 million individuals living with a traumatic brain injury-related disability. Attempts to understand mechanisms and possible therapeutic approaches to alleviate the consequences of repeat mild concussions or traumatic brain injury on cerebral vasculature depend on several aspects of the trauma, including: (1) the physical characteristics of trauma or insult that result in damage; (2) the time ''window'' after trauma in which neuropathological features develop; (3) methods to detect possible breakdown of the blood-brain barrier; and (4) understanding different consequences of a single concussion as compared with multiple concussions. We review the literature to summarize the current understanding of blood-brain barrier and endothelial cell changes post-neurotrauma in concussions and mild traumatic brain injury. Attention is focused on concussion and traumatic brain injury in humans, with a goal of pointing out the gaps in our knowledge and how studies of rodent model systems of concussion may help in filling these gaps. Specifically, we focus on disruptions that concussion causes to the blood-brain barrier and its multifaceted consequences. Importantly, the magnitude of post-concussion blood-brain barrier dysfunction may influence the time course and extent of neuronal recovery; hence, we include in this review comparisons of more severe traumatic brain injury to concussion where appropriate. Finally, we address the important, and still unresolved, issue of how best to detect possible breakdown in the blood-brain barrier following neurotrauma by exploring intravascular tracer injection in animal models to examine leakage into the brain parenchyma.

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“…The EBDalbumin conjugate can be identified macroscopically by its striking blue color within tissue and observed by red auto-fluorescence in tissue sections examined by fluorescence microscopy [40]. Sham-operated animals or ischemic/reperfused animals were injected with 0.1 ml of 4% EBD (Sigma) in 0.9% saline through a dissected femoral vein.…”

Section: Extravasation Of Evans Blue Dye (Ebd)mentioning

confidence: 99%

Blood-derived iron mediates free radical production and neuronal death in the hippocampal CA1 area following transient forebrain ischemia in rat

et al. 2010

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Abnormal brain iron homeostasis has been proposed as a pathological event leading to oxidative stress and neuronal injury under pathological conditions. We examined the possibility that neuronal iron overload would mediate free radical production and delayed neuronal death (DND) in hippocampal CA1 area after transient forebrain ischemia (TFI). Mitochondrial free radicals (MFR) were biphasically generated in CA1 neurons 0.5-8 and 48-60 h after TFI. Treatment with Neu2000, a potent spin trapping molecule, as well as trolox, a vitamin E analogue, blocked the biphasic MFR production and attenuated DND in the CA1, regardless of whether it was administered immediately or even 24 h after reperfusion. The late increase in MFR was accompanied by iron accumulation and blocked by the administration of deferoxamine-an iron chelator. Iron accumulation was attributable to prolonged upregulation of the transferrin receptor and to increased uptake of peripheral iron through a leaky blood-brain barrier. Infiltration of ironcontaining cells and iron accumulation were attenuated by depletion of circulating blood cells through X-ray irradiation of the whole body except the head. The present findings suggest that excessive iron transported from blood mediates slowly evolving oxidative stress and neuronal death in CA1 after TFI, and that targeting ironmediated oxidative stress holds extended therapeutic time window against an ischemic event.

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Acute Leakage Patterns of Fluorescent Plasma Flow Markers after Transient Focal Cerebral Ischemia Suggest Large Openings in Blood‐Brain Barrier

Cited by 51 publications

References 40 publications

A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood–Brain Barrier and Provides Neuroprotection

A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood–Brain Barrier and Provides Neuroprotection

Effects of concussion on the blood–brain barrier in humans and rodents

Blood-derived iron mediates free radical production and neuronal death in the hippocampal CA1 area following transient forebrain ischemia in rat

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