Biomedical subjects

B G Lyeth

Publications and source records attributed to B G Lyeth.

At least 55 records · Page 3Linked to original sources

PubMed1993

Hypothermia blunts acetylcholine increase in CSF of traumatically brain injured rats.

Activation of muscarinic acetylcholine (ACh) receptors contributes to the pathophysiological consequences of moderate experimental traumatic brain injury (TBI). Hypothermia (30 degrees C) provides protection in experimental TBI. We measured ACh levels in CSF and plasma 5 min after moderate fluid percussion TBI under normothermic or hypothermic conditions, because ACh in the CSF has been correlated with the severity of behavioral deficits after TBI. Three groups were examined: TBI with hypothermic brain (30 degrees C), TBI with normothermic brain (37 degrees C), or sham TBI with normothermic brain (37 degrees C). ACh concentrations in CSF were significantly higher in 37 degrees C TBI rats, but not in 30 degrees C TBI rats compared to shams. ACh concentrations in plasma did not differ between groups. These results suggest that a contributing factor to the neuroprotective effects of moderate hypothermia in TBI may be related to the reduction of excessive ACh levels in the central nervous system following injury.

Acetylcholine↗

PubMed1993

Cognitive impairment following traumatic brain injury: the effect of pre- and post-injury administration of scopolamine and MK-801.

In order to examine the effectiveness of pre- and post-injury administration of muscarinic cholinergic and NMDA antagonists in reducing cognitive deficits following traumatic brain injury (TBI), rats were injected with either scopolamine (1 mg/kg) or MK-801 (0.3 mg/kg) 15 min prior to or 15 min after fluid percussion TBI. Cognitive performance was assessed with the Morris water maze procedure on days 11-15 after TBI or sham injury. When scopolamine and MK-801 were injected 15 min before injury, Morris water maze deficits were significantly reduced (P < 0.01 and P < 0.05, respectively). When scopolamine and MK-801 were injected 15 min after TBI, neither drug was effective in attenuating Morris water maze deficits. Consistent with other research, these results suggest that the cognitive deficits produced by TBI are the consequence of a brief period of excessive excitation of cholinergic and NMDA receptor systems. The results of this experiment also suggest that the temporal therapeutic window for the treatment of cognitive dysfunction with receptor antagonist intervention appears to be quite brief (< 15 min) in the rat.

Animals↗

PubMed1993

Behavioral protection by moderate hypothermia initiated after experimental traumatic brain injury.

The effects of postinjury hypothermia on behavioral outcome following moderate fluid percussion traumatic brain injury (TBI) were examined. In Experiment I, three groups of rats were examined. The first group was normothermic (37.5 degrees C); and hypothermia (30 degrees C) was initiated 15 min and 30 min postinjury in the second and third groups, respectively. Whole body cooling was achieved by ventral ice pack. Cooling of the brain to 30 degrees C was achieved in 25 min and maintained for 60 min. Brain temperature was measured indirectly by a probe in the temporalis muscle. Behavioral outcome was assessed by beam-balance performance, beam-walking performance, and body weight loss measured daily for 5 days after TBI. Both the normothermic group and the 30-min postinjury hypothermic group exhibited significant (p < 0.05) beam-balance and beam-walking deficits on days 1 through 5 after TBI. In contrast, the 15-min postinjury hypothermic group exhibited significant (p < 0.05) beam-walking deficits only on day 1 after TBI and significant (p < 0.05) beam-balance deficits on days 1, 3, and 4 after TBI. In Experiment II, subcortical brain temperature was compared to temporalis muscle temperature in normothermic (37.5 degrees C) and hypothermic (30 degrees C) rats subjected to TBI. In both groups brain temperature tracked within 0.4 degree C of temporalis muscle temperature. These results are similar to post-TBI excitatory receptor antagonist studies and indicate a therapeutic window for moderate hypothermia of less than 30 min after moderate fluid percussion TBI in the rat.

Animals↗

PubMed1992

Enduring suppression of hippocampal long-term potentiation following traumatic brain injury in rat.

This study investigated changes in synaptic responses (population spike and population EPSP) of CA1 pyramidal cells of the rat hippocampus to stimulation of the Schaffer collateral/commissural pathways 2-3 h after traumatic brain injury (TBI). TBI was induced by a fluid percussion pulse delivered to the parietal epidural space resulting in loss of righting responses for 4.90-8.98 min. Prior to tetanic stimulation, changes observed after the injury included: (1) decreases in population spikes threshold but not EPSP thresholds; (2) decreases in maximal amplitude of population spikes as well as EPSPs. TBI also suppressed long-term potentiation (LTP), as evidenced by reductions in post-tetanic increases in population spikes as well as EPSPs. Since LTP may reflect processes involved in memory formation, the observed suppression of LTP may be an electrophysiological correlate of enduring memory deficits previously demonstrated in the same injury model.

Animals↗

PubMed1992

Postinjury scopolamine administration in experimental traumatic brain injury.

A single bolus dose of scopolamine (1.0 mg/kg) or saline (equal volume) was injected (i.p.) at 15, 30 or 60 min after fluid percussion traumatic brain injury in the rat. Scopolamine administered at 15 min postinjury significantly reduced beam walking deficits and body weight loss assessed for 5 days after injury. Scopolamine treatment at 30 or 60 min postinjury had no effect on behavioral outcome assessed for 5 days after injury. Plasma concentrations of scopolamine were measured with a radioreceptor assay. The plasma half-life for scopolamine was 21.6 min in injured rats and 17.3 min in normal rats (P less than 0.05). These results, along with evidence from previous studies, suggest that a brief period of excessive neuronal excitation can produce relatively long-lasting behavioral deficits. The temporal effectiveness of receptor antagonist intervention in this process appears to be brief.

Animals↗

PubMed1992

Moderate hypothermia reduces blood-brain barrier disruption following traumatic brain injury in the rat.

The effects of moderate hypothermia on blood-brain barrier (BBB) permeability and the acute hypertensive response after moderate traumatic brain injury (TBI) in rats were examined. TBI produced increased vascular permeability to endogenous serum albumin (IgG) in normothermic rats (37.5 degrees C) throughout the dorsal cortical gray and white matter as well as in the underlying hippocampi as visualized by immunocytochemical techniques. Vascular permeability was greatly reduced in hypothermic rats cooled to 30 degrees C (brain temperature) prior to injury. In hypothermic rats, albumin immunoreactivity was confined to the gray-white interface between cortex and hippocampi with no involvement of the overlying cortices and greatly reduced involvement of the underlying hippocampi. The acute hypertensive response in normothermic rats peaked at 10 s after TBI (187.3 mm Hg) and returned to baseline within 50 s. In contrast, the peak acute hypertensive response was significantly (P < 0.05) reduced in hypothermic rats (154.8 mm Hg, 10 s after TBI) and returned to baseline at 30 s after injury. These results demonstrate that moderate hypothermia greatly reduces endogenous vascular protein-tracer passage into and perhaps through the brain. This reduction may, in part, be related to hypothermia-induced modulation of the systemic blood pressure response to TBI.

Animals↗

PubMed1992

Cognitive deficits following traumatic brain injury produced by controlled cortical impact.

Traumatic brain injury produces significant cognitive deficits in humans. This experiment used a controlled cortical impact model of experimental brain injury to examine the effects of brain injury on spatial learning and memory using the Morris water maze task. Rats (n = 8) were injured at a moderate level of cortical impact injury (6 m/sec, 1.5-2.0 mm deformation). Eight additional rats served as a sham-injured control group. Morris water maze performance was assessed on days 11-15 and 30-34 following injury. Results revealed that brain-injured rats exhibited significant deficits (p less than 0.05) in maze performance at both testing intervals. Since the Morris water maze task is particularly sensitive to hippocampal dysfunction, the results of the present experiment support the hypothesis that the hippocampus is preferentially vulnerable to damage following traumatic brain injury. These results demonstrate that controlled cortical impact brain injury produces enduring cognitive deficits analogous to those observed after human brain injury.

Animals↗

PubMed1992

The effect of age on motor and cognitive deficits after traumatic brain injury in rats.

Age is one of the most important predictors of outcome after human traumatic brain injury. This study used fluid percussion brain injury to investigate the effects of aging on outcome after brain injury in rats. Three-month-old (n = 8) and 20-month-old (n = 11) rats were injured at a low level (1.7-1.8 atm) of fluid percussion brain injury or received a sham injury (n = 6 for both age groups). Body weight and motor function (beam balance and beam walking) were assessed before injury and for the first 5 days after injury. Cognitive outcome was assessed with the Morris water maze on Days 11 to 15 after injury. Injury did not produce significant weight loss in either age group. At the low level of brain injury used in this study, the 3-month-old rats did not demonstrate any significant motor deficits on the beam-balance or beam-walking tasks. However, the 20-month-old rats displayed significant beam-balance deficits on each of the 5 postinjury test days and significant beam-walking deficits for the first 3 postinjury days. Although Morris water maze performance was impaired in both age groups, the magnitude of impairment was greater in the aged animals. These data demonstrate that traumatic brain injury in the aged animal is marked by increased motor and cognitive deficits, in the absence of pronounced compromise of the animal's general health.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1992

Neurotransmitter-mediated mechanisms of traumatic brain injury: acetylcholine and excitatory amino acids.

Research into traumatic brain injury (TBI), focusing on changes in energy metabolism, cerebrovascular dysfunction, and brain parenchymal morphology, has not produced complete descriptions of mechanisms mediating the pathophysiology of TBI. New studies indicate that neurochemical alterations mediate important components of brain physiology associated with TBI, and these alterations may be responsive to pharmacologic therapy. We discuss rodent models of TBI, review current experimental evidence of muscarinic cholinergic and excitatory amino acid (EAA) receptor involvement in its pathophysiology, and address issues relevant to the interpretation of these data.

Acetylcholine↗

PubMed1992

Cholinergic and opioid mediation of traumatic brain injury.

There is considerable evidence for the involvement of cholinergic and opioid systems in the pathophysiological responses associated with traumatic brain injury (TBI). To some extent, interest in this area has been eclipsed by a strong focus on, and rapid progress in, studies of the role of excitatory amino acids in TBI. We present evidence that both cholinergic and opioid systems are important modulators of the pathophysiological response to TBI, potentially equally as important as excitatory amino acids. There is a relatively large body of experimental data documenting the involvement of these systems in TBI that has yielded important principles with general significance for laboratory studies of the neuropharmacology of TBI. In fact, the first demonstration of excitotoxic mechanisms of TBI involved studies of the role of acetylcholine in experimental TBI. There also are clinical data suggesting that modulation of opioid and cholinergic systems could benefit patients.

Acetylcholine↗

PubMed1991

Marked protection by moderate hypothermia after experimental traumatic brain injury.

These experiments examined the effects of moderate hypothermia on mortality and neurological deficits observed after experimental traumatic brain injury (TBI) in the rat. Brain temperature was measured continuously in all experiments by intraparenchymal probes. Brain cooling was induced by partial immersion (skin protected by a plastic barrier) in a water bath (0 degrees C) under general anesthesia (1.5% halothane/70% nitrous oxide/30% oxygen). In experiment I, we examined the effects of moderate hypothermia induced prior to injury on mortality following fluid percussion TBI. Rats were cooled to 36 degrees C (n = 16), 33 degrees C (n = 17), or 30 degrees C (n = 11) prior to injury and maintained at their target temperature for 1 h after injury. There was a significant (p less than 0.04) reduction in mortality by a brain temperature of 30 degrees C. The mortality rate at 36 degrees C was 37.5%, at 33 degrees C was 41%, and at 30 degrees C was 9.1%. In experiment II, we examined the effects of moderate hypothermia or hyperthermia initiated after TBI on long-term behavioral deficits. Rats were cooled to 36 degrees C (n = 10), 33 degrees C (n = 10), or 30 degrees C (n = 10) or warmed to 38 degrees C (n = 10) or 40 degrees C (n = 12) starting at 5 min after injury and maintained at their target temperatures for 1 h. Hypothermia-treated rats had significantly less beam-walking, beam-balance, and body weight loss deficits compared to normothermic (38 degrees C) rats. The greatest protection was observed in the 30 degrees C hypothermia group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Relationship between body and brain temperature in traumatically brain-injured rodents.

Recent work has shown that mild to moderate levels of hypothermia may profoundly reduce the histological and biochemical sequelae of cerebral ischemic injury. In the present study, the authors examined the effect of fluid-percussion injury on brain temperature in anesthetized rats and the effect of anesthesia on brain temperature in uninjured rats. The relationship between the brain, rectal, and temporalis muscle temperatures during normothermia, hypothermia, and hyperthermia was studied following a moderate magnitude of fluid-percussion brain injury (2.10 to 2.25 atmospheres) in rats. The results showed that mean brain temperature in 10 anesthetized injured rats, in 21 anesthetized uninjured rats, and in 10 unanesthetized uninjured rats was a mean (+/- standard error of the mean) of 36.04 degrees +/- 0.20 degrees C, 36.30 degrees +/- 0.08 degrees C, and 37.95 degrees +/- 0.09 degrees C, respectively. There was no significant difference in temperature under general anesthesia between injured and uninjured rats (p greater than 0.05). In the absence of brain injury, mean brain temperature was significantly lower in anesthetized rats than in unanesthetized rats (p less than 0.001). In anesthetized brain-injured rats, temporalis muscle temperature correlated well with brain temperature over a 30 degrees to 40 degrees C range, even when brain temperature was rapidly changed during induction of hypothermia or hyperthermia (r = 0.9986, p less than 0.0001). In contrast, rectal temperature varied inconsistently from brain temperature. These observations indicated that: 1) brain injury itself does not influence brain temperature in this model; 2) anesthesia alone decreases brain temperature to levels producing cerebral protection in this model; and 3) external monitoring of temporalis muscle temperature can provide a reliable indirect measure of brain temperature in the course of experimental brain injury. The authors believe that it is essential to monitor or control brain temperature in studies of experimental brain injury.

Animals↗

PubMed1991

The effect of age on outcome following traumatic brain injury in rats.

Age of the patient is one of the most important predictors of outcome following human traumatic brain injury. This study employs the fluid-percussion model to investigate the effects of aging on outcome following traumatic brain injury in rats. The results revealed that there was an age-associated increase in mortality rate following both low (1.7 to 1.8 atm) and moderate (2.00 to 2.25 atm) levels of traumatic brain injury. Age-related changes in systemic physiological, neurological, and histopathological indexes of brain injury were also examined following a low level of traumatic brain injury. Traumatic brain injury produced equivalent acute hypertension and increased plasma glucose levels in both young adult and aging rats. Injury produced an acute increase in heart rate in the young adult rat group, while the heart rate decreased in the aged rats. At low levels of brain injury, no significant gross histopathological alterations were produced in either age group. Neurological outcome was assessed by measuring the duration of suppression of a number of nonpostural and postural reflexes and more complex somatomotor functions (righting, escape, head support). Except for head support, there was a significant age-related increase in the duration of the suppression of these reflexes following brain injury. These data demonstrate that aging is associated with an increased mortality rate and greater acute neurological deficits following traumatic brain injury. These data also demonstrate the usefulness of the fluid-percussion model for studying the mechanisms responsible for the age-related increase in vulnerability to brain injury.

Aging↗

PubMed1990

Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat.

Prolonged neurological dysfunction that results from an insult to the brain is often attributed to irreversible structural damage such as loss of neurons or axonal degeneration. For example, following cerebral ischemia even partial hippocampal CA1 neuronal loss has been proposed to be sufficient to result in deficits in hippocampal dependent spatial memory. This study examined if hippocampal CA1 neuronal loss and/or axonal injury was necessary to produce prolonged spatial memory deficits resulting from traumatic brain injury (TBI). Prior to TBI Sprague-Dawley rats were trained on an 8-arm radial maze, a task sensitive to detecting specific lesions of the hippocampus or its extrinsic connections. Following a mild, moderate, or sham injury, rats were tested for working and reference memory for 25 days. After 25 days of maze testing, histological cell counts were made from consistent coronal sections of the mid-dorsal hippocampus. Rats subjected to mild or moderate TBI manifested working memory deficits for 5 and 15 days, respectively, after injury in the absence of overt (all brain regions) or quantitative (CA1 only) evidence of neuronal death. The number of CA1 pyramidal neurons of representative sections of the mid-dorsal hippocampi for injured maze-deficit rats and sham control rats were: 1626 (S.E.M. = +/- 66) and 1693 (S.E.M. = +/- 69) per 10(6) micron2, respectively. Additionally, no overt evidence of axonal injury was observed in any forebrain structure including major intrinsic or extrinsic connecting hippocampal pathways. These data strongly suggest that mild to moderate TBI is capable of producing prolonged spatial memory deficits in the rat without evidence of either neuronal cell death in the intrinsic hippocampus or overt axonal injury in hippocampal pathways.

Animals↗

PubMed1990

Excitatory amino acid receptor subtype binding following traumatic brain injury.

Sprague-Dawley rats were subjected to a moderate level (2.2 atm) of traumatic brain injury (TBI) using fluid percussion. Injured animals were allowed post-trauma survival periods of 5 min, 3 and 24 h. Regional glutamate receptor subtype binding was assessed with quantitative autoradiography in each group for N-methyl-D-aspartate (NMDA), quisqualate and kainate receptor subpopulations at approximately the -3.8 bregma level and compared to a sham control group. [3H]glutamate binding to the NMDA receptor was significantly (P less than 0.05) decreased at 3 h post-TBI in the hippocampal CA1 stratum radiatum, the molecular layers of the dentate gyri and the outer (layers 1-3) and inner (layers 5 and 6) overlying neocortex. NMDA receptor binding was significantly reduced in layers 5 and 6 of the neocortex at all post-trauma survival times but no further differences were seen in the hippocampi. No significant changes were observed with [3H]AMPA binding to quisqualate receptors and [3H]KA binding was significantly reduced only in layers 5 and 6 of the neocortex at 24 h after TBI. These data further confirm the pathological involvement of the NMDA receptor complex in brain regions selectively vulnerable to moderate levels of TBI in this model.

Animals↗

PubMed1990

Beta-endorphin in cerebrospinal fluid and serum after severe head injury.

Endogenous opioids have been implicated as a cause of secondary damage after neural injury. The basis for this statement is primarily indirect evidence from studies that demonstrate neurological or physiological improvement when opiate antagonists are given. This study directly evaluates the level of the endogenous opioid beta-endorphin in 15 patients with severe head injury. Levels of immunoreactive beta-endorphin (ir-beta E) from ventricular cerebrospinal fluid (vCSF) and serum were determined less than 24 hours after trauma. No significant correlation was found with the degree of initial injury, age, sex, or either 6- or 12-month outcome. Levels of ir-beta E from vCSF were significantly lower in patients who had received intravenous administration of morphine sulfate (48.4 +/- 5.8 versus 85.9 +/- 10.1 pg/ml, P = 0.008). No correlation was found between vCSF levels of ir-beta E and elapsed time after injury. Although vCSF and serum ir-beta E were correlated (r = 0.532, P = 0.050), the latter exhibited a different profile; the mean level of serum ir-beta E was not significantly different in those patients who received morphine, and serum ir-beta E had a significant negative correlation with time after injury (r = -0.587, P = 0.03). These results do not support a relationship between acute levels of vCSF or serum ir-beta E and the degree of neurological injury or outcome after severe head trauma. This article, therefore, is a contribution to the body of literature in which the purported detrimental effect of beta-endorphin was not demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Possible protective effect of endogenous opioids in traumatic brain injury.

Naloxone (0.1, 1.0, or 20.0 mg/kg), morphine (1.0 or 10.0 mg/kg), or saline was administered systemically intraperitoneally to rats 15 minutes prior to moderate fluid-percussion brain injury. The effects of the drugs were measured on systemic physiological, neurological, and body-weight responses to injury. The animals were trained prior to injury and were assessed for 10 days after injury on body-weight responses and neurological endpoints. Low doses of naloxone (0.1 or 1.0 mg/kg) significantly exacerbated neurological deficits associated with injury. Morphine (10.0 mg/kg) significantly reduced neurological deficits associated with injury. The drugs had no effect on neurological measures or body weight in sham-injured animals. Drug treatments did not significantly alter systemic physiological responses to injury. Data from these experiments suggest the involvement of endogenous opioids in at least some components of neurological deficits following traumatic brain injury and suggest the possibility that at least some classes of endogenous opioids may protect against long-term neurological deficits produced by fluid-percussion injury to the rat.

Animals↗

PubMed1989

Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury.

Fasted Wistar rats were subjected to either a mild mechanical injury, 6 min of transient forebrain ischemia, or a mild mechanical injury followed 1 h later by 6 min of forebrain ischemia. EEG and evoked potentials were assessed intermittently and morphological analyses were performed after 7 days postinjury survival. In all groups complete qualitative recovery of electrical activity and general behavior was observed with 7-day survival. However, rats subjected to combined concussion and ischemia displayed EEG spike activity and a delayed return of EEG and evoked potentials during acute recovery not evident in other groups. No overt neuronal cell loss was seen in trauma alone and was minimal or absent in ischemia alone. However, extensive bilateral CA1 and subicular pyramidal cell loss was found in the septal and mid-dorsal hippocampi in the combined trauma and ischemia group. In contrast, no overt axonal injury was found in any group. We conclude that even mild mechanical injury can potentiate selective ischemic hippocampal neuronal necrosis in the absence of overt axonal injury. This potentiation also occurs in conjunction with more generalized electrophysiological disturbances such as EEG evidence of postischemic neuronal hyperactivity suggesting that mild concussion may also decrease the threshold for post-ischemic neuronal excitation. These results suggest the potential of this model for examining common or different injury mechanisms in mechanical and ischemic brain injury.

Animals↗