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R N Auer

Publications and source records attributed to R N Auer.

At least 19 recordsLinked to original sources
PubMed1992

Combination therapy with nimodipine and dizocilpine in a rat model of transient forebrain ischemia.

BACKGROUND AND PURPOSE: We explored the effectiveness of dual blockade of calcium channels in preventing ischemic necrosis in a rat model of transient forebrain ischemia. METHODS: To assess all the major brain regions, the entire brain was subserially sectioned and examined histologically 1 week after ischemia in 44 male Wistar rats. Brain temperature was monitored and controlled to avoid hypothermia or intergroup temperature differences at the time drugs were administered. All regimens were begun 20 minutes after ischemia. Treated animals received either the L-type calcium channel blocker nimodipine (0.25 microgram/min x 24-hour i.v. infusion), the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine; 5 mg/kg i.v.), or both regimens in combination. RESULTS: In the neocortex (p less than 0.05) and striatum (p less than 0.05), only double-treated animals showed a statistically significant reduction in neuronal necrosis. Dual therapy eliminated neuronal necrosis in the caudate nucleus entirely. In the septal (densely ischemic) hippocampus, protection was weak and inconsistent (0.012 less than p less than 0.788), but in the temporal (incompletely ischemic) hippocampus, the dual-treated group showed the most significant reduction (p less than 0.006). CONCLUSIONS: We conclude that the combination of nimodipine and MK-801, if begun 20 minutes after ischemia, may offer a neuroprotective effect against neuronal necrosis in transient forebrain ischemia and that protection is maximal in the major extrahippocampal brain regions.

Animals↗
PubMed1991

Insulin attenuates ischemic brain damage independent of its hypoglycemic effect.

Insulin, an endogenously produced circulating peptide that enters the brain, has been shown to reduce ischemic brain and spinal cord damage in several animal models. Because of its potential clinical use in humans, the present study was undertaken to test the hypotheses that (a) survival and regional ischemic brain necrosis are improved by insulin; (b) insulin requires concomitant hypoglycemia to exert its neuroprotective effect; (c) insulin is still neuroprotective with delayed administration after an episode of postischemic hypotension; and (d) insulin is beneficial after normoglycemic, as well as hyperglycemic ischemia. Rats were subjected to 10.5 min two-vessel occlusion forebrain ischemia followed by 30 min of hypotension to increase the infarction rate. Insulin administered concomitantly with glucose significantly reduced the seizure rate, as well as cortical and striatal neuronal necrosis below that seen in untreated animals. Neuroprotection was seen whether insulin was given before or after a 30-min episode of postischemic hypotension. Insulin reduced pan-necrosis in addition to selective neuronal necrosis: The infarction rate was reduced in the cerebral cortex, thalamus, and substantia nigra pars reticulata. Normoglycemic ischemia produced only selective neuronal necrosis, but a beneficial effect on structural damage was also seen. The results indicate that insulin acts directly on the brain, independent of hypoglycemia, to reduce ischemic brain necrosis. Possible direct CNS mechanisms of action include an effect on central insulin receptors mediating inhibitory neuromodulation, an effect on central neurotransmitters, or a growth factor effect of insulin.

Animals↗
PubMed1991

Intraventricular infusion of the selective sigma-agonist 1,3-di-ortho-tolylguanidine (DTG) mitigates ischaemic brain damage in the hippocampus.

Experimental evidence suggests that neuronal pharmacologic sites termed sigma (sigma) may be related, but not identical to PCP sites in the ion channel linked to NMDA excitatory receptors. These receptors may play a role in schizophreniform psychoses, and clinical trials of putative sigma-ligands have begun. Because of this, and because of the relationship of sigma-ligands to NMDA receptors, we studied the effect of the most selective presently available sigma-ligand on ischaemic neuronal death throughout the rat brain after transient forebrain ischaemia. Ventricular delivery of DTG at 0.5 mumol/h via an osmotic minipump was chosen to allow continuous access of the drug to brain tissue, control animals receiving artificial CSF. After one week survival, selective neuronal necrosis was reduced in the hippocampus, but not in the neocortex or striatum, contrasting with our previous findings in this model with pure NMDA antagonists. The results indicate that ischaemic neuronal necrosis in the hippocampus may be mitigated by sigma-agonists, possibly via an interaction with NMDA receptors.

Animals↗
PubMed1991

Postischemic seizures and necrotizing ischemic brain damage: neuroprotective effect of postischemic diazepam and insulin.

Insulin has recently been shown experimentally to modify ischemic brain damage when administered either before or after the episode of ischemia. In controlled studies in the rat, high doses of insulin (greater than or equal to 8 IU/kg) result in seizures and early death. The present study was undertaken to determine whether diazepam, a potent, centrally penetrating GABAmimetic, alone or in combination with insulin, could mitigate postischemic seizures or regional selective neuronal necrosis and infarction. Forebrain ischemia was induced in rats for 10 1/2 minutes by carotid clamping and hypotension. The animals were observed clinically until elective perfusion-fixation and quantitative pathologic examination at 1-week recovery. Diazepam, either alone or with insulin, reduced regional brain necrosis and reduced the seizure rate. Insulin alone also led to reduced regional necrosis. However, the combination of diazepam plus insulin yielded the greatest proportion of undamaged brains in the hippocampus, thalamus, and midbrain. In the neocortex, the diazepam-only group showed the greatest number of normal hemispheres. Hypothalamic infarction was eliminated by all three treatments. Seizures per se were associated with increased damage in the cerebral cortex, thalamus, and brainstem, irrespective of treatment group. The findings indicate that ischemic brain necrosis can be mitigated by diazepam and insulin treatment begun in the immediate postischemic period.

Animals↗
PubMed1991

Excitotoxic mechanisms, and age-related susceptibility to brain damage in ischemia, hypoglycemia and toxic mussel poisoning.

Initial research by Olney, investigating the toxicity of glutamate as a food additive, demonstrated that irreversible (necrotic) changes could be produced in the CNS by glutamate. Subsequently, it became clear that the release of excitatory amino acids into the extracellular space of nervous tissue may play a role in CNS ischemia, and, later hypoglycemia. Experiments utilizing excitatory amino acid antagonists at the N-methyl-d-aspartate and other subtypes of excitatory receptor have shown neuronal protection, in both ischemia and hypoglycemia. The protection is robust enough to produce a detectable improvement in neurologic deficit on neurobehavioral testing, in addition to significantly reducing the number of necrotic cells in the brain. A third condition where excitotoxicity plays a role is toxic mussel poisoning. In contrast to ischemia and hypoglycemia, an excitotoxin which is exogenous to the brain plays a role. Domoic acid is contained in mussels which have filter-fed large quantities of domoate-rich phytoplankton, and when contaminated mussels are ingested in large quantities, serious and irreversible CNS effects, accompanied by necrosis, may result. In contrast to ischemia and hypoglycemia, however, damage is mediated at a different excitatory CNS receptor, namely the kainate receptor. In all three conditions, a constant aspect of the excitotoxic pathology is an increased susceptibility to excitotoxic damage with increasing age. This may be due to the dendritic location of excitatory receptors, and the richer branching of neuronal dendritic trees in aged animals, leading to enhanced susceptibility of the neuron to excitotoxic necrosis with age.

Aging↗
PubMed1990

The relationship of structural ischemic brain damage to neurobehavioural deficit: the effect of postischemic MK-801.

Global cerebral ischemia is well known to cause neuronal necrosis in selectively vulnerable sectors of the hippocampus. Since the hippocampus of the rat is involved in spatial navigation, learning, and memory, selective deficits in these abilities may arise from ischemic brain damage. Previous studies have shown (a) a detectable neurobehavioural deficit due to ischemic brain damage limited to half of the CA1 sector of the hippocampus and (b) a reduction of ischemic neuronal necrosis with the noncompetitive N-methyl-D-Aspartate (NMDA) antagonist MK-801. This study was designed to determine the relationship between the improvement in structural brain damage in postischemically treated rats and any improvement in neurobehavioural performance, using a learning-set water task. Seventeen male Wistar rats received 10.5 min of forebrain ischemia induced by carotid clamping and hypotension. Brain temperature was estimated with probes in the temporalis muscle. Ten of these animals received no therapy (controls), and seven animals received 5 mg/kg MK-801 iv, 20 min postischemia. Six additional rats underwent a sham operation. Postischemic hypothermia was prevented with heating lamps. Four controls and one MK-801 treated animal died. The survivors were then tested on a place learning-set task in a swimming pool paradigm, and quantitative histopathologic analysis of their entire brains was done. The learning-set task revealed defects in spatial navigation, reflected as increased errors and latency in the performance of the untreated control rats. The performance of the MK-801 treated group progressively approached that of sham-operated rats over the course of testing and was significantly better than controls. Importantly, no long-term detrimental effect of MK-801 on the learning-set task performance was seen. Quantitative neuropathology revealed significantly less damage in the MK-801 treated group in all major brain regions. In the hippocampus, MK-801 treated animals showed hippocampal damage limited to the vulnerable portion of the pyramidal cell band comprising 48.8% of the CA1 pyramidal cells, as opposed to 72.4% in untreated controls. Extra-hippocampal damage was evident only in untreated control animals. MK-801 totally prevented neuronal necrosis in both the cerebral cortex and striatum and also prevented infarction in the neocortex and thalamus. Three conclusions emerge from the study. First, postischemic MK-801 mitigates structural brain damage in several brain regions in the absence of concomitant hypothermia. Second, neurobehavioural performance appears to be improved by MK-801 when performance trends are examined, but is somewhat less sensitive than quantitated histopathology due to compounding interanimal variation in performance abilities.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Regional neuroprotective effects of the NMDA receptor antagonist MK-801 (dizocilpine) in hypoglycemic brain damage.

Current evidence points to an important role of N-methyl-D-aspartate (NMDA) receptor activation in the pathogenesis of hypoglycemic neuronal death. MK-801 [dizocilpine maleate, (+)-5-methyl-10,11-dihydro-5H-di[a,d]cyclohepten-5,10-imine] is an anticonvulsant compound also known to be a potent noncompetitive antagonist at NMDA receptors, readily crossing the blood-brain barrier after parenteral administration. Treatment of rats with dizocilpine (1.5-5.0 mg/kg) injected intravenously during profound hypoglycemia (blood glucose levels 1.5-2.0 mM) at the stage of delta-wave (1-4 Hz) slowing of the EEG mitigated selective neuronal necrosis in the hippocampus and striatum, assessed histologically after 1-week survival. The degree of neuroprotection in the striatum and in the CA1 pyramidal cells of the hippocampus was dose dependent. Because of concern for a possible hypothermic mechanism of brain protection by MK-801, core temperature was closely monitored and was found not to decrease significantly. Since CBF is normal or increased in hypoglycemia, a fall in brain temperature during hypoglycemia is unlikely to play a role in the mechanism of the neuroprotection seen with the drug. The findings indicate that in profound hypoglycemia, intravenous administration of the NMDA antagonist dizocilpine, even after the appearance of delta-wave EEG slowing, can reduce the number of necrotic neurons in several brain regions and suggest that the neuroprotective effect of MK-801 is not related to hypothermia.

Animals↗
PubMed1990

Brain and plasma quinolinic acid in profound insulin-induced hypoglycemia.

Profound insulin-induced hypoglycemia is associated with early-onset neuronal damage that resembles excitotoxic lesions and is attenuated in severity by antagonists of N-methyl-D-aspartate receptors. Hypoglycemia increases L-tryptophan concentrations in brain and could increase the concentration of the L-tryptophan metabolite quinolinic acid (QUIN), an agonist of N-methyl-D-aspartate receptors and an excitotoxin in brain. Therefore, we investigated the effects of 40 min of profound hypoglycemia (isoelectric EEG) and 1-2 h of normoglycemic recovery on the concentrations of QUIN in brain tissue, brain extracellular fluid, and plasma in male Wistar rats. Plasma QUIN increased 6.5-fold by the time of isoelectricity (2 h after insulin administration). Regional brain QUIN concentrations increased two- to threefold during hypoglycemia and increased a further two- to threefold during recovery. However, no change in extracellular fluid QUIN concentrations in hippocampus occurred during hypoglycemia or recovery as measured using in vivo microdialysis. Therefore, the increases in brain tissue QUIN concentrations may reflect elevations of QUIN in the intracellular space or be secondary to the increases in QUIN in the vascular compartment in brain per se. L-Tryptophan concentrations increased more than twofold during recovery only. Serotonin decreased greater than 50% throughout the brain during hypoglycemia, while 5-hydroxyindoleacetic acid concentrations increased more than twofold during hypoglycemia and recovery. In striatum, dopamine was decreased 75% during hypoglycemia but returned to control values during recovery, while striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid were increased more than twofold during both hypoglycemia and recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Immediate and long-lasting effects of MK-801 on motor activity, spatial navigation in a swimming pool and EEG in the rat.

In a series of experiments, rats received the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 and measures were made of motor behavior, spatial navigation in a swimming pool, and electroencephalographic (EEG) activity. High doses (0.25-10 mg/kg IV) produced somnolence and akinesia, impaired food consumption, locomotion and swimming, and also impaired navigation to a hidden platform but complete recovery on all measures was obtained between 3 and 5 days postinjection. Lower doses (0.05-0.10 mg/kg, IV) impaired acquisition of a new place response in a swimming pool and produced hyperactivity but did not impair performance on a new cue response or on a well-learned place response. Two forms of hippocampal EEG activity, atropine-sensitive and atropine-resistant EEG were present with the low doses. The results demonstrate that a single dose of MK-801 causes changes in motor behavior and learning lasting a few days, but complete recovery occurs within 5 days of administration of even very high doses of MK-801. They further demonstrate that low doses of the drug selectively impair acquisition of new place responses. Although the general changes in behavior produced by MK-801 suggest that NMDA receptors are involved in many aspects of the control of behavior, the results additionally suggest that NMDA receptors are important for place learning.

Animals↗
PubMed1989

Sensory neuron degeneration in familial Kugelberg-Welander disease.

A 53 year old man developed symptoms of motor neuron disease in childhood. There was a family history of a similar disorder and it was felt to represent a form of Kugelberg-Welander disease. In addition to the motor deficits, sensory abnormalities in his legs were documented during life. Autopsy revealed anterior horn cell loss throughout the length of the spinal cord, with preservation of the phrenic nucleus. The lumbar dorsal root ganglia showed active degeneration of sensory neurons, with nuclear changes exceeding cytoplasmic ones. The fasciculus gracilis showed Wallerian degeneration. The findings provide direct evidence that sensory neurons can degenerate in some forms of motor neuron disease, and that the "demyelination" or "degeneration" of posterior columns sometimes seen in the various forms of motor neuron disease may actually be secondary to cell body disease in the dorsal root ganglia.

Humans↗
PubMed1989

Neuropathy with onion bulb formations and pure motor manifestations.

A thirty-eight-year-old man presented with a six year history of symptoms resembling an anterior horn cell disorder. There was progressive upper extremity wasting and weakness in the absence of sensory complaints. Electrophysiologic abnormalities were confined to motor nerve conduction and indicated a demyelinating process involving the brachial plexus and major proximal upper extremity nerve trucks bilaterally. Biopsy of the proximal right ulnar nerve revealed changes suggesting a chronic demyelinating process, and onion-bulb formations were present. Immunohistochemical staining for S-100 protein was positive in the cells comprising the onion-bulbs, indicating a Schwann cell, not a perineurial origin of these cells. After 8 years, symptoms have failed to appear in the lower limbs. Recent reports in the literature have begun to delineate the syndrome, which appears to represent an unusual, localized or multifocal, sometimes inflammatory, clinically benign neuropathy that can mimic motor neuron disease in its earlier stages. We report the first such case with underlying pathology.

Adult↗
PubMed1989

Pre- and post-ischemic administration of dizocilpine (MK-801) reduces cerebral necrosis in the rat.

The purpose of this study was to determine the effectiveness of the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine, or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801) in mitigating ischemic neuronal necrosis in the rat. Ten minutes of transient forebrain ischemia was induced by a combination of bilateral carotid clamping and hypotension to 50 mm Hg. Control animals received intravenous saline, whereas treated animals received dizocilpine, either 1 mg/kg iv 20 min. pre ischemia, 1 mg/kg iv 20 min. post ischemia, 10 mg/kg iv 20 min. post ischemia, 10 mg/kg ip 2 hrs. post ischemia, 10 mg/kg ip 24 hrs. post ischemia. The groups receiving dizocilpine before or up to 20 min. after ischemia all showed a significant reduction in the number of dead neurons as assessed by quantitative histopathology in hippocampus, caudate nucleus and cerebral cortex after one week of recovery. However, dizocilpine administered either 2 or 24 hrs. after ischemia afforded no protection. These results suggest that the potent non-competitive NMDA antagonist dizocilpine may have some value in protecting the brain from hippocampal and cortical neuronal necrosis after a short insult consisting of dense transient cerebral ischemia. Noteworthy is the fact that pharmacologic intervention in the post-ischemic period was successful in preventing neuronal death, provided that drug administration occurred within dizocilpine's "therapeutic window".

Animals↗
PubMed1989

Intraventricular infusion of 2-amino-7-phosphonoheptanoate (APH) mitigates ischaemic brain damage.

Intracerebroventricular infusion of the competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-7-phosphonoheptanoate (APH) was evaluated as a neuroprotective regimen in a rat transient cerebral ischaemia model allowing long-term recovery. Ventricular delivery of APH via an osmotic minipump was chosen to allow continuous and direct access to brain tissue of this polar molecule, and because of the potential applicability of such a regimen in clinical situations where the brain is at risk from cerebral ischaemia and a ventricular catheter is in place. The highest tolerable concentration of APH, 50 mM, was given at 1 microliter/h. Selective neuronal necrosis was significantly reduced in the cerebral cortex and the incidence of infarction in the substantia nigra pars reticulata (SNPR) was decreased. A borderline protective effect was seen in the hippocampal CA1 pyramidal neurons, and no significant protection was seen in the caudate nucleus. The results suggest a limited usefulness for APH as a cerebral protective agent.

2-Amino-5-phosphonovalerate↗
PubMed1989

Postischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats.

We investigated the ability of postischemic insulin administration to modify the structural and neurobehavioral consequences of cerebral ischemia in rats. Forebrain ischemia was induced in fed rats by combining controlled systemic hypotension with bilateral carotid artery clamping for 10 1/2 minutes. Following clamp release, one group of six rats [corrected] was given insulin (2 IU/kg s.c. b.i.d.) for 1 week. An ischemic-control group of five rats [corrected] received no postischemic treatment. A sham-ischemia group of rats was used as a behavioral control. Throughout the recovery period until sacrifice, the drinking water of all rats was supplemented with 25% glucose. Rats were trained on two water maze place navigation tasks 1-2 months after ischemia. Escape latencies and swim patterns were recorded. Performance in the insulin-treated group was better than that in the ischemic-control group (p less than 0.05) on both tasks and did not differ significantly from that of the sham-ischemia group. Improvement in behavior correlated with a significant reduction in CA1 hippocampal necrosis in the insulin-treated group (p less than 0.05). Our findings demonstrate that postischemic treatment with insulin improves neurobehavioral performance in addition to lessening ischemic neuronal necrosis.

Animals↗
PubMed1989

Neurobehavioral deficit due to ischemic brain damage limited to half of the CA1 sector of the hippocampus.

It is well known that ischemia causes neuronal necrosis in selectively vulnerable sectors of the hippocampus. Since the hippocampus is involved in spatial navigation, learning, and memory, selective deficits in these areas may arise from ischemic brain damage. The objective of this study was to test whether a minimal ischemic insult, producing selective neuronal necrosis restricted to only a portion of the CA1 pyramidal cells of the hippocampus, could produce a detectable spatial navigation deficit. Male Wistar rats received 9 min of forebrain ischemia induced by carotid clamping and hypotension or sham operation with exposure of the carotid arteries. The rats were allowed to recover and were tested on a simple place task, a place learning-set task, and a pattern discrimination task in swimming pools paradigms. Subsequently, the rats were perfusion-fixed and their entire brains subjected to quantitative histopathologic analysis. Although both ischemic and sham-operated groups learned the simple place task, the learning-set task revealed defects in spatial navigation, reflected as increased errors and latency in the performance of the ischemic rats. In the subsequent pattern discrimination task, the ischemic group was superior to the control group, which perseverated by attempting to use a place strategy to solve the discrimination. Quantitative neuropathology revealed neuronal necrosis in the ischemia group limited to 50% of the CA1 zone of the hippocampus. Extrahippocampal damage consisted of rare cortical neuronal necrosis in 2 of 6 animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The effect of postischemic blood glucose levels on ischemic brain damage in the rat.

The effect of insulin-induced hypoglycemia following 10.5 minutes of forebrain ischemia was studied in the rat. All groups received preischemic glucose loading (2 gm/kg) to promote brain infarction. Following completion of ischemia, rats received either 2 to 3 IU/kg (low-dose group) or 8 to 20 IU/kg (high-dose group) insulin. During the survival period, blood glucose concentrations were maintained in the ranges of 1.2 to 2.9 mM and 2.9 to 4.9 mM, respectively, for the low-dose and high-dose insulin groups. Control rats were given 2 gm/kg glucose immediately following ischemia. During the recovery period, until perfusion at 7 days, they were given glucose, 2 gm/kg, twice daily by intraperitoneal injection, and their drinking water was supplemented with 25% glucose. Mortality (p less than 0.05) and postischemic seizure incidence (p less than 0.01) were significantly reduced in the low-dose insulin group compared to the control group. Mortality was increased in the high-dose insulin group compared to the control group and was associated with an increased incidence of postischemic seizures. Neuropathological examination revealed no cortical infarction in the low-dose or high-dose insulin-treated rats compared to a 60% incidence of cortical infarction in the control group. In addition, the high-dose insulin-treated group showed a significant reduction in striatal and hippocampal CA1 selective neuronal necrosis compared to control rats with comparable survivals (p less than 0.05). The findings suggest that postischemic blood glucose concentrations play an important role in modulating both ischemic infarction and selective neuronal necrosis.

Animals↗
PubMed1988

Biological differences between ischemia, hypoglycemia, and epilepsy.

Ischemia, hypoglycemia, and epilepsy have long been thought to produce similar or identical brain damage. Furthermore, these insults have been assumed to be additive in their damaging effects. These notions have been based on neuropathological observations in the hippocampus and cerebral cortex, and on the tenet that energy failure (ischemia, hypoglycemia) and increased demand for energy (epilepsy) similarly give rise to selective neuronal necrosis. Recently, other bases for considering these three insults identical have grown out of observations that loss of calcium homeostasis is common to all and that an excitotoxic mechanism of selective neuronal necrosis exists in all three conditions. Fundamental differences between ischemia, hypoglycemia, and epilepsy include the underlying neurochemical changes induced, the neuronal revival times, the time course of neuronal death, the distribution of selective neuronal necrosis, and the likely excitotoxins released. Lactic acid accumulation, implicated in damage to the neuropil as well as to neuronal cell bodies, also occurs to different degrees and in different distributions in the three conditions. The degree and distribution of pannecrosis is thus also different in ischemia, hypoglycemia, and epilepsy.

Animals↗