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T K McIntosh

Publications and source records attributed to T K McIntosh.

At least 181 records · Page 10Linked to original sources
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

An epidural intracranial pressure monitor for experimental use in the rat.

We described the construction and use of a simple and reliable catheter system that can be used to monitor intracranial pressure (ICP) from the epidural space in rats in an experimental setting. The catheter system is easily fabricated in the laboratory from readily available materials. The monitor is fitted flush with the inner table through a burr hole in the temporal squama. A side port is used to fill the system with saline and to irrigate the system should be catheter become obstructed. The distal end of the catheter is fitted to a pressure transducer that is connected to a graphic display and recording system. This system was used to record ICP in 30 anaesthetized adult rats. Seven were subjected to baseline ICP recording only and 23 were subjected to baseline recordings followed by epidural balloon compression of the contralateral hemisphere. Baseline ICP varied between 0 and 8 mmHg and respiratory variation could be detected on the tracings for 24 rats (75%). ICP responded directly and sensitively to epidural balloon inflation in all 23 rats tested. In 5 rats that died during balloon inflation, the decrease in ICP after death followed closely the loss of arterial blood pressure. There was a close correlation of numerical values obtained in two rats in which ICP was recorded simultaneously from the epidural catheter and from a catheter in the subarachnoid space at the cisterna magna. In one rat in which ICP increased to more than 70 mmHg, the epidural catheter continued to record ICP accurately while the cisternal catheter became obstructed with herniated brain.(ABSTRACT TRUNCATED AT 250 WORDS)

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↗
PubMed1988

Levels of endogenous opioids and effects of an opiate antagonist during regional cerebral ischemia in rats.

Changes in endogenous opioid concentrations and the effect of treatment with the opiate receptor antagonist WIN 44,441-3 (WIN) were evaluated after middle cerebral artery occlusion (MCA-O) in rats. Animals treated with WIN at doses of 0.4 to 400 micrograms/kg 15 min, 3 hr and 6 hr after MCA-O had significantly higher mean arterial blood pressure than saline controls (P less than .05). Twenty-four hours after MCA-O, WIN-treated rats had significantly greater recovery of EEG activity and higher neurological scores than the controls; these actions were greatest at a dose of 40 micrograms/kg (P less than .01). The neurological outcome correlated with recovery of the ipsilateral EEG (P less than .01). The mortality rate 24 hr after occlusion and the infarct size were not significantly different from controls. At 1 hr after MCA-O, there were no significant differences in regional concentrations of endogenous opioid peptides (dynorphin, Leu-enkephalin and beta-endorphin) between the injured and uninjured hemispheres. These are the first studies to evaluate the effects of an opiate antagonist over a wide dose range in cerebral ischemia. Dose-related beneficial actions were found with regard to several, but not all, outcome measures. The absence of regional opioid changes after regional ischemia, in contrast to previous studies of spinal cord ischemia and brain trauma, was unexpected, but may reflect limited regional and temporal sampling.

Animals↗
PubMed1987

Decrease in total and free magnesium concentration following traumatic brain injury in rats.

31P magnetic resonance spectroscopy was used to determine the intracellular free Mg2+ concentration prior to and following fluid percussion induced traumatic brain injury in rats. Prior to injury, cerebral intracellular free Mg2+ concentration in the rat was 0.93 +/- 0.19 mM (mean +/- SE; n = 5). Following injury, free Mg2+ in the injured cortex declined by 70% within the first hour, and did not recover over the next 3 hours. Total Mg2+ also declined by 10% over this time period; however, there were no changes in brain Na+ or tissue water content. Because of its primary role in cellular metabolism, the early decline in tissue Mg2+ following brain trauma may be a critical factor in the development of irreversible tissue injury.

Adenosine Triphosphate↗
PubMed1987

Alterations in regional concentrations of endogenous opioids following traumatic brain injury in the cat.

Delayed injury following trauma to the central nervous system (CNS) may be due to the release or activation of endogenous factors. Endogenous opioid peptides have been proposed as one such class of injury factors, based on pharmacological studies demonstrating a therapeutic effect of naloxone and other opiate receptor antagonists following CNS injury. However, changes in brain opioid concentrations following injury have not been evaluated. In the present study, we measured regional alterations in dynorphin (ir-Dyn), leucine-enkephalin (ir-Enk) and beta-endorphin immunoreactivity (ir-End) following low- (1.0-2.0 atmospheres (atm)) or high- (3.0-4.0 atm) level fluid-percussion brain injury in the cat. A significant decrease in ir-End was observed in the hypothalamus at 2 h following high- but not low-level injury. No changes were observed in tissue ir-Enk following either level of injury. Severe brain trauma but not low-level injury caused a significant increase in ir-Dyn in the striatum, frontal cortex, parietal cortex, pons and medulla. In the anterior pituitary, a significant increase in ir-End and a significant decrease in ir-Dyn was observed at 2 h following both levels of injury. Pathological damage to brain tissue after injury was most pronounced in those regions showing significant increases in ir-Dyn but not other opioids. In the medulla, the increase in ir-Dyn but not ir-End or ir-Enk was also significantly correlated with a fall in systemic mean arterial pressure (MAP) at 2 h following high- but not low-level injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Alterations in tissue Mg++, Na+ and spinal cord edema following impact trauma in rats.

Alterations in water content and total tissue Na+ and Mg++ of rat spinal cord tissue were followed over time after a 100 g-cm impact injury to the T-9 spinal cord segment. Rats subjected to laminectomy but not trauma served as controls. In the injured segment there was a progressive increase in water content with increased Na+ and decreased Mg++ at 1 hour and 24 hours after trauma. At seven days, water and Na+ content remained elevated, whereas Mg++ levels had returned to preinjury baseline values. Because of its important role in many metabolic and physiological regulatory processes the early decline in Mg++ concentration after trauma may contribute to the development of secondary tissue damage after spinal cord injury.

Animals↗
PubMed1987

Effects of traumatic brain injury on cerebral high-energy phosphates and pH: a 31P magnetic resonance spectroscopy study.

Traumatic injuries to the CNS produce tissue damage both through mechanical disruption and through more delayed autodestructive processes. Delayed events include various biochemical changes whose nature and time course remain to be fully elucidated. Magnetic resonance spectroscopy (MRS) techniques permit repeated, noninvasive measurement of biochemical changes in the same animal. Using phosphorus MRS, we have examined certain biochemical responses of rats over an 8-h period following lateralized brain injury (1.5-2.5 atmospheres) using a standardized fluid-percussion model recently developed in our laboratory. Following injury, the ratio of phosphocreatine to inorganic phosphate (PCr/Pi) showed a biphasic decline: The first decline reached its nadir (4.8 +/- 0.4 to 2.8 +/- 0.7) by 40 min post-trauma with recovery by 100 min, followed by a second decline by 2 h that persisted for the remaining 6-h observation period (mean 2.5 +/- 0.5). The first, but not the second, decrease in PCr/Pi was associated with tissue acidosis (pH 7.10 +/- 0.03 to 6.86 +/- 0.11). No changes in ATP occurred at any time during the injury observation period. Such changes may be indicative of altered mitochondrial energy production following brain injury, which may account for the reduced capacity of the cell to recover from traumatic injury.

Animals↗
PubMed1987

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

Fluid-percussion models of traumatic brain injury produce injury by rapidly injecting fluid volumes into the epidural space. In the present study, we characterized the physiological, histopathological, and neurological responses in a new model of midline (vertex) fluid-percussion injury of graded severity in the rat. All levels of injury produced transient (acute) hypertension, which was followed by a significant and prolonged hypotension at the higher levels of injury. There was also postinjury suppression if EEG amplitudes, which was related to the severity of injury. However, there were no significant changes in brainstem auditory evoked potentials (BAERs) at any level of injury. Neurological scores over a 4-week postinjury period were directly correlated with the severity of injury. Survival rates were significantly decreased at the higher magnitudes of injury. The extent of postinjury hemorrhage and blood-brain barrier disruption (as evidenced by extravasation of Evans Blue Albumin complex) was related to the magnitude of injury. These data demonstrate that the midline (vertex) model of fluid-percussion injury in the rat reproduces many of the features of head injury observed in other models and species and may serve as a useful cost-effective model for the study of the pathophysiology and treatment of traumatic brain injury.

Animals↗
PubMed1987

Traumatic brain injury in the rat: alterations in brain lactate and pH as characterized by 1H and 31P nuclear magnetic resonance.

Application of both phosphorus (31P) and proton (1H) magnetic resonance spectroscopy (MRS) to the study of brain metabolism permits the noninvasive measurement of intracellular pH and brain lactate level. We have used water-suppression 1H MRS with novel lactate-editing techniques, together with 31P MRS, to characterize sequential changes in brain lactate level and pH in vivo over an 8-h period following fluid-percussion brain injury of graded severity in the rat. A transient fall in intracellular pH (from 7.09 +/- 0.07 at baseline to 6.88 +/- 0.09 at 40 min postinjury) occurred in animals subjected to moderate- (1.5-2.2 atm) and high- (2.5-3.3 atm) but not low-level (0.1-1.2 atm) injury; intracellular pH returned to baseline by 90 min postinjury. Transient elevations in brain lactate level were observed that temporally paralleled and were significantly correlated with the pH changes for all injury levels (r = 0.93, p less than 0.001). Postinjury alterations in intracellular brain pH and lactate level were identical in magnitude in animals subjected to either moderate or high-level injury. However, animals subjected to moderate injury had a moderate chronic neurological deficit that persisted up to 4 weeks postinjury, whereas animals subjected to a high level of injury showed greater histopathological damage and a more severe chronic neurological deficit. These data suggest that the extent of posttraumatic intracellular cerebral acidosis in our model of experimental head injury is not directly related to the severity of functional neurological deficit.

Animals↗
PubMed1987

Endogenous opioids may mediate secondary damage after experimental brain injury.

Although endogenous opioids have been implicated in the pathophysiology of spinal cord injury and brain ischemia, the role of specific opioid peptides and opiate receptors in the pathophysiology of traumatic brain injury remains unexplored. This study examined regional changes in brain opioid immunoreactivity and cerebral blood flow (CBF) after fluid-percussion brain injury in the cat and compared the effect of an opiate antagonist (Win 44,441-3 [Win-(-)]) with its dextroisomer Win 44,441-2 [Win-(+)] (which is inactive at opiate receptors) in the treatment of brain injury. Dynorphin A immunoreactivity (Dyn A-IR) but not leucine-enkephalin-like immunoreactivity accumulated in injury regions after traumatic injury; Dyn-IR increases also occurred predominantly in those areas showing significant decreases in regional CBF. Administration of Win-(-) but not Win-(+) or saline at 15 min after injury significantly improved mean arterial pressure, electroencephalographic amplitude, and regional CBF and reduced the severity and incidence of hemorrhage. Win-(-) also significantly improved survival after brain injury. Taken together, these findings suggest that dynorphin, through actions at opiate receptors, may contribute to the pathophysiology of secondary brain injury after head trauma and indicate that selective opiate-receptor antagonists may be useful in treatment of traumatic brain injury.

Animals↗
PubMed1987

Prolonged alterations in plasma cortisol circadian rhythms following trauma in baboons.

Few studies have been performed concerning alterations in the circadian rhythmicity of adrenocortical function following trauma. The present study examined the effects of surgical trauma of varying severity on the secretory pattern of adrenocorticosteroids in the female baboon (Papio anubus). In 30 baboons, blood samples were obtained every hour for three 96-h periods: 1 wk prior to surgery; beginning 30 min following incision closure; and beginning 7 days following surgery. Animals were divided into three groups: anesthesia/surgical controls, low-trauma group [(LT), laparotomy plus 5-min bowel traction], or high-trauma group [(HT), laparotomy plus 20-min bowel traction]. A postoperative rise in plasma cortisol was observed that persisted up to 10 days postsurgery and could be significantly correlated with severity of trauma. The episodic nature of cortisol secretion was unaffected by surgery. The circadian rhythm of cortisol was phase shifted in the LT group and abolished up to 8 days postsurgery in the HT group. We conclude that the magnitude of posttrauma rise and circadian disruption of plasma cortisol is correlated with magnitude of surgical trauma. However, contrary to previous reports, elevated levels of cortisol may persist for an extended time (10 days) following the primary insult.

Analysis of Variance↗
PubMed1987

Prolonged disruption of plasma beta-endorphin dynamics after trauma in the nonhuman primate.

Recent evidence has suggested that a circadian rhythm exists for plasma beta-endorphin-like immunoreactivity. The purpose of the present study was to examine the long term effects of surgical trauma on plasma beta-endorphin dynamics. Blood samples for RIA were obtained from female baboons every 4 h for three 48-h periods: one beginning 1 week before surgical trauma, the second 30 min after surgical trauma, and the third 1 week after surgical trauma. Animals were subjected to laparotomy and 30-min anesthesia (n = 8), 5-min surgical trauma under 30-min anesthesia (low trauma; n = 8), or 20-min surgical trauma under 30-min anesthesia (high trauma; n = 8). Computer analysis of beta-endorphin levels as a function of clock time demonstrated a true preoperative circadian rhythm for all animals, with a mean of 87.9 pg/ml. In the immediate 48-h postoperative period, a postoperative alteration in circadian beta-endorphin dynamics occurred that was correlated with the severity of trauma. A disruption of circadian rhythms of plasma beta-endorphin occurred in the high trauma group only, in which it persisted for longer than 1 week after trauma. These studies establish a relationship between the alteration of circadian rhythmicity of plasma beta-endorphin-like immunoreactivity and the magnitude of trauma and injury.

Anesthesia↗