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Biomedical subjects

R N Auer

Publications and source records attributed to R N Auer.

At least 19 recordsLinked to original sources
PubMed2005

Subcortical middle cerebral artery ischemia abolishes the digit flexion and closing used for grasping in rat skilled reaching.

That rats reach for and grasp a food item using a single paw has prompted their use in neurobiological studies of skilled movements and modeling neural injury including middle cerebral artery stroke. Although motor system lesions have been shown to disrupt various qualitative aspects of the transport of a limb to a food target and withdrawal of the limb with the food, no lesion has been found to abolish digit flexion for grasping. Here, rats received unilateral transient middle cerebral artery ischemia that was restricted mainly to subcortical tissue of the forebrain (caudate-putamen, globus pallidus, and associated fibers) or a sham operation. Both paws were later trained and evaluated on skilled reaching using a rating scale for digit use. Middle cerebral artery rats did not flex and close their digits to grasp food when using their contralateral-to-lesion limb. The grasp impairment was not due to a failure to learn the task as middle cerebral artery rats used the ipsilateral limb as successfully as control rats and they were reinforced for reaching by raking food into the reaching box using an open paw. The impairment was also not due to an inability to move the digits, as they were flexed and closed in other phases of the reach. The paradigm should prove useful for further studies of rehabilitation in relation to the idea that digit closure may be controlled by the joint action of a number of neural systems that converge in the basal ganglia.

Animals↗
PubMed2002

Embryonic intermediate filament, nestin, expression following traumatic spinal cord injury in adult rats.

Precursor cells in the ependyma of the lateral ventricles of adult mammalian brain have been reported in brain, and also in the spinal cord. The present study used antibody to the intermediate filament protein (nestin) as an immunohistochemical marker for neural stem cells and precursor cells in a rat model of spinal cord trauma. Male Sprague-Dawley rats (n=25) had a laminectomy at Thll-Thl2, and spinal cord contusion was created by compression with 30 g of force for 10 min. The rats were killed at 24 h, 1 week and 4 weeks after injury, and four levels of the spinal cord were examined: 5 mm and 10 mm, both rostral and caudal region to the injury center. Time- and region-dependent alterations of nestin immunoreactivity were analyzed. Revealed at 24 h post-injury, 5 mm rostral and caudal to the lesions, nestin expression was observed in ependymal cells and around the hemorrhagic and necrotic lesion located in dorsal spinal cord, peaking at 1 week after injury. Moreover, nestin expression was also observed in the white matter of ventral spinal cord, extending into arborizing processes centripetally from the pial surface toward the central canal. At 4 weeks after injury, nestin expression in ependyma decreased 10 mm from the injury site. But nestin expression in white matter increased dramatically with a 100-fold increase in nestin originating from the pial surface, and extension now to all the white matter. The latter was accompanied by glial fibrillary acidic protein positivity into very long arborizing processes, morphologically compatible with radial glia. The findings suggest two possible sources of precursor cells in adult mammalian spinal cord; ependyma of the central canal and subpial astrocytes. Subpial astrocytes may be associated with neural repair and regeneration after spinal cord injury.

Age Factors↗
PubMed2001

Encephalopathy with staphylococcal endocarditis: multiple neuropathological findings.

BACKGROUND: Infective endocarditis is associated with serious neurological sequelae. OBJECTIVE: Here, we report a patient with Staphylococcus aureus endocarditis, secondary to congenital heart disease, with subacute onset of multiple neurological complications. RESULTS: Despite prompt antibiotic treatment with rapid sterilization of blood cultures, the patient died with brain herniation within 96 hours of admission. Neuropathological examination showed intraparenchymal hemorrhages, mycotic aneurysms, micro-abscesses and septic arteritis with accompanying infarction. Immunocytochemical studies revealed enhanced CD45 and GFAP immunoreactivity, together with adenosine A1 receptor detection on macrophages and microglia. CONCLUSIONS: Infective endocarditis is associated with multiple neuropathological lesions, which may contribute to its poor clinical outcome and activation of cells of monocyte-microglial lineage throughout the brain.

Adult↗
PubMed2001

Non-pharmacologic (physiologic) neuroprotection in the treatment of brain ischemia.

Clinical trials for ischemic stroke have been characterized by a disappointing series of negative results, using a panoply of pharmacologic agents. This paper emphasizes five physiologic measures that can be taken to mitigate ischemic brain damage. These are (1) hypothermia, (2) insulin, (3) arterial hyperoxemia, (4) blood pressure control and (5) magnesium. Hypothermia is protective in both focal and global ischemia, even postischemically protecting against selective neuronal necrosis and infarction. The total equation for protection includes the (i) postischemic delay, (ii) depth, and (iii) duration of hypothermia. Insulin operates by lowering glucose levels to the normal range in focal ischemia. It is possible that very low glucose levels are detrimental in focal ischemia with paradoxical augmentation of the infarct size, and that spreading depression plays a role in this. Controlled arterial hyperoxemia seems effective experimentally in reducing infarct size, operating mechanistically by either a direct effect of oxygen, or vasoconstriction causing shunting of blood into the infarct, or both. Blood pressure is a critical determinant of infarct size, and raising blood pressure improves collateral blood flow and reduces stroke size. To be used clinically, however, hemorrhage must be ruled out. The most dramatic clinical effects of blood pressure are seen in aneurysm patients with vasospasm, where minor increases in blood pressure reverse temporary hemiparesis by reducing ischemia. Magnesium is likely the safest NMDA antagonist, with a long history of safe administration to pregnant women with eclampsia. There is potential interaction with insulin, in that magnesium causes hyperglycemia, which requires insulin to counteract it. Magnesium and insulin together have been shown effective in experimental brain ischemia. In the absence of safe and effective pharmacologic neuroprotection agents, clinical trials should be designed and launched to test these physiologic measures, singly and in combination, to reduce brain damage after ischemia.

Animals↗
PubMed2001

Understanding and managing ischemic stroke.

Transient or permanent focal brain injury following acute thromboembolic occlusion develops from a complex cascade of pathophysiological events. The processes of excitotoxicity, peri-infarct depolarisation, inflammation, and apoptosis within the ischemic penumbra are proposed. While the translation of therapeutic agents from the animal models to human clinical trials have been disappointing, there remains an atmosphere of optimism as a result of the development of new diagnostic and therapeutic approaches, which include physiological, as opposed to pharmacological, intervention. This article provides an insight into the understanding of cerebral ischemia, together with current and future treatment strategies.

Animals↗
PubMed2000

Hypoxia, hyperoxia, ischemia, and brain necrosis.

BACKGROUND: Human brains show widespread necrosis when death occurs after coma due to cardiac arrest, but not after hypoxic coma. It is unclear whether hypoxia alone can cause brain damage without ischemia. The relationship of blood oxygenation and vascular occlusion to brain necrosis is also incompletely defined. METHODS: We used physiologically monitored Wistar rats to explore the relationship among arterial blood oxygen levels, ischemia, and brain necrosis. Hypoxia alone (PaO2 = 25 mm Hg), even at a blood pressure (BP) of 30 mm Hg for 15 minutes, yielded no necrotic neurons. Ischemia alone (unilateral carotid ligation) caused necrosis in 4 of 12 rats, despite a PaO2 > 100 mm Hg. To reveal interactive effects of hypoxia and ischemia, groups were studied with finely graded levels of hypoxia at a fixed BP, and with controlled variation in BP at fixed PaO2. In separate series, focal ischemic stroke was mimicked with transient middle cerebral artery (MCA) occlusion, and the effect of low, normal, and high PaO2 was studied. RESULTS: Quantitated neuropathology worsened with every 10 mm Hg decrement in BP, but the effect of altering PaO2 by 10 mm Hg was not as great, nor as consistent. Autoradiographic study of cerebral blood flow with 14C-iodoantipyrine revealed no hypoxic vasodilatation during ischemia. In the MCA occlusion model, milder hypoxia than in the first series (PaO2 = 46.5 +/- 1.4 mm Hg) exacerbated necrosis to 24.3 +/- 4.7% of the hemisphere from 16.6 +/- 7.0% with normoxia (PaO2 = 120.5 +/- 4.1 mm Hg), whereas hyperoxia (PaO2 = 213.9 +/- 5.8 mm Hg) mitigated hemispheric damage to 7.50 +/- 1.86%. Cortical damage was strikingly sensitive to arterial PaO2, being 12.8 +/- 3.1% of the hemisphere with hypoxia, 7.97 +/-4.63% with normoxia, and only 0.3 +/- 0.2% of the hemisphere with hyperoxia (p < 0.01), and necrosis being eliminated completely in 8 of 10 animals. CONCLUSIONS: Hypoxia without ischemia does not cause brain necrosis but hypoxia exacerbates ischemic necrosis. Hyperoxia potently mitigates brain damage in this MCA occlusion model, especially in neocortex.

Animals↗
PubMed1999

Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia.

It has been repeatedly claimed that neuronal death in the hippocampal CA1 sector after untreated global ischemia occurs via apoptosis. This is based largely on DNA laddering, nick end labeling, and light microscopy. Delineation of apoptosis requires fine structural examination to detect morphological events of cell death. We studied the light and ultrastructural characteristics of CA1 injury after 5 min of untreated global ischemia in gerbils. To increase the likelihood of apoptosis, some ischemic gerbils were subjected to delayed postischemic hypothermia, a treatment that mitigates injury and delays the death of some neurons. In these gerbils, 2 d of mild hypothermia was initiated 1, 6, or 12 hr after ischemia, and gerbils were killed 4, 14, or 60 d later. Ischemia without subsequent cooling killed 96% of CA1 neurons by day 4, whereas all hypothermia-treated groups had significantly reduced injury at all survival times (2-67% loss). Electron microscopy of ischemic neurons with or without postischemic hypothermia revealed features of necrotic, not apoptotic, neuronal death even in cells that died 2 months after ischemia. Dilated organelles and intranuclear vacuoles preceded necrosis. Unique to the hypothermia-treated ischemic groups, some salvaged neurons were persistently abnormal and showed accumulation of unusual, morphologically complex secondary lysosomes. These indicate selective mitochondrial injury, because they were closely associated with normal and degenerate mitochondria, and transitional forms between mitochondria and lysosomes occurred. The results show that untreated global ischemic injury has necrotic, not apoptotic, morphology but do not rule out programmed biochemical events of the apoptotic pathway occurring before neuronal necrosis.

Animals↗
PubMed1999

The effects of temperature and scopolamine on N-methyl-D-aspartate antagonist-induced neuronal necrosis in the rat.

The effects of temperature and scopolamine on dizocilpine maleate-induced neuronal necrosis in the rat cingulate/retrosplenial cortex, entorhinal/olfactory cortices and the dentate gyrus were studied. Mild, protracted hypothermia (48 h at a brain temperature of 34 degrees C), induced by a servo-controlled "exposure technique" in the awake female rat, significantly reduced dizocilpine maleate (5.0 mg/kg, i.p.)-induced neuronal death in the cingulate/retrosplenial and entorhinal/olfactory cortices seven days following drug administration. Scopolamine (0.25 mg/kg, i.p.), putatively neuroprotective [Olney J. W. et al. (1991) Science 254, 1515-1518], did not reduce injury in the cingulate/retrosplenial cortex of female rats following one injection, but did following two and three doses. Scopolamine had no significant effect in the other brain regions. A temperature elevation of only 1 degree C above baseline for 48 h in awake female rats increased dizocilpine maleate-induced damage. Finally, the sex differences in N-methyl-D-aspartate antagonist toxicity were replicated and extended to other structures, and found not to be due to temperature differences. Our data show that dizocilpine maleate neurotoxicity is temperature sensitive. Scopolamine treatment needed to be prolonged in order to reduce injury, and even then was only efficacious in one of three brain regions. The results underscore the importance of using neuronal necrosis in several brain regions as the endpoint and for the use of prolonged therapeutic interventions. Furthermore, given the potential hypothermic action of other putative neuroprotective drugs, a mechanistic re-evaluation of N-methyl-D-aspartate antagonist-induced injury is needed, with precise brain temperature measurement.

Animals↗
PubMed1998

Characterization of postischemic behavioral deficits in gerbils with and without hypothermic neuroprotection.

Five minutes of global ischemia in gerbil results in delayed hippocampal CA1 neuronal degeneration, which is accompanied by working memory impairments and hyperactivity in novel environments. In this study, postischemic activity was characterized in familiar and in novel environments to determine whether hyperactivity was due to impaired spatial habituation or another form of motor hyperactivity. This study also determined whether 6-h delayed hypothermia, which reduces CA1 neuronal injury, would attenuate functional impairments. Gerbils were subjected to 5 min of normothermic ischemia or sham operation 2 days following implantation of brain temperature probes. One of two ischemic groups was cooled (>48 h) starting at 6-h postischemia. Locomotor activity in a familiar cage was measured for 6 days while activity in three novel environments was intermittently measured on days 4, 5 and 6. Open field behavior and working memory in a T-maze were also assessed. Untreated ischemia caused marked hyperactivity in the familiar cage on day 1, which reverted to near-normal by day 2. Nonetheless, these gerbils showed hyperactivity during novel environment sessions on days 4-6. This maze behavior, which predicted hippocampal CA1 injury, was not due to different habituation rates nor baseline hyperactivity. Conversely, open field sessions on day 8 revealed ischemic habituation rate deficits. Ischemia also impaired working memory in the T-maze. Delayed hypothermia, which reduced neuronal loss in the CA1 sector to 12% from 81%, reduced all functional impairments. Ischemic gerbils quickly developed spontaneous locomotion hyperactivity that returned to near-normal after 1 day. This motor hyperactivity did not explain the elevated activity found with delayed testing in novel environments. Regardless, only the open field test on day 8 revealed a habituation-like deficit.

Animals↗
PubMed1998

Molecular cloning of a novel potassium-dependent sodium-calcium exchanger from rat brain.

We have isolated a novel cDNA clone from rat cerebral cortex encoding a protein of 670 amino acids (NCKX2) that has significant similarity to the 1199-amino acid-long Na/Ca-K exchanger of bovine rod outer segment (NCKX1). NCKX2 transcripts are 10.5 kilobase pairs in length and are expressed abundantly in neurons throughout the brain and with much lower abundance in selected other tissues. The predicted topology of the rat NCKX2 protein is very similar to that of bovine NCKX1, beginning with a solitary transmembrane segment (M0), which is removed as a "signal peptide" in bovine NCKX1, an extracellular loop, a cluster of five transmembrane spanning segments (M1 to M5), a long cytoplasmic loop, and a final hydrophobic cluster (M6 to M11). Within the hydrophobic clusters, rat NCKX2 shares 80% identity and 91% similarity with bovine NCKX1. The two larger hydrophilic loops are much shorter in NCKX2 than in NCKX1, accounting largely for the difference in length between the two proteins, and are dissimilar in sequence except for a 32-amino acid stretch with 69% identity in the cytosolic loop. NCKX2 was epitope-tagged in the extracellular domain and was shown to be expressed at the surface of transfected HEK cells. Analysis of NCKX2 function by fluorescent imaging of fura-2-loaded transfected cells demonstrated that NCKX2 is a potassium-dependent sodium/calcium exchanger.

Amino Acid Sequence↗
PubMed1998

Behavioral testing does not exacerbate ischemic CA1 damage in gerbils.

BACKGROUND AND PURPOSE: Previous research studying ablative lesions has suggested that functional use may exacerbate brain injury. If true, this would have considerable ramifications not only for the mechanistic understanding of neuronal injury but also for the clinical use of physiotherapy. In this report the hypothesis that behavioral use of brain tissue exacerbates ischemic hippocampal injury was tested. METHODS: Gerbils were subjected to sham operation or 5 minutes of normothermic ischemia. To produce borderline hippocampal CA1 injury and enhance susceptibility to exacerbation, 2 of 3 ischemic groups were cooled (>48 hours) beginning at 6 hours after ischemia. Increased use of the hippocampus was produced by a battery of tests involving 3 novel small mazes, a T maze, and an open field. One hypothermic group was not tested and served as a control. RESULTS: Behavioral testing failed to worsen ischemic damage since neuronal loss in the behaviorally tested and untested hypothermic groups was 12% and 8%, respectively, while that in the untreated ischemic group was 81% at a 1-month survival. Accordingly, protected CA1 cells tolerated the neuronal activity associated with behavioral testing. Concomitant with marked CA1 neuroprotection, a significant reduction in behavioral deficits with the hypothermic treatment was observed. Importantly, behavioral testing was found to transiently elevate brain temperature. CONCLUSIONS: CA1 neuronal survival was unaffected by behavioral testing or the associated mild fever. Hypothermia delayed for 6 hours provided sustainable CA1 neuroprotection.

Animals↗
PubMed1998

Insulin, blood glucose levels, and ischemic brain damage.

Intensive efforts are presently directed toward developing pharmacologic therapy to protect the ischemic brain. Preclinical data from animal models indicate that insulin, already available for human use, may reduce damage in both global and focal ischemia. Two kinds of mechanisms may be involved: one in which insulin interacts directly with brain tissue and one in which insulin acts indirectly by reducing peripheral blood glucose levels. Animal data indicate that part of the former, direct mechanism is mediated by insulin-like growth factor-1 receptors. The direct effect appears to predominate in global ischemia. In focal ischemia, unlike global ischemia, the effect of insulin is predominantly via peripheral hypoglycemia, because neuroprotection is largely annulled by co-administration of glucose. The two clinical counterparts of global and focal ischemic models are, respectively, cardiac arrest encephalopathy and focal ischemic stroke. Insulin use in both of these clinical situations could be evaluated in clinical trials that attempt to reduce ischemic brain damage, because insulin has a long and safe history of human use in diabetes treatment.

Animals↗
PubMed1997

Structural neurotoxicologic investigation of the glycine antagonist 5-nitro-6,7-dichloroquinoxalinedione (ACEA-1021).

NMDA antagonists of glutamate have psychotomimetic side effects and structural side effects which have been shown to be lethal to CNS neurons in the cingulate and retrosplenial cortex of rodents, yet these compounds may reduce focal ischemic brain damage. This investigation used 38 Wistar rats to determine whether the structural toxicologic profile of a newly developed halogenated quinoxalinedione derivative, a pharmacologic antagonist of the glycine site on the NMDA receptor complex, is identical to that seen with MK-801. In the cingulate and retrosplenial cortex, examination of glutaraldehyde perfusion-fixed, plastic-embedded tissue 4 to 6 hours after intravenous administration of 10 mg/kg of the glycine antagonist 5-nitro-6,7-dichloroquinoxalinedione (ACEA-1021), no changes were seen by light or electron microscopy. At a dose of 30 mg/kg, neurons were seen containing 1 to 2 microns granules in perikarya and axons. Vacuolated neurons, as described in NMDA-antagonist neurotoxicity, were exceedingly rare, comprising only 4 in the entire study. Electron microscopy of the granulated profiles showed intracytoplasmic areas containing grouped mitochondria and lysosomes, located in neuronal perikarya, and rarely in myelinated axons. Neuronal necrosis was evaluated in formaldehyde perfusion-fixed, paraffin-embedded tissue at one week survival, and was absent. MK-801 5 mg/kg, in contrast, caused irreversible (necrotizing) neuronal changes. The results demonstrate that this glycine antagonist is devoid of lethal neurotoxicity, but causes a reversible alteration in a small proportion of cingulate and retrosplenial cortical neurons. Since previous studies have shown anti-ischemic efficacy of this compound in focal, but not global ischemia, it appears that the therapeutic profile of this antagonist of the strychnine-insensitive glycine site is similar, but the toxicologic structural profile is different, from NMDA receptor antagonists.

Animals↗
PubMed1997

-(S)-Alpha-phenyl-2-pyridine-ethanamine Dihydrochloride-, a low affinity uncompetitive N-methyl-D-aspartic acid antagonist, is effective in rodent models of global and focal ischemia.

[(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low affinity uncompetitive N-methyl-D-aspartic acid receptor antagonist that was tested in animal models of anoxia and ischemia. Pretreatment of rodents with ARL 15896AR extended survival time during exposure to hypoxia. With the rat four-vessel occlusion model of global ischemia (20 min), oral dosing commencing at reflow, resulted in significant protection of the CA1 hippocampal neurons. ARL 15896AR was, however, ineffective in the rat two-vessel occlusion model and in the gerbil models of forebrain ischemia, the latter due to an inability to attain suitable plasma levels. In the spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) (2 hr plus 22 hr reflow), acute dosing with ARL 15896AR (i.p.) beginning from 30 min before or up to 1 hr post-MCAO significantly reduced cortical infarct volume. The ability of ARL 15896AR to influence infarct size, as well as functional correlates was examined in SHR after 90 min of MCAO. T2 weighted magnetic resonance images taken at 2 and 6 days post-MCAO revealed significantly smaller lesion sizes in the group receiving injections with ARL 15896AR beginning 30 min after occlusion. Spontaneously hypertensive rats were subsequently tested (30-42 days post-MCAO) and found to be deficient in skilled use of the forepaws (staircase test). The contralateral forepaw was most severely impaired, however, ARL 15896AR treatment prevented motor impairment in only the ipsilateral forepaw. Histopathological examination of cortical infarct size was unremarkable between treated and control rats. The findings indicate that ARL 15896AR exhibits neuroprotection in global and focal models of ischemia

Animals↗
PubMed1996

Hypoglycaemic brain damage: effect of a dihydropyridine calcium channel antagonist in rats.

Hypoglycaemic brain damage consists of selective necrosis of cerebral neurons related to the extracellular release of excitatory amino acids. Neuronal excitatory amino acid receptors are activated and calcium channels are opened. The present investigation was designed to test the effectiveness of dihydropyridine blockade of voltage-sensitive calcium channels in hypoglycaemic brain damage. Sixty-four rats were given either high-dose nimodipine, consisting of an initial bolus of 300 micrograms/kg nimodipine administered at the stage of EEG slowing (blood glucose levels of 1.0-1.5 mmol/l), followed by continuous intravenous nimodipine infusion at 1.5 micrograms.kg-1.min-1, low-dose nimodipine, consisting of an initial bolus of 30 micrograms/kg at the time of EEG slowing, followed by 0.15 microgram.kg-1.min-1, an equal volume of vehicle solution, or 154 mmol/l NaCl. Animals receiving either low- or high-dose nimodipine had higher mortality, and increased brain damage compared with controls. Examination of the perfusion-fixed brains 1 week after recovery with glucose revealed that quantitated neuronal necrosis was worsened by nimodipine in the hippocampus, caudate nucleus and cerebral cortex. The present results in profound hypoglycaemia (accompanied by a flat EEG) contrast with the beneficial effect of nimodipine in brain ischaemia.

Animals↗
PubMed1996

Asymptomatic large pituitary adenomas discovered at autopsy.

BACKGROUND: Pituitary adenomas over 1 inch (2.5 cm) in diameter might seem to warrant surgical intervention by virtue of their inevitable compression and distortion of surrounding neural tissues. METHODS: We report three pituitary adenomas over 1 inch in diameter, causing gross distortion of the optic nerves, chiasm, and tracts, as well as surrounding brain structures. All three tumors were asymptomatic and were discovered incidentally at autopsy in patients 65, 79, and 101 years of age. RESULTS: Tumor diameters were 2.5, 4.0, and 2.5 cm, respectively. Histologically, all were chromophobe adenomas, free of either hemorrhage or necrosis. In the absence of hormonal secretion or pituitary apoplexy, symptom-free giant adenomas of the pituitary are compatible with a long life. CONCLUSIONS: We conclude that the need for surgical intervention in pituitary adenomata should be determined by considerations other than mere tumor presence and size.

Adenoma↗