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Biomedical subjects

R Vink

Publications and source records attributed to R Vink.

At least 73 records · Page 4Linked to original sources
PubMed1989

Phospholipase C activity reduces free magnesium concentration.

The events leading to decline of intracellular free magnesium concentration following traumatic brain injury are unknown. One possible mechanism that may lead to such declines is an alteration in the number and nature of magnesium binding sites within cell membranes following a traumatic event. Although both alterations in membrane structure and decrease in free magnesium concentration have been independently demonstrated to occur following brain trauma, no correlations between the two events have been shown. In the present study, rat brain phospholipids were extracted and reconstituted in MgATP containing aqueous solutions. Using 31P magnetic resonance spectroscopy to measure free magnesium concentration, enzymatic hydrolysis of the artificial membrane vesicles by phospholipase C was shown to reduce the free magnesium concentration. Since activation of phospholipase C has been demonstrated to occur following traumatic brain injury, we propose that this event may initiate decline in free magnesium levels in vivo.

Adenosine Triphosphate↗
PubMed1989

Traumatic spinal cord injury in rabbits decreases intracellular free magnesium concentration as measured by 31P MRS.

The mechanisms by which traumatic injury to the central nervous system cause irreversible tissue damage remain speculative. Recent reports suggest that a decrease in tissue total and free Mg2+ concentration may be an important factor in the development of such injury after experimental brain trauma. Although total Mg changes have been reported following spinal cord trauma, no studies have examined spinal cord-free Mg2+. In the present study, we have used phosphorus magnetic resonance spectroscopy to determine intracellular free Mg2+ concentration and atomic absorption spectrophotometry to measure total tissue Mg concentration in rabbit spinal cord prior to and following impact trauma. We report that intracellular free Mg2+ concentration decreases from a pre-injury value of 0.80 +/- 0.12 mM (mean +/- S.E.M.) to 0.31 +/- 0.05 mM at 2 h post-trauma. Following injury there was an associated decrease in total tissue Mg and K concentration, but no alterations in tissue Na or water content.

Animals↗
PubMed1989

The role of excitatory amino acids and NMDA receptors in traumatic brain injury.

Brain injury induced by fluid percussion in rats caused a marked elevation in extracellular glutamate and aspartate adjacent to the trauma site. This increase in excitatory amino acids was related to the severity of the injury and was associated with a reduction in cellular bioenergetic state and intracellular free magnesium. Treatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dextrophan or the competitive antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid limited the resultant neurological dysfunction; dextrorphan treatment also improved the bioenergetic state after trauma and increased the intracellular free magnesium. Thus, excitatory amino acids contribute to delayed tissue damage after brain trauma; NMDA antagonists may be of benefit in treating acute head injury.

Animals↗
PubMed1989

Magnesium protects against neurological deficit after brain injury.

The biochemical factors that mediate secondary or delayed damage to the central nervous system (CNS) remain speculative. We have recently demonstrated that brain injury in rats causes a rapid decline in brain intracellular free magnesium (Mg2+) and total magnesium concentrations that is significantly correlated with the severity of injury. In order to further investigate the relationship between Mg2+ and brain injury, we examined the effect of Mg2+ treatment on posttraumatic neurological outcome following fluid-percussion brain injury (2.0 atm) in rats. Since administration of ATP-MgCl2 has been shown to be beneficial in a variety of models of organ ischemia, we also examined the efficacy of ATP-MgCl2 or ATP alone in the treatment of experimental brain injury. Animals treated with low (12.5 mumol) or high (125 mumol) dose MgCl2 at 30 min postinjury showed a significant dose-dependent improvement in neurological function when compared to saline-treated controls. Treatment with ATP-MgCl2 (12.5 mumol) or ATP alone (12.5 mumol) caused no significant improvement in chronic neurological outcome. MgCl2-treated animals showed no change in postinjury mean arterial blood pressure (MAP), whereas animals treated with either ATP-MgCl2 or ATP alone showed a transient but significant fall in MAP (P less than 0.01) during the drug-infusion period. Our results suggest that postinjury treatment with MgCl2 is effective in limiting the extent of neurological dysfunction following experimental traumatic brain injury in the rat.

Adenosine Triphosphate↗
PubMed1989

Metabolic changes in rabbit spinal cord after trauma: magnetic resonance spectroscopy studies.

Combined phosphorus and proton magnetic resonance spectroscopy (MRS), using double-tuned surface coils, was used to monitor certain metabolic changes in the L-3 spinal segment of anesthetized rabbits prior to and following experimental spinal cord trauma. Following severe trauma, resulting in spastic paraplegia, there was a delayed and progressive accumulation of lactic acid, a decline in intracellular pH, and a loss of high-energy phosphates. Maximal alterations occurred between 2 and 3 hours after the trauma, with little further change by 4 hours. Histological examination 2 weeks after trauma showed tissue necrosis and cavitation. These findings support the concept of secondary tissue injury after spinal cord trauma and suggest that early changes in metabolism, as shown by MRS, may predict irreversible tissue damage.

Adenosine Triphosphate↗
PubMed1989

Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model.

Experimental fluid-percussion models produce brain injury by rapidly injecting saline into the closed cranium. In the present study we characterize the physiological, histopathological and neurological responses to mechanical brain injury in the rat produced by lateral fluid-percussion injury of graded severity. Physiological experiments (n = 105) demonstrated that all levels of injury produced an acute and transient systemic hypertension and bradycardia. Acute hypertension followed by significant hypotension occurred at higher magnitudes of injury. Post-injury suppression of electroencephalographic amplitude was related to the severity of injury. An increase in slow wave (delta/theta) electroencephalographic activity with a concomitant decrease in alpha/beta electroencephalographic activity were observed only at moderate and high magnitude of injury and were correlated with a worsened neurological outcome (r = 0.84; P less than 0.05) and increased mortality (r = 0.66; P less than 0.05). Alterations in brainstem auditory-evoked potentials were also observed only at the higher levels of injury. Histopathological analysis revealed that the extent of post-injury hemorrhage, cavitation and vascular disruption (as measured by extravasation of Evans Blue dye) was greater at the higher magnitudes of injury. Neurological scoring performed over a 4-week post-injury period demonstrated that lateral fluid-percussion brain injury produces a chronic neurological deficit that is directly related to the severity of injury. Survival was also significantly reduced at the higher magnitudes of injury. These data demonstrate that the lateral model of fluid-percussion injury in the rat reproduces many of the features of head injury observed in other models and species and may therefore be a useful experimental model for the study of the pathophysiology of traumatic brain injury.

Animals↗
PubMed1989

Effects of the N-methyl-D-aspartate receptor blocker MK-801 on neurologic function after experimental brain injury.

Pharmacologic inhibition of excitatory amino acid (EAA) neurotransmission attenuates cell death in models of global and focal ischemia and hypoglycemia and improves neurologic outcome after experimental traumatic spinal cord injury. The present study examined the effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor blocker MK-801 on cardiovascular and neurologic function after experimental fluid-percussion (FP) brain injury in the rat. Animals received either an intravenous bolus of MK-801 (1 mg/kg) or saline (equal volume) 15 min prior to FP brain injury or 15 min following FP brain injury. MK-801 pretreatment significantly improved postinjury cardiovascular variables and attenuated postinjury neurologic dysfunction. Postinjury treatment with MK-801 also significantly improved cardiovascular variables, but had little effect on postinjury neurologic scores. These results suggest that EAA neurotransmitters may be involved in the pathophysiological sequelae of traumatic brain injury and that noncompetitive blockade of the NMDA receptor prior to brain injury may reduce EAA-induced damage and limit neurologic dysfunction.

Amino Acids↗
PubMed1989

Thyrotropin-releasing hormone and central nervous system trauma.

TRH and TRH analogues improve physiological function, survival, and neurological outcome in a variety of models of CNS trauma, including impact spinal cord injury in cats and rats, fluid-percussion-induced brain injury in rats, and compression-induced brain injury in cats. The mechanism by which TRH improves such functions may relate to its ability to improve blood flow and metabolism in the region of injury. Beneficial effects on blood flow may possibly relate to antagonism of the physiological effects of endogenous opioids, leukotrienes, or platelet-activating factor.

Animals↗
PubMed1988

Treatment with the thyrotropin-releasing hormone analog CG3703 restores magnesium homeostasis following traumatic brain injury in rats.

Treatment with thyrotropin-releasing hormone (TRH) analogs following traumatic injury to the central nervous system (CNS) improves neurological outcome through mechanisms that remain unclear. Previous studies have shown that traumatic brain injury is associated with a profound decline in intracellular free magnesium (Mgf) and in total tissue magnesium (Mgt), the extent of Mgf decline being linearly correlated to the severity of injury and resultant neurological deficit. We have used 31P magnetic resonance spectroscopy and atomic absorption spectrophotometry, respectively, to measure cerebral Mgf concentration and Mgf content in rats following fluid percussion brain trauma and treatment with the TRH analog, CG3703. Treatment at 30 min postinjury with CG3703 significantly improved Mgf when compared to saline-treated controls. There were no significant changes in Mgt, Na+, K+ or water content following CG3703 treatment. Since a decline in intracellular free magnesium may affect cellular bioenergetic status, calcium flux, activity of excitatory amino acids, opiate receptors, and the release of eicosanoids, these results suggest that the beneficial effects of treatment with TRH analogs after CNS trauma may be mediated through magnesium-dependent mechanisms.

Animals↗
PubMed1988

Decline in intracellular free Mg2+ is associated with irreversible tissue injury after brain trauma.

Much of the tissue damage resulting from trauma to the central nervous system appears to result from secondary, delayed biochemical changes that follow primary mechanical injury. However, the early biochemical events remain to be elucidated. In the present studies, we have used phosphorus (31P) magnetic resonance spectroscopy (MRS) to examine in vivo, the temporal changes in brain intracellular free Mg2+ concentration following fluid percussion head injury in rats. We report that injury caused a profound and rapid decrease in intracellular free Mg2+ which was significantly correlated with the severity of injury. At high levels of injury, the decrease in intracellular free Mg2+ concentration was associated with a decrease in total Mg2+ concentration as determined by atomic absorption spectrophotometry. Prophylactic treatment with MgSO4 prevented the post-traumatic decrease in intracellular free Mg2+ and resulted in a significant improvement in acute neurological outcome. Because magnesium is essential for a number of critical enzyme reactions, including those of glycolysis, oxidative and substrate level phosphorylation, protein synthesis, and phospholipid synthesis, changes in free Mg2+ after brain trauma may represent a critical early factor leading to irreversible tissue damage.

Algorithms↗
PubMed1988

31P NMR characterization of graded traumatic brain injury in rats.

Irreversible tissue injury following central nervous system trauma is believed to result from both mechanical disruption at the time of primary insult, and more delayed "autodestructive" processes. These delayed events are associated with various biochemical changes, including alterations in phosphate energy metabolism and intracellular pH. Using 31P NMR, we have monitored the changes in phosphorus energy metabolism and intracellular pH in a single hemisphere of the rat brain over an 8-h period following graded, traumatic, fluid percussion-induced brain injury. Following trauma the ratio of phosphocreatine to inorganic phosphate (PCr/Pi) declined in each injury group. This decline was transitory with low injury (1.0 +/- 0.5 atm), biphasic with moderate (2.1 +/- 0.4 atm) and high (3.9 +/- 0.9 atm) injury, and sustained following severe injury (5.9 +/- 0.7 atm). The initial PCr/Pi decline in the moderate and high injury groups was associated with intracellular acidosis; however, the second decline occurred in the absence of any pH changes. Alterations in ATP occurred only in severely injured animals and such changes were associated with marked acidosis and 100% mortality rate. After 4h, the posttraumatic PCr/Pi ratio correlated linearly with the severity of injury. We suggest that a reduced posttraumatic PCr/Pi ratio may be indicative of altered mitochondrial energy production and may predict a reduced capacity of the cell to recover from traumatic injury.

Animals↗
PubMed1988

Traumatic brain injury in the rat: effects on lipid metabolism, tissue magnesium, and water content.

Tissue levels of free fatty acids (FFA), total phospholipid, cholesterol, thromboxane B2, water, Na+, K+, and Mg2+ were measured in rat brain after lateral fluid-percussion brain injury of moderate severity (2.0-2.2 atm). Brains of injured animals and sham-operated controls were frozen in situ with liquid N2 at 10 min, 4 h, and 24 h postinjury and removed. The left parietal cortex, which has been shown previously histologically to be the site of maximal injury, was dissected for analysis. Traumatic injury was associated with small increases in FFA levels at 10 min and 4 h and much larger increases at 24 h postinjury. Among the FFA, the largest increases were observed in stearate, arachidonate, and docosahexaenoate. Total phospholipid and cholesterol levels were decreased significantly at all experimental time points. Thromboxane levels were markedly elevated (30-fold) at 10 min posttrauma but substantially declined by 4 h and approached control values at 24 h. Total Mg2+ levels were significantly below control values at 4 h and 24 h posttrauma. No changes in water content were observed at any of these time points. Small decreases in tissue K+ occurred at 4 h; tissue Na+ levels were found to be slightly increased only at 24 h. These results are consistent with the hypothesis that changes in lipid metabolism and Mg2+ content of brain after injury may play a role in the pathophysiology of irreversible, posttraumatic tissue damage. In contrast, significant edema formation does not occur in this model and does not, therefore, appear to be a factor in the injury process.

Animals↗
PubMed1988

Magnesium deficiency exacerbates and pretreatment improves outcome following traumatic brain injury in rats: 31P magnetic resonance spectroscopy and behavioral studies.

The biochemical mechanisms mediating delayed or secondary tissue injury after central nervous system trauma remain speculative. We have demonstrated previously that traumatic brain injury in rats causes a rapid decline in tissue intracellular free magnesium [Mg]f and total magnesium [Mg]t concentrations, which were significantly correlated with injury severity. In order to examine the relationship between magnesium and traumatic brain injury, we assessed whether (1) magnesium deficiency exacerbates or (2) magnesium treatment improves posttraumatic outcome following fluid-percussion brain injury (2.0-2.4 atm) in rats. Animals placed on magnesium-deficient diet for 14 days showed a 15% decrease in brain [Mg]f as measured by phosphorus (31P) magnetic resonance spectroscopy (MRS). Magnesium deficiency significantly exacerbated neurologic dysfunction and increased mortality following injury when compared to normally fed saline-treated controls. Conversely, pretreatment with magnesium sulfate (0.1 mEq) 15 min before brain injury prevented the fall in [Mg]f observed by 31P MRS in saline-treated animals and significantly improved both cellular bioenergetic state and chronic posttraumatic neurologic outcome. These combined observations suggest that alterations in brain [Mg]f after trauma may play a role in the pathophysiology of traumatic brain injury.

Animals↗
PubMed1988

Changes in cellular bioenergetic state following graded traumatic brain injury in rats: determination by phosphorus 31 magnetic resonance spectroscopy.

Phosphorus 31 magnetic resonance spectroscopy (31P MRS) was used to study noninvasively the intracellular free Mg2+ concentration and cellular bioenergetic state of rat brain in vivo before and after fluid percussion-induced traumatic brain injury of graded severity. Brain injury was induced at four levels: low (1.0 +/- 0.5 atm); moderate (2.1 +/- 0.4 atm); high (3.9 +/- 0.9 atm); and severe (5.9 +/- 0.7 atm). Prior to injury, mean intracellular values for all groups (n = 24; mean +/- SE) were as follows: pH = 7.11 +/- 0.03; free [Mg2+] = 0.99 +/- 0.07 mM; cytosolic [ADP] = 25.2 +/- 0.8 nmol/g wet weight; cytosolic [AMP] = 0.29 +/- 0.02 nmol/g wet weight; cytosolic phosphorylation potential = 118.5 +/- 3.1 X 10(3) M-1; free energy of ATP hydrolysis = 62.11 +/- 0.04 kJ/mole; and energy charge = 0.99 +/- 0.01. Following every level of injury, there were decreases in intracellular free Mg2+ concentration, and alterations in the intracellular pH. These posttraumatic changes in Mg2+ and pH induced shifts in the equilibrium constants of the creatine kinase, adenylate kinase, and ATPase reactions, resulting in alterations in [ADP], [AMP], cytosolic phosphorylation potential, and free energy of hydrolysis, but not in the energy charge. The alterations in cytosolic phosphorylation potential following trauma were linearly correlated with the changes in intracellular free Mg2+ concentration. None of the individual bioenergetic parameters could be correlated with the severity of injury over the entire injury range; however, an association between cytosolic phosphorylation potential and reversibility of injury was apparent. These results suggest that reductions in cellular bioenergetic state following traumatic brain injury occur through a posttraumatic decrease in the cells' capacity for oxidative phosphorylation, which itself may be directly related to the intracellular free Mg2+ concentration.

Adenine Nucleotides↗
PubMed1988

An analogue of thyrotropin-releasing hormone improves outcome after brain injury: 31P-NMR studies.

The effects of a long-acting, centrally active thyrotropin-releasing hormone (TRH) analogue, CG3703, on neurological outcome, survival, and intracellular metabolism were evaluated after experimental fluid-percussion (FP) brain injury (2.0-2.4 atm) in the rat. In control (saline-treated) animals, FP brain injury caused a fall in mean arterial pressure (MAP) and resulted in a 58% mortality rate. Surviving control animals showed a pronounced neurological deficit over the following 4-wk period. Administration of CG3703 at 30 min posttrauma significantly increased MAP (mean increase, 21 mmHg). All animals treated with CG3703 survived and demonstrated significantly improved chronic neurological scores compared with saline-treated controls. In a subpopulation of injured animals, phosphorus magnetic resonance spectroscopy (31P-MRS) was used to evaluate changes in brain intracellular metabolism after trauma in control and CG3703-treated animals. A fall in phosphocreatine-to-inorganic phosphate ratio (PCr/Pi) was observed in all animals after FP injury. The PCr/Pi ratio failed to recover in saline controls but demonstrated significant recovery in CG3703-treated animals. Furthermore, an increased phosphomonoester peak was observed after CG3703 but not after saline administration. These results suggest that the centrally active TRH analogue CG3703 can improve neurological outcome and survival after brain injury, perhaps through direct effects on cerebral metabolism.

Animals↗