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T K McIntosh

Publications and source records attributed to T K McIntosh.

At least 163 records · Page 9Linked to original sources
PubMed1991

Evaluation of memory dysfunction following experimental brain injury using the Morris water maze.

Memory dysfunction, a common clinical feature of traumatic brain injury (TBI), is thought to be related to secondary damage of key anatomic structures in the brain, including the hippocampus. In the present study, we have characterized and evaluated a novel experimental paradigm using the Morris water maze (MWM) technique, to measure post-TBI memory retention after lateral (parasagittal) fluid percussion (FP) brain injury in rats. Male Sprague-Dawley rats (n = 37) received a total of 20 training trials over 2 days in the MWM. Two and a half hours after the last training trial, the animals received FP brain injury of moderate severity (2.3 atmospheres, n = 12), high severity (2.6 atm, n = 13), or no injury (n = 12). Forty-two hours after FP brain injury, we observed a highly sufficient memory dysfunction in animals from both injury groups compared to the uninjured group (p less than 0.001). The degree of memory dysfunction was found to be directly related to the severity of injury, with the high severity group scoring significantly worse than the moderately injured group (p = 0.15). In addition, hippocampal cell loss was observed after brain injury, but only unilaterally. These data suggest that lateral FP brain injury causes memory dysfunction possibly related to concurrent hippocampal cell loss and that posttraumatic memory deficits may be sensitively quantitated using the memory testing paradigm described.

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PubMed1991

Fetal cortical transplants in adult rats subjected to experimental brain injury.

Fetal cortical tissue was injected into injured adult rat brains following concussive fluid percussion (FP) brain injury. Rats subjected to moderate FP injury received E16 cortex transplant injections into lesioned motor cortex 2 days, 1 week, 2 weeks, and 4 weeks post injury. Histological assessment of transplant survival and integration was based upon Nissl staining, glial fibrillary acidic protein (GFAP) immunocytochemistry, and staining for acetylcholinesterase. In addition to histological analysis, the ability of the transplants to attenuate neurological motor deficits associated with concussive FP brain injury was also tested. Three subgroups of rats receiving transplant 1 week, 2 weeks, and 4 weeks post injury were chosen for evaluation of neurological motor function. Fetal cortical tissue injected into the injury site 4 weeks post injury failed to incorporate with injured host brain, did not affect glial scar formation, and exhibited extensive GFAP immunoreactivity. No improvement in neurological motor function was observed in animals receiving transplants 4 weeks post injury. Conversely, transplants injected 2 days, 1 week, or 2 weeks post injury survived, incorporated with host brain, exhibited little GFAP immunoreactivity, and successfully attenuated glial scarring. However, no significant improvement in motor function was observed at the one week or two week time points. The inability of the transplants to attenuate motor function may indicate inappropriate host/transplant interaction. Our results demonstrate that there exists a temporal window in which fetal cortical transplants can attenuate glial scarring as well as be successfully incorporated into host brains following FP injury.

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PubMed1990

The novel 21-aminosteroid U-74006F attenuates cerebral oedema and improves survival after brain injury in the rat.

The present study evaluated the effect of the non-glucocorticoid 21-aminosteroid U74006F on the development of regional cerebral oedema after lateral fluid-percussion (FP) brain injury in the rat. Male Sprague-Dawley rats (n = 20) were anaesthetized and subjected to lateral FP brain injury of moderate severity (2.5-2.6 atmospheres). Fifteen minutes after brain injury, animals randomly received an i.v. bolus of either U74006F (3 mg/kg, n = 11) followed by a second bolus (3 mg/kg) at 3 hours vs buffered saline vehicle (equal volume, n = 9). At 48 hours postinjury, animals were sacrificed and brains tissue assayed for water content using wet weight/dry weight methodology. Administration of U74006F significantly attenuated the increase in water content observed in control animals in the ipsilateral hippocampus (adjacent to the site of maximal injury, p less than 0.05). Administration of U74006F also significantly reduced post-injury mortality from 28% in control animals to zero in treated animals (p less than 0.001). These results suggest that lipid peroxidation may be involved in the pathophysiological sequelae of brain injury and that 21-aminosteroids may be beneficial in the treatment of brain injury.

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PubMed1990

Development of regional cerebral oedema after lateral fluid-percussion brain injury in the rat.

Most studies attempting to characterize post-traumatic oedema formation have focused on the acute postinjury period. We have recently developed a new model of lateral (parasagittal) fluidpercussion (FP) brain injury in the rat. The purpose of the present study was to characterize the temporal course of oedema formation and resolution in this experimental model of brain injury. Male Sprague-Dawley rats (n = 67) were anaesthetized and subjected to FP brain injury of moderate severity. Animals were sacrified at 1 hour, 6 hours, 24 hours, 2 days, 3 days, 5 days and 7 days after brain injury, brains removed and assayed for water content using either specific gravitimetric or wet weight/dry weight techniques. In the injured left parietal cortex, a significant increase in water content was observed by 6 hours postinjury (p less than 0.05) that persisted up to 5 days postinjury. A prolonged and significant increase in water content was also observed in the left (ipsilateral) hippocampus which began at 1 hour postinjury (p less than 0.05) and continued up to 3 days. Other regions examined showed no significant regional oedema after brain injury. These results suggest that lateral FP brain injury produces an early focus oedema that persists for a prolonged period after trauma. This model may be useful in the evaluation of novel pharmacological therapies designed to reduce cerebral oedema after brain injury.

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PubMed1990

Mitochondrial metabolism following traumatic brain injury in rats.

Although a number of studies of traumatic brain injury have implicated mitochondrial dysfunction as a cause of altered posttraumatic energy metabolism, no studies to date have isolated mitochondria and measured their respiratory capacity following trauma. The present study sought to determine whether mitochondrial capacity for oxidative phosphorylation is adversely affected by fluid-percussion-induced traumatic brain injury in rats. Prior to brain injury, the mitochondrial respiratory control ratio was 4.3 +/- 0.2 and the ratio of nmoles of ADP phosphorylated per natom oxygen consumed (ADP/O ratio) was 2.66 +/- 0.09. After injury (2.8 atm; t = 4 h), there were slight but not significant alterations in ADP/O ratio (2.41 +/- 0.07) and state 3 respiratory rate (ADP stimulated); however, there were no changes in the respiratory control ratio. These data suggest that traumatic brain injury, unlike ischemia, does not cause uncoupling of ATP synthesis from respiration, and that brain mitochondria are quite resistant to trauma-induced injury.

Adenosine Diphosphate↗
PubMed1990

Effect of noncompetitive blockade of N-methyl-D-aspartate receptors on the neurochemical sequelae of experimental brain injury.

Pharmacological inhibition of excitatory neurotransmission attenuates cell death in models of global and focal ischemia and hypoglycemia, and improves neurological outcome after experimental spinal cord injury. The present study examined the effects of the noncompetitive N-methyl-D-aspartate receptor blocker MK-801 on neurochemical sequelae following experimental fluid-percussion brain injury in the rat. Fifteen minutes after fluid-percussion brain injury (2.8 atmospheres), animals received either MK-801 (1 mg/kg, i.v.) or saline. MK-801 treatment significantly attenuated the development of focal brain edema at the site of injury 48 h after brain injury, significantly reduced the increase in tissue sodium, and prevented the localized decline in total tissue magnesium that was observed in injured tissue of saline-treated animals. Using phosphorus nuclear magnetic resonance spectroscopy, we also observed that MK-801 treatment improved brain metabolic status and promoted a significant recovery of intracellular free magnesium concentrations that fell precipitously after brain injury. These results suggest that excitatory amino acid neurotransmitters may be involved in the pathophysiological sequelae of traumatic brain injury and that noncompetitive N-methyl-D-aspartate receptor antagonists may effectively attenuate some of the potentially deleterious neurochemical sequelae of brain injury.

Adenosine Triphosphate↗
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.

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PubMed1990

Pharmacological and physiological effects of magnesium on experimental traumatic brain injury.

It is now generally accepted that in addition to mechanical or primary injury to the central nervous system (CNS) resulting from a traumatic event, much of the irreversible neural injury occurring after CNS trauma is caused by secondary factors. One of the secondary injury factors implicated in the development of irreversible tissue injury, and associated mortality and morbidity after neurotrauma, is magnesium. This review focuses on recent evidence suggesting that magnesium plays a critical role in the injury process, not only by having direct effects on cellular metabolism, but also by regulating other proposed secondary injury factors such as excitatory amino acids, calcium, lipid hydrolysis, opioid peptides, and energy metabolism. Treatments that have a demonstrated neuroprotective effect following neurotrauma are shown to restore brain cellular magnesium homeostasis after injury.

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PubMed1990

Opiate antagonist nalmefene improves intracellular free Mg2+, bioenergetic state, and neurologic outcome following traumatic brain injury in rats.

Treatment of CNS trauma with the opiate antagonist naloxone improves outcome, though the mechanisms of action remain speculative. Nalmefene is another opiate-receptor antagonist, but it has substantially greater potency and duration of action than naloxone. It also has increased activity at kappa opiate receptors and has recently been shown to limit histological changes and neurological dysfunction after traumatic spinal cord injury. The present study examined the effects of treatment with nalmefene on outcome after fluid-percussion-induced traumatic brain injury in rats, using magnetic resonance spectroscopy to monitor acute metabolic changes and behavioral tests to determine chronic neurological recovery. Single-dose treatment with nalmefene (100 micrograms/kg, i.v.) at 30 min after trauma significantly improved (p less than 0.05) neurological outcome (up to 4 weeks) as compared to saline-treated controls. Early changes in intracellular free-magnesium concentration, adenosine diphosphate concentration, and cytosolic phosphorylation potential were all significantly improved by nalmefene treatment, reflecting improved bioenergetic state. We suggest that the ability of nalmefene to improve cellular bioenergetics after trauma may in part account for the neuroprotective effects of this and related compounds.

Adenosine Triphosphate↗
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

Experimental fluid percussion brain injury: vascular disruption and neuronal and glial alterations.

Because of the potential relationship between vascular disturbances and secondary tissue damage, we identified areas of brain which exhibited hemorrhage and leakage of protein during the acute stage after experimental brain injury and subsequently studied the development of pathologic changes, including cavity formation, neuronal necrosis, and gliosis within these regions. The development of pathologic changes was evaluated at 1, 6, and 24 h and 1, 2, and 4 weeks after lateral, fluid percussion (FP) brain injury of moderate severity in the rat. Vascular disruption in the acute stages, as evidenced by hemorrhage and leakage of Evans blue albumin, was most prominent 6 h postinjury and was maximal in the parieto-occipital cortex. From 1 to 24 h after injury, regions of the injured hemisphere, including the cortex and hippocampus, exhibited abnormal neurons which stained with acid fuchsin and Alizarin red, histochemical markers for injured neurons and calcium, respectively. These same regions suffered significant neuronal cell loss from 1 to 4 weeks after injury. The distribution of reactive astrocytes was also evaluated by immunocytochemical localization of glial fibrillary acidic protein (GFAP). By 2 weeks postinjury, a prominent cavity was present in the frontoparietal and occipital cortices. Although astrogliosis was most pronounced in the cortex surrounding the cavity, prominent reactive astrocytes were widely distributed throughout the injured hemisphere. This study characterized the pathological changes which occur after experimental traumatic brain injury. In particular, we propose that neuronal cell injury in the hippocampus serves as a useful 'window' to assess beneficial efficacy of pharmacological intervention in the treatment of brain injury.

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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.

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PubMed1989

Effects of traumatic brain injury on regional cerebral blood flow in rats as measured with radiolabeled microspheres.

To clarify the effect of experimental brain injury on regional CBF (rCBF), repeated rCBF measurements were performed using radiolabeled microspheres in rats subjected to fluid-percussion traumatic brain injury. Three consecutive microsphere injections in six uninjured control rats substantiated that the procedure induces no significant changes in hemodynamic variables or rCBF. Animals were subjected to left parietal fluid-percussion brain injury of moderate severity (2.1-2.4 atm) and rCBF values were determined (a) prior to injury and 15 min and 1 h following injury (n = 7); and (b) prior to injury and 30 min and 2 h following injury (n = 7). At 15 min post injury, there was a profound reduction of rCBF in all brain regions studied (p less than 0.01). Although rCBF in the hindbrain had recovered to near-normal by 30 min post injury, rCBF in both injured and contralateral (uninjured) forebrain areas remained significantly suppressed up to 1 h post injury. At 2 h post injury, recovery of rCBF to near-normal values was observed in all brain regions except the focal area of injury (left parietal cortex) where rCBF remained significantly depressed (p less than 0.01). This prolonged focal oligemia at the injury site was associated with the development of reproducible cystic necrosis in the left parietotemporal cortex at 4 weeks post injury. Our results demonstrate that acute changes in rCBF occur following experimental traumatic brain injury in rats and that rCBF remains significantly depressed up to 2 h post injury in the area circumscribing the trauma site.

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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.

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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.

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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

Selective sparing of NADPH-diaphorase neurons in neonatal hypoxia-ischemia.

Excitatory amino acids have been implicated in ischemic neuronal injury. To test this hypothesis in neonatal hypoxia-ischemia, lesions of the cortex and striatum were induced in 7-day-old rats by unilaterally ligating their carotid arteries and subjecting them to hypoxic conditions for 2 hours. Brains examined 1 week later demonstrated, within the regions of ischemic damage, a striking preservation of neurons that stained histochemically for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity. Concentrations of the neuropeptides somatostatin and neuropeptide Y, which colocalize in neurons containing NADPH-d, were unaffected in the areas of ischemic damage. The same pattern of injury with sparing of NADPH-d-reactive neurons was reproduced by focal microinfusion of the excitotoxin quinolinic acid, an endogenous N-methyl-d-aspartate (NMDA) agonist, into the striatum. These results support the hypothesis that neonatal hypoxic-ischemic injury is mediated through excitatory transmitters acting at the NMDA receptor and that the NADPH-d-reactive neurons in the neonate are resistant to excitotoxic damage. This pattern of cell vulnerability is unique to the developing striatum and may relate to the distinct pathological appearance of the basal ganglia that follows neonatal asphyxia.

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