Biomedical subjects

R Vink

Publications and source records attributed to R Vink.

At least 19 recordsLinked to original sources

PubMed1998

Blood-free magnesium concentration declines following graded experimental traumatic brain injury.

Traumatic brain injury has been shown to result in a decrease in brain-free magnesium concentration that is associated with the development of neurologic motor deficits. Although these changes have been well characterized in the brain, changes in free magnesium homeostasis have not been characterized in other fluid compartments. The current experiments use ion selective electrodes to measure alterations in blood-free magnesium concentration following graded experimental brain injury in rats and to compare these changes with subsequent neurologic outcome. After severe impact-acceleration-induced injury, blood-free magnesium levels significantly declined (p < 0.05) by 25% and remained depressed for at least 4 days after injury. After moderate injury, the decline in blood-free magnesium was less than that observed in the severe injury group with respect to both degree of decline and duration of decline. The post-traumatic blood-free magnesium concentration correlated to observed motor deficits as assessed by rotarod evaluation (p < 0.001). We conclude that blood-free magnesium levels may be a prognostic indicator of outcome following severe traumatic brain injury.

Animals↗

PubMed1998

Neuroprotective effects of MgSO4 and MgCl2 in closed head injury: a comparative phosphorus NMR study.

Previous studies have shown that free magnesium levels decline after traumatic brain injury and that magnesium salt administration improves posttraumatic outcome. These earlier studies, however, have been limited to models of injury that do not produce a significant degree of diffuse axonal injury and have used either MgSO4 or MgCl2 as the magnesium salt. The present study compares the neuroprotective efficacy of MgSO4 and MgCl2 in a severe model of diffuse axonal injury in rats using phosphorus nuclear magnetic resonance spectroscopy and the rotarod test to monitor effects on metabolism and neurologic outcome, respectively. Both MgSO4 and MgCl2 given as a bolus of 100 micromoles/kg at 30 min after severe, closed head injury significantly improved brain intracellular free magnesium concentration and neurologic outcome. These findings suggest that both salts penetrate the blood-brain barrier after brain trauma, enter injured tissue, and subsequently improve neurologic outcome.

Animals↗

PubMed1997

Magnesium sulphate improves neurologic outcome following severe closed head injury in rats.

While recent evidence suggests that brain intracellular free magnesium concentration declines following severe diffuse traumatic brain injury, no studies have examined whether magnesium administration following such injury can improve subsequent neurologic outcome. The present study shows that MgSO4 administered as a bolus at 30 min following severe closed head injury in rats significantly improves posttraumatic neurologic outcome as assessed by both rotarod and angleboard tests. Moreover, this improvement in outcome was evident with both intravenous and intramuscular drug administration. We conclude that parenteral administration of magnesium sulphate may be neuroprotective following severe closed head injury of a diffuse nature.

Animals↗

PubMed1997

Blood glucose concentration does not affect outcome in brain trauma: A 31P MRS study.

Effects of blood glucose concentration on biochemical and neurologic outcome following lateral fluid percussion-induced traumatic injury of moderate severity (2.8 atm) in rats were studied using radioactive phosphorus (31P) magnetic resonance spectroscopy (MRS) and a battery of tests designed to evaluate posttraumatic neurologic motor function. Prior to injury, male Sprague-Dawley rats (n = 18) were randomly assigned to receive either dextrose, 2 ml 50% (wt/vol), zinc insulin (10 IU/kg) or no treatment, thus dividing the animals into hyperglycemic, hypoglycemic, and normoglycemic groups, respectively. Animals were then injured, monitored for 4 h by 31P MRS before being allowed to recover, and assessed for posttraumatic motor function. Following brain injury, there was no difference in brain intracellular pH between groups over the 4-h posttraumatic MRS monitoring period. Similarly, intracellular free magnesium, cytosolic phosphorylation potential, and neurologic outcome posttrauma were not significantly different between groups. We conclude that, unlike models of ischemia, blood glucose concentration may not be a significant factor affecting outcome in traumatic brain injury.

Animals↗

PubMed1996

Traumatic brain axonal injury produces sustained decline in intracellular free magnesium concentration.

Decline in brain intracellular free magnesium concentration following experimental traumatic brain injury has been widely reported in a number of studies. However, to date, these studies have been confined to focal models of brain injury and temporally limited to the immediate 8-h period post-trauma. Recently, a new model of impact-acceleration brain injury has been developed which produces nonfocal diffuse axonal injury more typical of severe clinical trauma. The present study has used phosphorus magnetic resonance spectroscopy and the rotarod motor test to characterise magnesium homeostasis and neurologic outcome over a period of 8 days after induction of severe impact-acceleration injury in rats. Severe impact-acceleration induced injury resulted in a highly significant and sustained decline in intracellular free magnesium concentration that was apparent for 4 days post-trauma with recovery to preinjury levels by day six. There were no significant changes in pH or ATP concentration at any time point post-injury. All animals demonstrated a significant neurologic deficit over the assessment period. The extended period of magnesium decline after severe diffuse brain trauma suggests that repeated administration may be required for pharmacotherapies targeted at restoring magnesium homeostasis.

Animals↗

PubMed1996

Acute and prolonged alterations in brain free magnesium following fluid percussion-induced brain trauma in rats.

Several studies have reported declines in brain total and free magnesium concentration after a traumatic insult to the CNS. Although the evidence suggests that this magnesium decline is associated with eventual neurologic outcome after trauma, the duration of free magnesium decline and its impact on related bioenergetic variables are relatively unknown. The present study has therefore used phosphorus magnetic resonance spectroscopy to determine the length of time that free magnesium remains suppressed after traumatic brain injury in rats. Immediately after the traumatic event, brain intracellular free magnesium declined to < 60% of preinjury values and remained significantly depressed (50 +/- 8%; p < 0.001) for 5 days before recovering to preinjury levels by day 8. Cytosolic phosphorylation ratio and mitochondrial oxidative capacity also significantly decreased (p = 0.008) and increased (p = 0.002), respectively, after trauma. However, unlike the time of maximum magnesium change, the maximum changes in these bioenergetic variables occurred at 16-24 h after trauma and thereafter remained stable until after the magnesium had recovered. We conclude that free magnesium decline after trauma precedes changes in bioenergetic variables. Furthermore, therapies targeted at reestablishing magnesium homeostasis after trauma may require administration over a 1-week period.

Animals↗

PubMed1995

Chronic alcohol exposure decreases brain intracellular free magnesium concentration in rats.

Phosphorus magnetic resonance spectroscopy was used to determine effects of acute and chronic alcohol exposure on brain intracellular free magnesium concentration (Mgf) and bioenergetic state in rats. Acute alcohol (3 mg kg-1, i.p.) resulted in a transient ( < 2h) decline in brain Mgf and cytosolic phosphorylation ratio, and an increase in mitochondrial oxidative capacity. In contrast, chronic exposure to alcohol for 30 days by vapour inhalation resulted in a depletion of brain Mgf with no significant change in bioenergetic parameters. Subsequent exposure of chronically alcoholised rats to an acute dose of alcohol (3 g kg-1) did not result in any further changes. We conclude that chronic exposure to alcohol results in a depletion of brain Mgf and compromised bioenergetic regulation.

Administration, Inhalation↗

PubMed1995

Intrathecal dynorphin-A infusion in rat spinal cord causes energy depletion, edema and neurologic dysfunction.

The opioid dynorphin-A (dynA) is thought to contribute to the secondary injury process following spinal cord trauma although little is known about the biochemical mechanisms involved. In the present study, we have used a combination of magnetic resonance imaging (MRI) and spectroscopy (MRS) and hindlimb motor function tests to examine the effects of intrathecal dynA infusion on rat spinal cord. Infusion of 100 nmol of dynA (1-17) caused pronounced edema development as determined by MRI at 24 h after infusion. Infusion of 100 nmol of the dynA (2-17) fragment, which does not have any activity at opiate receptors, also produced profound edema whereas 100 nmol of the low potency kappa opiate receptor ligand dynA (1-8) or artificial CSF (ACSF) did not produce any edema. Both dynA (1-17) and dynA (2-17) produced significant hindlimb motor deficits at 24 h when compared to dynA (1-8) and ACSF (P < 0.05), but the deficits in the dynA (1-17) group were significantly worse than in the dynA (2-17) treated animals (P < 0.05). Similarly, mortality in the dynA (1-17) treated animals was significantly higher than in the other groups (P = 0.002). Phosphorus MRS demonstrated that the dynA (1-17) and dynA (2-17) treated animals also had a pronounced decline in high energy phosphates in the spinal cord 24 h after infusion. We conclude that dynA contributes to spinal cord cell death by causing metabolic failure and edema development.

Analysis of Variance↗

PubMed1995

Impact acceleration-induced severe diffuse axonal injury in rats: characterization of phosphate metabolism and neurologic outcome.

Diffuse axonal injury (DAI) occurs in over half of all severe cases of traumatic brain injury and has been associated with the development of a persistent vegetative state. Although a number of studies have examined the biochemical and physiological events following brain trauma, none of these has concentrated on events associated with the occurrence of severe DAI. The present study has used phosphorus magnetic resonance spectroscopy (MRS) and the rotarod motor test to characterize metabolic and neurologic consequences of severe diffuse axonal injury in rats induced by impact acceleration. Traumatic brain injury was induced in male rats by dropping a 450-g brass weight a distance of 2 m onto a 10-mm stainless-steel disc (3 mm wide) attached to the closed skull. Changes in brain intracellular pH, free magnesium concentration, cytosolic phosphorylation ratio, and mitochondrial oxidative metabolism after injury were monitored by phosphorus MRS while neurologic motor outcome over 1 week was assessed using the rotarod test. Impact acceleration-induced injury resulted in a highly significant decline in free magnesium concentration, cytosolic phosphorylation ratio, and an increased rate of mitochondrial oxidative phosphorylation, but no significant change in pH. These changes were associated with the occurrence of a significant neurologic deficit over 1 week postinjury. The similarity in metabolic events associated with production of neurologic deficits in this and other models of traumatic brain injury suggests that these bioenergetic changes may be common to all models of brain trauma.

Animals↗

PubMed1995

Effects of acute ethanol intoxication on experimental brain injury in the rat: neurobehavioral and phosphorus-31 nuclear magnetic resonance spectroscopy studies.

Using the lateral fluid-percussion model of experimental brain injury in the rat, the authors investigated the effect of acute ethanol (EtOH) intoxication on cardiovascular changes, neurological motor deficits, brain bioenergetics, and mortality associated with traumatic brain injury. Two hours after gastric administration of EtOH (low dose in 20 animals, 1.5 g/kg; high dose in 28, 3.0 g/kg) or saline (equal volume), animals were subjected to a fluid-percussion brain injury centered over the left parietal cortex. These injuries were of either moderate (X = 2.2 atm; 10 animals/treatment) or high severity (X = 3.0 atm; 18 animals/saline, 10 animals/low-dose EtOH, and 18 animals/high-dose EtOH). Neurological motor function was evaluated daily over a 1-week period, while a subset of eight animals receiving high-dose EtOH and subjected to brain injury of high severity were monitored for 4 hours using phosphorus-31 nuclear magnetic resonance spectroscopy to determine intracellular pH, free magnesium, and brain cytosolic phosphorylation potential. A significant (p < 0.05) and prolonged (up to 1 hour) hypotension was observed in animals pretreated with either low- or high-dose EtOH. Neither low-dose (blood-EtOH concentration = 110 +/- 40 mg/dl) nor high-dose (blood-EtOH = 340 +/- 70 mg/dl) EtOH had any effect on survival or neurological motor function after moderate brain injury. Following severe brain injury, animals pretreated with high-dose (blood-EtOH concentration = 352 +/- 65 mg/dl) EtOH showed a significantly increased mortality and markedly worsened neurological deficits at 24 hours postinjury. Following injury, free magnesium and cytosolic phosphorylation potential declined in both groups by approximately 50% to 60%, with no significant differences between groups with respect to these variables. In contrast, brain intracellular pH in the EtOH-treated animals was consistently higher than in the control group after injury. These data suggest that prior exposure to EtOH, particularly at high concentrations, may have detrimental effects on neurobehavioral function and survival in the acute period (up to 24 hours) after severe brain injury, and may be associated with posttraumatic cerebral alkalosis.

Alcoholic Intoxication↗

PubMed1994

Inhibition of phospholipase C with neomycin improves metabolic and neurologic outcome following traumatic brain injury.

Activation of phospholipase C has been implicated as a factor in the development of irreversible tissue damage following injury to the central nervous system. We have used phosphorus magnetic resonance spectroscopy and a battery of postinjury motor function tests to characterize the role that phospholipase C activity may play in determining biochemical and neurologic outcome following traumatic brain injury in rats. Moderate (2.7 atmospheres) fluid percussion induced lateral brain injury caused a decline in free magnesium concentration, phosphorylation potential, and increased mitochondrial rate of oxidative phosphorylation. Neurologic motor score at 24 h and 1 week posttrauma in these animals was consistent with moderate injury. In contrast, treatment with the phospholipase C inhibitor neomycin B (15 mg/kg i.v.) immediately prior to injury significantly improved free magnesium status, bioenergetic state and neurological outcome (P < 0.01) after injury. We propose that phospholipase C activated second messenger pathways affecting magnesium homeostasis are involved in determining outcome after brain injury.

Animals↗

PubMed1994

Dissociation of adenosine levels from bioenergetic state in experimental brain trauma: potential role in secondary injury.

Intracellular bioenergetic state and extracellular adenosine levels were monitored in rat brain prior to and following traumatic brain injury (TBI) using phosphorus magnetic resonance spectroscopy and microdialysis, respectively. Fluid percussion-induced TBI (2.6 +/- 0.2 atm) resulted in significant reductions in free cytosolic [Mg2+], cytosolic [ATP]/[ADP] [P(i)], and delta GATP and elevations in cytosolic [ADP] and [5'-AMP]. Intracellular ATP concentration and pH did not change significantly after trauma. Mitochondrial capacity for oxidative phosphorylation (indexed by V/Vmax) increased significantly from approximately 0.45 prior to injury to approximately 0.58 following TBI. All metabolic changes were maximal at 2-3 h post-TBI. Conversely, extracellular adenosine concentrations increased transiently following TBI, with levels peaking at 10 min posttrauma, then declining rapidly to preinjury values by 50 min. Thus, despite pronounced long-term depression in bioenergetic status and a marked rise in [5'-AMP], formation and release of adenosine were elevated only transiently within the first hour following TBI. Since steady-state adenosine levels were essentially unchanged beyond 1 h posttrauma, mooted neuroprotective actions of endogenous adenosine would be minimized. Intracerebroventricular injections of 2-chloroadenosine (0.5 and 2.5 nmol) immediately prior to TBI dose-dependently attenuated metabolic disturbances and improved posttraumatic neurologic outcome (p < 0.05). The observations indicate that (a) TBI results in dissociation of adenosine release from intracellular bioenergetic state, a phenomenon possibly contributing to secondary injury following TBI; and (b) supplementing brain with an adenosine agonist attenuates irreversible injury.

2-Chloroadenosine↗

PubMed1994

Bioenergetic analysis of oxidative metabolism following traumatic brain injury in rats.

Studies of fluid percussion-induced traumatic brain injury have shown that moderate trauma results in ionic imbalances, with resultant increases in energy demand to restore these ion gradients. Because there are also increased rates of glucose metabolism during periods of focal decline in blood flow, it has been suggested that the mitochondria may be incapable of sufficient oxidative metabolism to cope with this increased energy demand after injury and that ATP derived from substrate level phosphorylation must meet this demand. In the present study, we used phosphorus magnetic resonance spectroscopy to determine the mitochondrial capacity for oxidative phosphorylation after moderate brain trauma. Before injury, mean oxidative capacity was 54% +/- 1%. After injury, mean capacity increased significantly (p < 0.001) to a maximum of 61% +/- 1%, indicating that mitochondrial oxidative metabolism was enhanced after trauma. Increased oxidative capacity was accompanied by increases in ADP, AMP, and inorganic phosphate concentrations and was correlated to decreases in cytosolic phosphorylation ratio. We conclude that moderate brain trauma increases mitochondrial rate of ATP synthesis over the first 4 h posttrauma, and that during this time of increased ATP turnover, positive feedback regulation of glycolysis by increased concentrations of ADP, AMP, and inorganic phosphate contributes to maintenance of metabolic steady state.

Adenosine Diphosphate↗

PubMed1994

Diffusion-weighted imaging differentiates ischemic tissue from traumatized tissue.

BACKGROUND AND PURPOSE: Diffusion-weighted magnetic resonance imaging (MRI) has been shown to be particularly effective in detecting early (0 to 4 hours) pathophysiological changes in localized brain regions after cerebral ischemia. The present study sought to establish whether diffusion-weighted MRI would be similarly effective in predicting outcome after traumatic brain injury. METHODS: Diffusion-weighted MRI images and T2-weighted MRI images were obtained over 4 hours after either moderate fluid percussion-induced traumatic brain injury or unilateral carotid ligation in rats. RESULTS: Diffusion-weighted MRI images of traumatic brain injury demonstrated focal regions of image hypointensity as early as 1 hour after trauma. The relative diffusion coefficient in these hypointense regions was significantly increased (P < .005) by 4 hours after trauma compared with the noninjured hemisphere, but only in the transverse plane in the x direction. In contrast, induction of diffuse, nonfocal ischemia by unilateral carotid ligation resulted in scattered regions of hyperintensity with a significant (P < .001) decrease in relative diffusion coefficient as early as 1 hour after ligation compared with the noninjured hemisphere. This decrease exhibited no directionality. CONCLUSIONS: We conclude that traumatic brain injury results in an increased water diffusion distance with the directionality indicative of bulk flow of extracellular fluid toward the lateral ventricles (vasogenic edema). In contrast, the decreased water diffusion distance with no apparent directionality observed in ischemia is most likely indicative of cytotoxic edema. Diffusion-weighted MRI therefore has the potential to differentiate cases of traumatic brain injury with no focal ischemia from those instances of traumatic brain injury in which focal ischemia is a complication.

Animals↗

PubMed1993

Estrogen improves biochemical and neurologic outcome following traumatic brain injury in male rats, but not in females.

Phosphorus magnetic resonance spectroscopy was used in conjunction with neurologic motor function tests to assess the effects of estrogen on biochemical and neurologic outcome following traumatic brain injury in male and female rats. Male (n = 18) and female (n = 18) rats were randomly assigned into three groups, and 4 h prior to injury received either 17 beta-estradiol (144 micrograms/kg intraperitoneally), equal volume vehicle (30% ethanol in saline), or no treatment. Traumatic brain injury was induced at 2.8 atm using a fluid percussion injury device, and animals monitored for 4 h using phosphorus magnetic resonance spectroscopy to determine brain intracellular pH, free magnesium concentration and cytosolic phosphorylation potential. Males treated with estrogen demonstrated a significant improvement in free magnesium concentration, and slightly improved values of cytosolic phosphorylation potential after trauma when compared to controls. There was also a significant improvement in post-traumatic motor function at 1 week after trauma. In contrast, estrogen treatment in females lowered cytosolic phosphorylation potential after trauma, but did not affect free magnesium concentration after trauma. Mortality in all female groups was significantly worse than in males. We conclude that estrogen is protective in males, but exacerbates brain injury in females through effects mediated by estrogen receptor binding.

Animals↗

PubMed1993

Nuclear magnetic resonance characterization of secondary mechanisms following traumatic brain injury.

Much of the injury that occurs following a traumatic insult to the central nervous system is the result of physiological and biochemical processes initiated by the primary traumatic event. These processes occur over a period of hours to days following the insult, and although a number of factors have been identified as being associated with this secondary injury process, their role and interrelationship with one another is unclear. Nuclear magnetic resonance spectroscopy has been utilized to characterize many of these secondary factors and their relationship to eventual neurological outcome. In particular, the role of high energy phosphates, pH, lactic acid, excitatory amino acids, and magnesium has been investigated, along with pharmacotherapies directed toward altering the status of these factors following traumatic injury. This review critically examines the role that each of these factors may play in the secondary injury process, and proposes a scheme which theoretically accounts for the interrelationships among the various factors.

Animals↗

PubMed1992

Nuclear magnetic resonance spectroscopy and the study of tissue oxygen metabolism: a review.

Nuclear magnetic resonance (NMR) techniques are being increasingly utilised as an in vivo method to monitor tissue oxygen concentration in various organs. In muscle and heart, proton NMR spectroscopy of myoglobin has been used to calculate local oxygen tension through the oxygen sensitivity of the histidine group signal intensity. Similarly, spin lattice relaxation times of perfluorocarbon emulsions are oxygen sensitive, and this property has been taken advantage of to produce oxygen maps of brain by fluorine NMR imaging. Phosphorus NMR spectroscopy has also been extensively used to monitor bioenergetic state, which under some conditions, is directly related to tissue oxygen tension. This review will focus on these NMR techniques for oxygen determination, and will critically assess their utility for further studies.

Animals↗

PubMed1992

Increased mortality in female rats after brain trauma is associated with lower free Mg2+.

Male and female Sprague-Dawley rat siblings (200-350 g) were monitored by phosphorus magnetic resonance spectroscopy for 4 h after moderate (2.8 atmospheres) fluid-percussion-induced traumatic brain injury. Following injury, two of nine male animals died whereas 100% of all female rats (n = 16) died (p < 0.01). Prior to injury, brain free magnesium concentration in males was 0.58 +/- 0.05 mM and in females 0.41 +/- 0.09. After injury, mean brain free magnesium concentration in males declined to 0.32 +/- 0.06 whereas mean brain free magnesium concentration in ventilated females (n = 6) after injury declined to 0.17 +/- 0.03 (p < 0.05). There were no significant differences between groups with respect to any other measured variables. We conclude that female rats are more susceptible to irreversible injury after brain trauma, and that this increased susceptibility to injury may be related to brain free magnesium levels.

Adenosine Triphosphate↗