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Fangyi Zhang, Shane M. Sprague, Farrokh Farrokhi, Matthew N. Henry, Minnette G. Son and Dennis G. Vollmer

Object. Traumatic brain injury (TBI) attenuates the cerebral vasodilation to hypercapnia. Cortical spreading depression (CSD) also transiently reduces hypercapnic vasodilation. The authors sought to determine whether the CSD elicited by a controlled cortical impact (CCI) injury masks the true effect of TBI on hypercapnic vasodilation, and whether a nitric oxide (NO) donor can reverse the attenuation of hypercapnic vasodilation following CCI.

Methods. Anesthetized rats underwent moderate CCI. Cerebral blood flow was monitored with laser Doppler flowmetry and the response to hypercapnia was determined for injured and sham-injured animals. The effect of the NO donor, S-nitroso-N-acetylpenicillamine (SNAP), on this response was also assessed.

At an uninjured cortical site ipsilateral to the CCI, a single wave of CSD was recorded and the CO2 response at this location was significantly attenuated for up to 30 minutes (seven rats, p < 0.05). At the injured cortex, hypercapnic vasodilation continued to be attenuated for 7 hours. The cerebral vasodilation to CO2 was 37 ± 5% in injured rats (six) compared with 84 ± 10% in the sham-injured group (five rats, p < 0.05). After 30 minutes of topical superfusion with SNAP, hypercapnic vasodilation was restored to 74 ± 7% (nine rats, p > 0.1 compared with that in the sham-injured group). In contrast, papaverine, an NO-independent vasodilator, failed to reverse the attenuation of the CO2 response to CCI.

Conclusions. The authors conclude that CSD elicited by CCI can mask the true effect of TBI on hypercapnic vasodilation for at least 30 minutes. Exogenous NO, but not papaverine, can reverse the attenuation of cerebrovascular reactivity to CO2 caused by TBI. This result supports the hypothesis that NO production is reduced after TBI and that the NO donor has a potential beneficial role in the clinical management of head injury.

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Raul Reyes, Miao Guo, Kathryn Swann, Siddharth U. Shetgeri, Shane M. Sprague, David F. Jimenez, Constance M. Barone and Yuchuan Ding

Object

A relationship has been found between peripheral thermal injury and cerebral complications leading to injury and death. In the present study, the authors examined whether tumor necrosis factor–α (TNF-α) and matrix metalloproteinase–9 (MMP-9) play a causative role in blood-brain barrier (BBB) disruption after peripheral thermal injury.

Methods

Thirty-two male Sprague-Dawley rats were subjected to thermal injury. One hour later, 8 rats were injected with TNF-α neutralizing antibody, and 8 were injected with doxycycline, an inhibitor of the MMP family proteins; 16 rats did not receive any treatment. Brain tissue samples obtained 7 hours after injury in the treated animals were examined for BBB function by using fluorescein isothiocyanate–dextran and by assessing parenchymal water content. Protein expression of basement membrane components (collagen IV, laminin, and fibronectin) was quantified on Western blot analysis, and MMP-9 protein expression and enzyme activity were determined using Western blot and gelatin zymography. Thermally injured rats that did not receive treatment were killed at 3, 7, or 24 hours after injury and tested for BBB functioning at each time point. Histological analysis for basement membrane proteins was also conducted in untreated rats killed at 7 hours after injury. Results of testing in injured rats were compared with those obtained in a control group of rats that did not undergo thermal injury.

Results

At 7 hours after thermal injury, a significant increase in the fluorescein isothiocyanate–dextran and water content of the brain was found (p < 0.05), but BBB dysfunction was significantly decreased in the rats that received TNF-α antibody or doxycycline (p < 0.05). In addition, the components of the basal lamina were significantly decreased at 7 hours after thermal injury (p < 0.01), and there were significant increases in MMP-9 protein expression and enzyme activity (p < 0.05). The basal lamina damage was reversed by inhibition of TNF-α and MMP-9, and the increase in MMP-9 protein was reduced in the presence of doxycycline (p < 0.05). The authors found that MMP-9 enzyme activity was significantly increased after thermal injury (p < 0.01) but decreased in the presence of either TNF-α antibody or doxycycline (p < 0.01).

Conclusions

The dual, inhibitory activity of both TNF-α and MMP-9 in brain injury suggests that a TNF-α and MMP-9 cascade may play a key role in BBB disruption. These results offer a better understanding of the pathophysiology of burn injuries, which may open new avenues for burn treatment beyond the level of current therapies.

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Lauren Fletcher, Sanjivan Kohli, Shane M. Sprague, Robert A. Scranton, Stuart A. Lipton, Augusto Parra, David F. Jimenez and Murat Digicaylioglu

Object

Individually, the cytokines erythropoietin (EPO) and insulin-like growth factor–I (IGF-I) have both been shown to reduce neuronal damage significantly in rodent models of cerebral ischemia. The authors have previously shown that EPO and IGF-I, when administered together, provide acute and prolonged neuroprotection in cerebrocortical cultures against N-methyl-d-aspartate–induced apoptosis. The aim of this study was to determine whether intranasally applied EPO plus IGF-I can provide acute neuroprotection in an animal stroke model and to show that intranasal administration is more efficient at delivering EPO plus IGF-I to the brain when compared with intravenous, subcutaneous, or intraperitoneal administration.

Methods

The EPO and IGF-I were administered intranasally to mice that underwent transient middle cerebral artery occlusion (MCAO). Stroke volumes were measured after 1 hour of MCAO and 24 hours of reperfusion. To evaluate the long-term effects of this treatment, behavioral outcomes were assessed at 3, 30, 60, and 90 days following MCAO. Radiography and liquid scintillation were used to visualize and quantify the uptake of radiolabeled 125I-EPO and 125I–IGF-I into the mouse brain after intranasal, intravenous, subcutaneous, or intraperitoneal administration.

Results

Intranasal administration of EPO plus IGF-I reduced stroke volumes within 24 hours and improved neurological function in mice up to 90 days after MCAO. The 125I-EPO and 125I–IGF-I were found in the brain within 20 minutes after intranasal administration and accumulated within the injured areas of the brain. In addition, intranasal administration delivered significantly higher levels of the applied 125I-EPO and 125I–IGF-I to the brain compared with intravenous, subcutaneous, or intraperitoneal administration.

Conclusions

The data demonstrate that intranasal EPO plus IGF-I penetrates into the brain more efficiently than other drug delivery methods and could potentially provide a fast and efficient treatment to prevent chronic effects of stroke.