Changes in Local Microvascular Permeability and in the Effect of Intervention with 21-Aminosteroid (Tirilazad) in a New Experimental Model of Focal Cortical Injury in the Rat

Mathew, P; Bullock, Ross; Teasdale, Graham M.; McCulloch, James

doi:10.1089/neu.1996.13.465

Cited by 14 publications

(13 citation statements)

References 32 publications

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“…The main previous studies of injury–induced CNS barrier dysfunction to small molecules are those of Hartl et al . (1997) in rabbits following brain injury, Mathew et al . (1996) in rats following brain injury and Popovich et al .…”

Section: Discussionmentioning

confidence: 98%

“…(1997) reported increased visible extravasation of Na‐fluorescein (385 Da) from pial blood vessels on the surface of the brain in rabbits 1 h after a fluid percussion injury, but by 6 h postinjury the fluorescein was already confined to the vessel lumen (these authors did not investigate later time points or other times between 1 and 6 h). Mathew et al . (1996) and Popovich et al .…”

Section: Discussionmentioning

confidence: 99%

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Changes in blood–brain barrier permeability to large and small molecules following traumatic brain injury in mice

Habgood

Bye

Dziegielewska

et al. 2007

Eur J of Neuroscience

201

161

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The entry of therapeutic compounds into the brain and spinal cord is normally restricted by barrier mechanisms in cerebral blood vessels (blood-brain barrier) and choroid plexuses (blood-CSF barrier). In the injured brain, ruptured cerebral blood vessels circumvent these barrier mechanisms by allowing blood contents to escape directly into the brain parenchyma. This process may contribute to the secondary damage that follows the initial primary injury. However, this localized compromise of barrier function in the injured brain may also provide a 'window of opportunity' through which drugs that do not normally cross the blood-brain barriers are able to do so. This paper describes a systematic study of barrier permeability in a mouse model of traumatic brain injury using both small and large inert molecules that can be visualized or quantified. The results show that soon after trauma, both large and small molecules are able to enter the brain in and around the injury site. Barrier restriction to large (protein-sized) molecules is restored by 4-5 h after injury. In contrast, smaller molecules (286-10,000 Da) are still able to enter the brain as long as 4 days postinjury. Thus the period of potential secondary damage from barrier disruption and the period during which therapeutic compounds have direct access to the injured brain may be longer than previously thought.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Changes in blood–brain barrier permeability to large and small molecules following traumatic brain injury in mice

Habgood

Bye

Dziegielewska

et al. 2007

Eur J of Neuroscience

201

161

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“…Our finding of the significantly increased BBB permeability at 4 h post trauma is in accordance with a previous report that the barrier leakage to a-aminoisobutyric acid peaks at 4 h after a focal cortical contusion. 44 The elevation of the BBB permeability between 1 and 4 h following injury might be due to further damage of the disrupted barrier post trauma, which is caused by the ischemia right after TBI, 44 or the greater surface area of the leaky BBB induced by the higher perfusion of the disrupted vessels via the above mentioned bypass.…”

Section: Cerebral Microvascular Responses In Injured Brain Y Lin Et Almentioning

confidence: 99%

Blood–brain barrier permeability is positively correlated with cerebral microvascular perfusion in the early fluid percussion-injured brain of the rat

Lin

Pan

Wang

et al. 2012

Laboratory Investigation

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The blood-brain barrier (BBB) opening following traumatic brain injury (TBI) provides a chance for therapeutic agents to cross the barrier, yet the reduction of the cerebral microvascular perfusion after TBI may limit the intervention. Meanwhile, optimizing the cerebral capillary perfusion by the strategies such as fluid administration may cause brain edema due to the BBB opening post trauma. To guide the TBI therapy, we characterized the relationship between the changes in the cerebral capillary perfusion and BBB permeability after TBI. First, we observed the changes of the cerebral capillary perfusion by the intracardiac perfusion of Evans Blue and the BBB disruption with magnetic resonance imaging (MRI) in the rat subjected to lateral fluid percussion (FP) brain injury. The correlation between two variables was next evaluated with the correlation analysis. Since related to BBB breakdown, matrix metalloproteinase-9 (MMP-9) activity was finally detected by gelatin zymography. We found that the ratios of the perfused microvessel numbers in the lesioned cortices were significantly reduced at 0 and 1 h post trauma compared with that in the normal cortex, which then dramatically recovered at 4 and 24 h after injury, and that the BBB permeability was greatly augmented in the ipsilateral parts at 4, 12, and 24 h, and in the contralateral area at 24 h after injury compared with that in the uninjured brain. The correlation analysis showed that the BBB permeability increase was related to the restoration of the cerebral capillary perfusion over a 24-h period post trauma. Moreover, the gelatin zymography analysis indicated that the MMP-9 activity in the injured brain increased at 4 h and significantly elevated at 12 and 24 h as compared to that at 0 or 1 h after TBI. Our findings demonstrate that the 4 h post trauma is a critical turning point during the development of TBI, and, importantly, the correlation analysis may guide us how to treat TBI.

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“…This is not surprising, given tirilazad's demonstrated efficacy in animal models of head injury, subarachnoid hemorrhage (SAH) and cerebral ischemia (Smith et al, 1994;Hall, 1996Hall, , 1997. Tirilazad has been shown to attenuate the post-injury rise in cortical «OH levels and to protect the blood-brain barrier (BBB) following impact injury in the rat and mouse Smith et al, 1994;Mathew et al, 1996), and to improve microvascular hypoperfusion as well as decrease BBB damage, edema, and delayed vasospasm in SAH (Hall and Travis, 1988a;Zuccarello and Anderson, 1989;Hall, 1996). We have also reported that a signifi-cant loss of cortical tissue, indicative of progressive neuronal degeneration, occurs in shaken infant rats 7-14 days post-injury (Smith et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…Blood-brain barrier damage has also been observed following the intraventricular infusion of NMDA in rats (Dietrich et al, 1992). NMDA receptor antagonists and glutamate release inhibitors, on the other hand, have been shown to decrease edema and infarct volume following head injury and hypoxia-ischemia in both neonatal (McDonald and Johnston, 1990; and adult rats (Mclntosh et al, 1990;Povlishock, 1993;Wahl et al, 1996;Du et al, 1996). Similarly, BBB damage is reportedly reduced following transient focal ischemia in adult rats pretreated with the NMDA antagonists, MK-801 or dextrorphan (Yang et al, 1994;Du et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Tirilazad Widens the Therapeutic Window for Riluzole-Induced Attenuation of Progressive Cortical Degeneration in an Infant Rat Model of the Shaken Baby Syndrome

Smith¹,

Hall²

1998

Journal of Neurotrauma

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Our infant rat model of traumatic subarchnoid hemorrhage combines violent shaking and hypoxia to produce subdural hemorrhaging and progressive cortical degeneration similar to that seen in victims of the shaken baby syndrome. Anesthetized, 6-day-old male rats were subjected to one episode of shaking under hypoxic conditions. Brain histologies revealed moderate-to-severe cortical hemorrhaging at 48 h postinjury and progressive cortical degeneration, as indicated by a 15.3% and 20.2% reduction in cortical wet weight, at 7 and 14 days postinjury, respectively. The purpose of the present study was to assess the effects of two antioxidant lipid peroxidation inhibitors (tirilazad mesylate and PNU-101033E), and the glutamate release inhibitor (riluzole), upon the brain pathology seen in this model. A significant, 54.3-75.3%, reduction in cortical hemorrhaging was observed in rats that were treated with a total of three doses of tirilazad (10 mg/kg, i.p.): 10 min before or 5-30 min after injury, and again at 2 and 24 h postinjury (p < 0.01 vs. vehicle). However, treatment with tirilazad or the more potent, brain-penetrating pyrrolopyrimidine, PNU-101033E (10 min before plus 2, 24, 48, and 72 h after), did not attenuate the progressive cortical degeneration typically seen at 14 days postinjury. These results suggest that free radicals play an important role in the pathophysiology of secondary brain hemorrhaging due to shaking + hypoxia, but may not be critical in the mediation of the subsequent neurodegeneration. Rather, glutamate neurotoxicity may be a key factor here. This is suggested by our observation that the glutamate release inhibitor, riluzole, significantly reduced cortical degeneration when it was administered up to 1 h postinjury in the present model. Specifically, the cortical wet weights of rats treated with 8 mg/kg riluzole (i.p.) 10 min before or 1 h after shaking + hypoxia (and again at 24 h postinjury) were 95.3% and 97.4% of noninjured controls, respectively, at 14 days postinjury (p < 0.02 vs. vehicle). Riluzole treatment beyond 1 h (e.g., 2 or 4 h postinjury) did not reduce the neurodegeneration. Lastly, we attempted to demonstrate that the therapeutic window for riluzole-induced attenuation of cortical degeneration could be extended beyond 1 h through the use of combination therapy. In this experiment, rat pups were treated with 10 mg/kg tirilazad (i.p.) at 30 min postinjury followed by 8 mg/kg riluzole (i.p.) at 4 and 24 h postinjury. At 14 days postinjury, the cortical wet weights of these rats were 94.5% of noninjured controls, thus demonstrating significant neuroprotection (p < 0.05 vs. vehicle) and a widening of the therapeutic window from 1 to 4 h in length. These results suggest that early attenuation of free radical-induced lipid peroxidation may slow down the biochemical cascade of events related to glutamate-induced excitotoxicity and, in doing so, prolong the time during which a glutamate release inhibitor, such as riluzole, is effective.

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Changes in Local Microvascular Permeability and in the Effect of Intervention with 21-Aminosteroid (Tirilazad) in a New Experimental Model of Focal Cortical Injury in the Rat

Cited by 14 publications

References 32 publications

Changes in blood–brain barrier permeability to large and small molecules following traumatic brain injury in mice

Changes in blood–brain barrier permeability to large and small molecules following traumatic brain injury in mice

Blood–brain barrier permeability is positively correlated with cerebral microvascular perfusion in the early fluid percussion-injured brain of the rat

Tirilazad Widens the Therapeutic Window for Riluzole-Induced Attenuation of Progressive Cortical Degeneration in an Infant Rat Model of the Shaken Baby Syndrome

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