Biomedical subjects

Robert Vink

Publications and source records attributed to Robert Vink.

22 records · Page 2Linked to original sources

PubMed2002

Inhibition of cyclooxygenase 2 by nimesulide improves cognitive outcome more than motor outcome following diffuse traumatic brain injury in rats.

Prostanoid synthesis is regulated by the enzyme cyclo-oxygenase (COX) that is present in at least two isoforms: COX-1, the constitutive form, and COX-2, the inducible form. Expression of COX-2 has recently been shown to be an important determinant of the cytotoxicity connected with inflammation following ischemic injury to the brain. The present study examines the temporal and spatial profiles of COX-2 expression following diffuse traumatic brain injury (TBI) in rats, and the effects of the COX-2 inhibitor nimesulide on cognitive and motor outcomes. Adult, male Sprague-Dawley rats were injured using the 2-meter impact acceleration model of diffuse TBI. At preselected time points after injury, animals were killed and the expression of COX-2 was measured in the hippocampus and parietal cortex by immunohistochemistry and Western blotting techniques. Effects of nimesulide (6 mg/kg daily over ten days) on cognitive and motor outcome was assessed in a separate group of animals using the Barnes circular maze and rotarod test, respectively. A highly significant up-regulation of COX-2 expression was found in the hippocampus as early as 3 h post-trauma and persisting for at least 12 days after TBI. In contrast, a slight but significant upregulation of COX-2 expression occurred in the cortex only at 3 days after trauma. Administration of the COX-2 inhibitor nimesulide resulted in a significant and substantial improvement in cognitive function compared to vehicle-treated controls, while motor deficits after injury was only improved at 24 h after injury. We conclude that COX-2 is involved in the development of functional deficits following diffuse TBI, particularly cognitive deficits, and that these can be improved by administration of COX-2 inhibitors.

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PubMed2002

Intratracheal administration of glucocorticoids using surfactant as a vehicle.

1. Glucocorticoids are an effective treatment in the amelioration of chronic lung disease in neonates. However, systemic administration of glucocorticoids to neonates is associated with significant side-effects that preclude them as an early intervention to prevent onset of the condition. Conversely, local intratracheal administration of glucocorticoids may prevent inflammatory insult to the lungs without the development of systemic side-effects. We therefore investigated whether local intratracheal delivery of corticosteroids could be facilitated using surfactant as a vehicle. 2. Addition of dexamethasone to either diluted or commercial artificial surfactant, Survanta (Abbott Industries, Sydney, NSW, Australia), did not alter the surface properties of the surfactant. 3. After intratracheal instillation to rats, radiolabelled dexamethasone in Survanta was well distributed throughout all four lobes of the lungs. A concentration gradient of the steroid was observed between the root and the peripheral sections of all lobes. 4. Our results suggest that surfactant is an effective vehicle for intratracheal delivery of glucocorticoids. Moreover, we propose that prophylactic intratracheal administration of glucocorticoids administered shortly after birth may prevent inflammatory insult to the lungs and thereby reduce the likelihood of chronic lung disease developing.

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PubMed2002

Temporal characterisation of pro- and anti-apoptotic mechanisms following diffuse traumatic brain injury in rats.

Few studies have characterised apoptosis in a brain injury model that causes a significant degree of diffuse axonal injury. Such characterisation is essential from a clinical viewpoint since diffuse axonal injury is a major component of human head injury. The present study therefore, examines the expression of active and proactive caspase-3, and the bax, bcl-2 and bcl-x members of the bcl-2 family, to characterise the temporal profile of apoptosis in a model of traumatic brain injury in rats that produces significant diffuse axonal injury. Pentobarbital anaesthetised male Sprague-Dawley rats were injured using the 2m impact-acceleration model of diffuse traumatic brain injury. After injury, diffuse trauma resulted in an increased bax expression followed by induction of caspase-3. The increase in caspase-3 was simultaneous with an increase in anti-apoptotic bcl-2 expression. Bcl-x levels were increased after induction of caspase-3 and the increased levels of bcl-x were sustained to the end of the 5-day observation period. Increased active caspase-3 expression was associated with the appearance of TUNEL positive cells. These cells were detected in different brain regions at different times, with some regions showing no apoptotic cells until 3 days after injury. No TUNEL positive cells were detected at 7 and 14 days after injury. DNA electrophoresis confirmed that DNA fragmentation was maximal at 3 days after injury. Increased active caspase-3 levels were also significantly correlated with increased bcl-2 levels (r=0.80; P<0.001) suggesting that the apoptotic cascade after diffuse traumatic brain injury is a carefully controlled cellular homeostatic response. Pharmacological manipulation of this balance may offer a therapeutic approach for preventing cell death and improving outcome after diffuse traumatic brain injury.

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PubMed2002

Novel therapies in development for the treatment of traumatic brain injury.

In industrialised countries, the mean per capita incidence of traumatic brain injury (TBI) that results in a hospital presentation is 250 per 100,000. In Europe and North America alone, this translates to > 2 million TBI presentations annually. Approximately 25% of these presentations are admitted for hospitalisation. Despite the significance of these figures, there is no single interventional pharmacotherapy that has shown efficacy in the treatment of clinical TBI. This lack of efficacy in clinical trials may be due, in part, to the inherent heterogeneity of the traumatic brain injury population. However, it is the multifactorial nature of secondary injury that also poses a major hurdle, particularly for those therapies that have been designed to specifically target an individual injury factor. It is now becoming increasingly recognised that any successful TBI therapy may have to simultaneously affect multiple injury factors, somewhat analogous to other broad spectrum interventions. Recent efforts in experimental TBI have therefore focussed on developing novel pharmacotherapies that may affect multiple injury factors and thus improve the likelihood of a successful outcome. While a number of interventions are noteworthy in this regard, this review will focus on three novel compounds that show particular promise: magnesium, substance P antagonists and cyclosporin A.

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