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Biomedical subjects

L L Iversen

Publications and source records attributed to L L Iversen.

At least 55 records · Page 3Linked to original sources
PubMed1987

Senktide, a selective neurokinin B-like agonist, elicits serotonin-mediated behaviour following intracisternal administration in the mouse.

Behavioural responses to tachykinins were observed following intracisternal administration in mice. The synthetic NK-3 agonists senktide and L-363,851 caused behaviour typically associated with serotonergic stimulation, including head twitches, reciprocal forepaw treading and hindlimb splaying. Neurokinin B produced some features of the serotonin (5-HT) syndrome, while substance P, neurokinin A and eledoisin failed to elicit any such behaviours. Senktide-induced head twitches were prevented by pretreatment with the 5-HT2 antagonists ketanserin and ritanserin, while forepaw treading was attenuated by the 5-HT1 antagonists (-)-pindolol and methysergide. These data suggest that NK-3 agonists interact with central 5-HT mechanisms.

Animals↗
PubMed1987

Age and histopathologic heterogeneity in Alzheimer's disease. Evidence for subtypes.

In support of heterogeneity in Alzheimer's disease (AD), the existence of clinical and biologic subtypes has been claimed. We have investigated this claim by a statistical analysis of the relationships between the number of neurons in nucleus locus ceruleus (nLC), cortical levels of neurotransmitters, number of cortical plaques and tangles, and age. We separated AD patients into two groups: AD-1, with a less severe loss of nLC neurons; and AD-2, with a greater loss. The AD-2 cases were associated with less choline acetyltransferase activity, smaller concentrations of somatostatin and norepinephrine, and more plaques and tangles in the cerebral cortex. Although the mean age at death was less and the duration of dementia was greater in AD-2 patients than in AD-1 patients, the differences in these age-related variables were not significant. Further evidence of heterogeneity came from discriminant function analyses based on nLC neuronal counts and age at death. These findings, suggesting two subtypes of AD, suggest heterogeneity.

Age Factors↗
PubMed1987

The interaction between MK-801 and receptors for N-methyl-D-aspartate: functional consequences.

Electrophysiological studies using a cortical slice preparation revealed that MK-801 is a potent, non-competitive, antagonist of N-methyl-D-aspartate (NMDA)-induced depolarisations. Also, MK-801 was a highly selective antagonist, exhibiting a high degree of use-dependency. It completely blocked responses to NMDA and quinolinic acid but had no effect on responses produced by kainic acid or quisqualic acid. Using [3H]MK-801, high affinity binding sites for MK-801 were detected in membranes of the rat brain. The pharmacological specificity and regional distribution of binding sites for MK-801 were consistent with an action of the compound at the level of the NMDA receptor-associated ion channel. Administered parenterally, MK-801 had a remarkable neuroprotective role. It caused essentially complete protection against loss of neurones produced by injection of neurotoxic doses of NMDA or quinolinic acid into the striatum or hippocampus. Furthermore, MK-801 was highly effective in preventing loss of hippocampal neurones following bilateral occlusion of the common carotid arteries in the gerbil.

Anesthetics↗
PubMed1987

Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer disease.

Relationships were examined between neuronal degeneration in the nucleus locus ceruleus (nLC), a parameter of central noradrenergic impairment, and neocortical markers of Alzheimer disease (AD). The loss of nLC neurons was found to correlate significantly with norepinephrine concentration, choline acetyltransferase (ChAT) activity, and numbers of plaques and tangles on Brodmann area 24 (cingulate); ChAT and plaque counts in area 21 (temporal); and with ChAT activity in area 10 (frontal). In addition, nLC neuronal counts were correlated significantly with the severity and estimated duration of dementia. The number of neurofibrillary tangles in nLC, which did not correlate significantly with neocortical markers of AD, correlated with the estimated duration and severity of dementia. These data suggest that changes in central noradrenergic pathways are related to the pathophysiology of AD.

Aged↗
PubMed1986

Multiple tachykinin binding sites in peripheral tissues and in brain.

Tachykinin binding sites in guinea pig urinary bladder (GPUB), rat salivary gland (RSG), hamster urinary bladder (HUB), rat vas deferens (RVD) and rat cerebral cortex (RCC) were compared using 125I-Bolton Hunter conjugates of substance P (125I-BHSP), eledoisin (125I-BHE) and neurokinin A (125I-BHNKA). In typical SP-P tissues (GPUB, RSG) and in RCC, SP was the most potent displacer of 125I-BHSP and [Glp6,D-Pro9]-SP(6-11) was 90 times less active than [Glp6,L-Pro9]-SP(6-11) while SP methyl ester (SPOMe) was 5-10 times more active than the Bolton Hunter conjugate of SPOMe (I-BHSPOMe). On the other hand, in typical SP-E tissues (HUB, RVD), neurokinin A was most potent in displacing 125I-BHE and [Glp6,D-Pro9]-SP(6-11) was over 300 times more active than [Glp6,L-Pro9]-SP(6-11) while SPOMe was 160 times less active than I-BHSPOMe. In rat cerebral cortex, the rank order of potency of tachykinins and related analogues in displacing 125I-BHE was distinct from that of peripheral SP-E sites, with neurokinin B being the most potent displacer, and SPOMe was over 1,000 times more active than I-BHSPOMe; 125I-BHE binding sites in CNS may represent a third category of tachykinin receptor, designated SP-N.

Animals↗
PubMed1986

Calcitonin gene-related peptide: novel neuropeptide.

Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide encoded in the calcitonin gene. Its expression is dependent on tissue-specific alternative RNA processing: mRNA for CGRP predominates in the brain, whilst calcitonin (CT) mRNA predominates in thyroid C cells. The existence of this hitherto unsuspected peptide was predicted by mRNA analysis and demonstrated using antibodies raised against a synthetic peptide corresponding to the predicted C-terminal sequence of CGRP. The distribution of CGRP in the central and peripheral nervous system and its co-localization in some neurons with substance P (SP) or acetylcholine suggests several possible roles in autonomic, sensory and motor functions. Its actions appear to depend on the existence of specific CGRP receptors in target tissues, distinct from the receptors for CT but bearing some resemblance to them.

Acetylcholine↗
PubMed1986

The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist.

The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant.

Animals↗
PubMed1985

Selective extraction of small and large molecules from the cerebrospinal fluid by Purkinje neurons.

Cerebellar Purkinje neurons accumulated propidium iodide, granular blue, and horseradish peroxidase conjugated to wheat germ agglutinin but not unconjugated horseradish peroxidase, bisbenzimide, or Evans blue when these compounds were infused into the lateral cerebral ventricles of awake, unrestrained rats. Accumulation of propidium iodide by Purkinje neurons of the vermis was associated with a reproducible behavioral abnormality characterized by truncal tremor, ataxia, and nystagmus. Both the accumulation of propidium iodide in Purkinje cells and the behavioral abnormality were prevented by prior intracerebroventricular administration of ouabain or colchicine, drugs that block neuronal transport processes. The ability of cerebellar Purkinje neurons to extract small and large molecules from the cerebrospinal fluid has important implications for their physiology and pathology.

Animals↗
PubMed1985

Modulation of [3H]diazepam binding in rat cortical membranes by GABAA agonists.

GABAA receptor agonists modulate [3H]diazepam binding in rat cortical membranes with different efficacies. At 23 degrees C, the relative potencies for enhancement of [3H]diazepam binding by agonists parallel their potencies in inhibiting [3H]gamma-aminobutyric acid [( 3H]GABA) binding. The agonist concentrations needed for enhancement of [3H]diazepam binding are up to 35 times higher than for [3H]GABA binding and correspond closely to the concentrations required for displacement of [3H]bicuculline methochloride (BMC) binding. The maximum enhancement of [3H]diazepam varied among agonists: muscimol = GABA greater than isoguvacine greater than 3-aminopropane sulphonic acid (3APS) = imidazoleacetic acid (IAA) greater than 4,5,6,7-tetrahydroisoxazolo (4,5,6)-pyridin-3-ol (THIP) = taurine greater than piperidine 4-sulphonic acid (P4S). At 37 degrees C, the potencies of agonists remained unchanged, but isoguvacine, 3 APS, and THIP acquired efficacies similar to GABA, whereas IAA, taurine, and P4S maintained their partial agonist profiles. At both temperatures the agonist-induced enhancement of [3H]diazepam binding was reversible by bicuculline methobromide and by the steroid GABA antagonist RU 5135. These results stress the importance of studying receptor-receptor interaction under near-physiological conditions and offer an in vitro assay that may predict the agonist status of putative GABA receptor ligands.

Androstanes↗
PubMed1984

The Ferrier Lecture, 1983. Amino acids and peptides: fast and slow chemical signals in the nervous system?

The classical monoamine neurotransmitters, acetylcholine and the catecholamines, are used by only a small proportion of synapses in mammalian c.n.s. The amino acids GABA (gamma-aminobutyric acid) and L-glutamate may be the principal inhibitory and excitatory neurotransmitters used for fast point-to-point transmission in the c.n.s. The monoamines and the large number of neuropeptides (over 30) now known to exist in c.n.s. may be chemical signals used for a different type of chemically addressed form of information transmission between neurons in c.n.s. characterized by less precise spatial connections, a slower time course and a far richer diversity of chemical signals than used in classical synaptic neurotransmission. In this context the brain can be viewed as a neuroendocrine secretory organ of great complexity.

Amines↗
PubMed1984

Neurochemical characteristics of early and late onset types of Alzheimer's disease.

Brains of 49 patients who had died with Alzheimer's disease and 54 controls were examined. The Alzheimer group exhibited noticeably reduced activity of the cholinergic marker enzyme choline acetyltransferase in the cerebral cortex, but cortical concentrations of noradrenaline, gamma-aminobutyric acid, and somatostatin were also significantly reduced. Analysis of the results according to age at death showed that the older patients, dying in their 9th and 10th decades, had a relatively pure cholinergic deficit confined to temporal lobe and hippocampus, together with a reduced concentration of somatostatin confined to temporal cortex. By contrast, the younger patients, dying in their 7th and 8th decades, had a widespread and severe cholinergic deficit together with the abnormalities of noradrenaline, gamma-aminobutyric acid, and somatostatin, and the younger patients accounted for most of the abnormalities in these systems observed in the overall group. Comparison of the young subjects with Alzheimer's disease with the older controls did not support the concept of Alzheimer's disease representing an acceleration of the aging process. These results suggest that Alzheimer's disease in people aged under 80 may represent a distinct form of presenile dementia which differs in important respects from the dementia of old age.

Age Factors↗
PubMed1984

Reduced binding of [3H]ketanserin to cortical 5-ht2 receptors in senile dementia of the Alzheimer type.

Using [3H]ketanserin, a specific ligand for the 5-HT2 receptor, the amount of specific binding was measured in preparations of post-mortem frontal cortex from subjects diagnosed as suffering from dementia. A highly significant 42% loss of binding was observed which reflected a decrease in receptor density compared to psychiatrically normal controls. This was found to be independent of age in the demented patients and thus unlikely to be related to the cholinergic deficit. Measurement of 5-HT and its metabolite 5-HIAA indicated a smaller, non-significant decrease in presynaptic 5-HT function.

Age Factors↗