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PubMed1993

Autoradiographic distribution of binding sites for the non-NMDA receptor antagonist [3H]CNQX in human motor cortex, brainstem and spinal cord.

The distribution of non-NMDA receptors in the normal human motor cortex, brainstem and spinal cord has been investigated using [3H]CNQX. In the motor and premotor cortex, specific [3H]CNQX binding was present in all cortical laminae with the highest density of binding sites in laminae I, II and the upper part of III. In the normal brainstem, non-NMDA receptors labelled by [3H]CNQX had a heterogeneous distribution. Brainstem motor nuclei subserving eye movements, which tend to be spared in motor neuron disease (MND), had a higher density of [3H]CNQX binding sites compared to other cranial nerve motor nuclei (VII, X, XII) which tend to be affected. Specific [3H]CNQX binding was present throughout the spinal grey matter, the greatest density of binding being found in the substantia gelatinosa. Excitotoxicity at non-NMDA receptors has been implicated in chronic neurodegenerative diseases such as motor neuron disease. This study suggests that the density of non-NMDA receptors, labelled by [3H]CNQX, does not account for selective vulnerability of motor neurons in this disorder.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1995

The role of L-type voltage dependent calcium channels in stimulated [3H]norepinephrine release from canine hippocampal slices following global cerebral ischemia and reperfusion.

The hippocampus is among those brain regions which are selectively vulnerable to ischemic damage. Hippocampal damage due to transient cerebral ischemia is mainly of the delayed, non-necrotic type which may arise after disruption or activation of specific cellular systems, including transmitter release through excitatory amino acid receptors. We investigated the contribution of L-type voltage dependent calcium channels (VDCCs) to glycine (GLY) potentiated N-methyl-D-aspartate (NMDA) receptor- and potassium-stimulated [3H]norepinephrine (NE) release in a canine model of global cerebral ischemia and reperfusion. Tissue was collected from four experimental groups: non-arrested controls (NA), global cerebral ischemia induced by 10 minute cardiac arrest (CA), and CA followed by 30 min or 24 hours reperfusion after restoration of spontaneous circulation. Brain slices prepared from all groups accumulated approximately equivalent amounts of [3H]NE. The sensitivity of [3H]NE release to stimulation by NMDA/GLY or elevated potassium was unchanged after ischemia and reperfusion. About 30% of release stimulated by the addition of 20 mM potassium was inhibited by the NMDA receptor-operated channel antagonist MK801 in all groups except CA in which only 4% of release was inhibited by MK801. The ability of 1 microM nitrendipine (NTP) to block stimulated release indicated that the contribution of the L-type VDCC to potassium or NMDA/GLY-stimulated release was significant only in NA and 24 hour reperfused animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Effects of excitatory amino acid lesions upon neurokinin B and acetylcholine neurons in the nucleus basalis of the rat.

The nucleus basalis magnocellularis (NBM) contains cholinergic neurons that project to the neocortex and is densely innervated by excitatory amino acid-containing terminals. A dysfunction in the balance of excitatory inputs or an alteration in the sensitivity of NBM cells to glutamate may underlie the selective vulnerability to aging. Some large NBM neurons contain neurokinin B (NKB) mRNA. The present study investigated whether alpha-2-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) differentially destroy NKB-containing, NKB-receptive, or cholinergic NBM cells, and whether this vulnerability is altered by aging. Injections of AMPA or NMDA significantly decreased neocortical ChAT activity, as compared to control levels, across all three age groups, with no interaction between lesion and age group. The results of in situ hybridization histochemistry and NKB receptor studies suggest that NKB-containing neurons in the NBM, and the neurons they innervate, are not vulnerable to NMDA or AMPA in either young or old rats. While NKB mRNA-positive cells were diffusely distributed throughout the basal forebrain, only a small proportion of the large NBM cells contained NKB mRNA. The results suggest that NKB does not extensively colocalize with acetylcholine within the basal forebrain of rats and that NBM NKB neurons do not directly innervate cholinergic cells.

Acetylcholine↗

PubMed1987

Desensitization of PGE2 and PGI2 induced contractions in different smooth muscles of guinea-pig unmasking relaxing properties of prostanoids.

Prostaglandin E2 (PGE2) and 16,16-dimethyl PGE2 (16,16-dm PGE2) caused contraction of guinea-pig taenia caeci, contraction and at higher concentrations relaxation of trachea and relaxation of ureter smooth muscle. The prostacyclin derivative iloprost induced contraction of taenia caecum, while it was inactive in the other preparations. After pretreatment of the smooth muscles with 16,16-dm PGE2, stimulation of the PGE2 receptors in taenia caeci and trachea and of PGI2 receptors in taenia caeci caused relaxation. The results indicate that the prostanoid receptor mediating contraction is selectively vulnerable for desensitization in contrast with the receptor mediating smooth muscle relaxation.

16,16-Dimethylprostaglandin E2↗

PubMed1993

MK-801 is neuroprotective but does not improve survival in severe forebrain ischemia.

The effects of MK-801 on postischemic recovery, survival and neuronal preservation in the cortex, hippocampus and striatum were studied in Mongolian gerbils. The drug was administered 30 min prior to 20 of min forebrain ischemia induced by bilateral ligation of the carotids. Neurological recovery and survival were monitored for 7 days. At the end of the monitoring period neuronal damage was analyzed in the brains of the survivors in both groups. Treatment with MK-801 did not improve either neurological recovery or end-point survival. However, significant (P < 0.01) neuronal protection was observed in the hippocampi and striata of the drug treated animals while cortical neurons were not significantly protected. These findings demonstrate that protection against ischemic neuronal damage can be observed without concomitant improvement in either postischemic neurological recovery or survival. Protection of selectively vulnerable brain regions, often used as the predictor of the therapeutic potential of an agent, does not appear to correlate well with postischemic survival in this animal model of ischemia.

Animals↗

PubMed1992

Density and distribution of excitatory amino acid receptors in the developing human fetal brain: a quantitative autoradiographic study.

The binding of [alpha-3H]amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to quisqualate receptors, [3H]kainate (KA) to KA receptors, and L-[3H]glutamate to N-methyl-D-aspartate (NMDA) receptors was determined by quantitative autoradiography in brains obtained from twelve aborted human fetuses ranging from 16.5 to 26 weeks of gestational age. Among the three receptor subtypes, specific binding to AMPA was the highest, followed by NMDA and KA, respectively, in all age groups. Receptor binding was already apparent by 16.5 weeks in the hippocampus, thalamus, and subthalamic nucleus, rose sharply by 20-21.5 weeks, and subsequently declined to their lowest levels by 24-26 weeks. Anatomically distinct binding patterns for each of the three major excitatory amino acid (EAA) receptor subtypes were well established by 20-21.5 weeks. Within the hippocampus, AMPA was localized primarily in the stratum pyramidale, NMDA in the stratum radiatum, and KA in the molecular layer of the dentate gyrus and in the stratum lucidum of the CA3 region. The cerebral cortex showed dense labeling of AMPA in the outer layers, whereas KA binding was more prominent within the inner layers. The putamen and globus pallidus also showed relatively dense receptor binding in all age groups. The sharp rise in receptor density at 20-21.5 weeks of age suggests involvement of EAA pathways in developmental plasticity, including reorganization of neuronal processes or synapses, during this period of development. Developmental changes in the density and distribution of EAA receptors, as shown in this study, may also provide insight into shifts in the localization of age-dependent selective vulnerability within the developing human fetal brain.

Autoradiography↗

PubMed1995

Specific lesions in the extrapyramidal system of the rat brain induced by 3-nitropropionic acid (3-NPA).

The irreversible mitochondrial toxin 3-nitropropionic acid (3-NPA) is a specific inhibitor of succinate dehydrogenase. We performed stereotaxic unilateral injections of 3-NPA into the nigrostriatal dopaminergic pathway in rats in order to examine its specific effects on the dopamine system. The 3-NPA-treated rats displayed unidirectional apomorphineinduced rotations, suggesting that 3-NPA selectively damages dopaminergic neurons when injected into the nigrostriatal pathway. In situ hybridization 7 weeks postinjection indicated a decrease in tyrosine hydroxylase (TH) mRNA to 30% of the noninjected side in the substantia nigra pars compacta (P < 0.05) and decreased to 62% of the noninjected side in the ventral tegmental area (VTA) (nonsignificant) of 3-NPA-lesioned rats. The number of TH mRNA positive cells showed statistically significant decreases in substantia nigra and VTA (P < 0.001) within the lesioned side. In contrast, expression of mRNAs encoding choline acetyltransferase, p75 low-affinity NGF receptor, neurotrophin tyrosine kinase receptors Trk and TrkB, and brain-derived neurotrophic factor showed neuronal sparing in several other regions of the brain. The results suggest that the nigrostriatal dopaminergic system might be selectively vulnerable to 3-NPA and demonstrate that it is possible to employ 3-NPA in a model of partial lesion of the nigrostriatal dopaminergic system resembling early stages of Parkinson's disease.

Animals↗

PubMed1985

Modification of focal cerebral ischemia by cardiac output augmentation.

Intravascular volume expansion has been employed successfully for treatment of ischemic stroke from cerebral vasospasm and from cerebrovascular occlusive disease. The physiologic mechanism responsible for this success has not previously been delineated in controlled experimentation. The objective of this investigation was to delineate the effects of cardiac output and of hemodilution in a primate model of focal cerebral ischemia. Two groups of anesthetized rhesus monkeys received extensive cardiovascular monitoring, and local cerebral blood flow (lCBF) was determined in both ischemic and nonischemic brain regions by the hydrogen clearance method. Both groups were subjected to unilateral middle cerebral artery occlusion. One group then underwent blood volume expansion with Dextran 40 (cardiac output augmentation), and one group underwent isovolemic hemodilution with Dextran 40, cardiac output being maintained constant. Significant increases in lCBF occurred in ischemic regions only and occurred only in response to augmentation of cardiac output. Isovolemic hemodilution failed to produce any changes in lCBF. This investigation indicates that ischemic brain regions are selectively vulnerable to alterations in cardiac output, these effects being independent of alterations in blood pressure. Blood viscosity changes may play only a minor role. This study strongly suggests an important role of intravascular volume expansion and cardiac output augmentation in treatment of acute ischemic stroke.

Animals↗

PubMed1983

The distribution of herpes simplex type 1 antigen in mouse central nervous system after different routes of inoculation.

Herpes simplex type 1 virus was inoculated into 3-week-old mice via four different routes; intracerebral, intravenous, intranasal and directly into the sciatic nerve. Virus antigen-containing cells in the central nervous system were identified by both an immunofluorescence and immunoperoxidase method. The portal of entry of virus into the CNS appeared to be the major determinant of distribution of virus antigen. Direct haematogenous seeding of virus into the CNS was not proven. It seems probable that infection was first established in sensory ganglia. Within the CNS, regions of high virus antigen concentration paralleled high cell density suggesting cell to cell spread. Consistent involvement of certain neuron groups may be due to their selective vulnerability. These animal experiments provide some explanation for the patterns of CNS herpetic infection observed in man.

Animals↗

PubMed1987

Contrasting patterns of virus spread and neuropathology following microinjection of herpes simplex virus into the hippocampus or cerebellum of mice.

Two strains of herpes simplex virus type 1 (HSV) were microinjected into either the hippocampus or cerebellum of two different mouse strains. Immunoperoxidase staining revealed rapid and extensive spread of virus within the hippocampus and certain of its afferent connections. In contrast, only scattered peroxidase positive cells were observed following cerebellar inoculation. Extensive lesions were observed only in animals surviving intrahippocampal inoculations. These results suggest that localization of the pathological process in HSV encephalitis is due in part to a selective vulnerability of telencephalic or limbic structures.

Animals↗

PubMed1994

The role of intracellular free calcium in motor neuron disease.

The intracellular calcium (Ca2+) concentrations of motoneurons can be altered by the influx of Ca2+ into the cell by the opening of voltage-dependent Ca2+ channels and ligand-gated channels linked to Ca2+ influx, especially by the N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor. Intracellular Ca2+ concentration is also affected by the release of Ca2+ buffered in mitochondria and endoplasmic reticulum. Evidence that motoneurons may be selectively vulnerable to Ca(2+)-induced cell death include the following observations: (i) the presence of excitatory amino acid receptors on the cell membranes of motoneurons, some of which would permit Ca2+ influx (e.g. NMDA receptors); (ii) the availability of the presynaptic terminal for antibody-mediated effects leading to changes in cell permeability and Ca2+ influx; and (iii) the limited amounts of intracellular Ca(2+)-binding proteins such as calbindin D28K and parvalbumin in motoneurons. Elevation of intracellular free Ca2+ may also be a common event in a number of independent mechanisms leading to motoneuron death in motor neuron disease.

Animals↗

PubMed1995

A positron emission tomography study of frontal lobe function (verbal fluency) in amyotrophic lateral sclerosis.

Positron emission tomography (PET) was used to investigate the location of cerebral cortical and subcortical abnormalities in non-demented patients with amyotrophic lateral sclerosis (ALS). Involvement of the frontal lobes was investigated with a task of executive frontal lobe function (verbal fluency/word generation), using a PET activation paradigm. Two groups of ALS patients defined by the presence or absence of cognitive impairment were tested. ALS patients who had cognitive impairments showed a region of cortical and subcortical dysfunction which extended across a wide area of the frontal lobes, and included the insular cortex and thalamic nuclear complex. These findings support the notion that extra-motor involvement is relatively common in ALS and broadens concepts of selective vulnerability in ALS.

Amyotrophic Lateral Sclerosis↗

PubMed1992

Recombinant human superoxide dismutase can attenuate ischemic neuronal damage in gerbils.

The effects of recombinant human superoxide dismutase (r-hSOD) on ischemic neuronal injury were examined. Cerebral ischemia was produced in Mongolian gerbils by occluding bilateral common carotid arteries for 5 min. Preischemic treatment with r-hSOD clearly reduced hippocampal neuronal damages while postischemic treatment did not. This result suggests that oxygen free radicals play an important role in selective vulnerability to ischemia and r-hSOD has a potential clinical usefulness against cerebral ischemia.

Analysis of Variance↗

PubMed1987

Primary afferent terminal function following acrylamide: alterations in the dorsal root potential and reflex.

The dorsal root potential (DRP) and the dorsal root reflex (DRR) were studied in acrylamide (ACR)-induced axonopathy to determine the nature and extent of primary afferent terminal (PAT) dysfunction. Cats were administered 30 mg/kg/day ACR for either 5 (ACR 5D) or 10 (ACR 10D) days. The day after the last injection, the spinal cord as isolated in situ and the DRP and DRR were elicited. It was found that only 21% of the ACR 10D animals exhibited a DRP. Furthermore, in that 21%, the DRP appeared to degrade over distance differently from the control group. There was no change in the DRP evoked in the ACR 5D group. ACR affected the DRR when evoked from the cutaneous sural nerve (SU) to a greater extent than when evoked from the medial gastrocnemius (MG) nerve. A SU-evoked DRR could not be elicited in any of the animals in the ACR 10D group and in only 20% of the ACR 5D group. There was no difference in the ability to elicit a MG-evoked DDR in either ACR-treated group when compared to control. However, the maximum-evoked area under the DRR elicited from the MG nerve was significantly smaller in the ACR-treated groups than in control. These data show that ACR does indeed impair PAT function. ACR preferentially affects the PAT processing of the SU when compared to the MG nerve, which may indicate that the selective vulnerability of the largest diameter fibers to ACR is not necessarily true.

Acrylamide↗

PubMed1990

Organometal-induced increases in oxygen reactive species: the potential of 2',7'-dichlorofluorescin diacetate as an index of neurotoxic damage.

The effects of the neurotoxic metals methylmercury (MeHg) and trimethyltin (TMT) on oxygen reactive species formation within a crude synaptosomal fraction (P2), using the probe 2',7'-dichlorofluorescin diacetate (DCFH-DA), and intracellular calcium ([Ca2+]i), with the fluorescent indicator fluo-3, have been investigated. Two and seven days after a single injection of MeHg (1 mg/kg) the formation rate of cerebellar oxygen reactive species was significantly increased. Hippocampal and frontocortical oxygen reactive species were elevated 2 days after TMT injection (3 mg/kg). In vitro exposure to MeHg (10-20 microM) increased the formation rate of oxygen reactive species, while TMT (5-40 microM) was without effect. Levels of [Ca2+]i were unaltered in P2 fractions from cerebellum and hippocampus of animals treated with either organometal. The data demonstrate that oxygen reactive species are elevated in brain regions, cerebellum (MeHg) and hippocampus (TMT), believed to be selectively vulnerable to these toxic agents. Findings suggest that oxidative damage may be a mechanism underlying the toxicity of both organometals. The use of DCFH-DA may have potential in the nervous system as an indicator of neurotoxic damage.

Animals↗

PubMed1992

Lifelong ethanol consumption enhances the age-related changes in rat sympathetic neurons.

The effects of aging and chronic ethanol administration on the histochemical and morphometric features of rat superior cervical ganglion were studied in a rat strain selected for voluntary alcohol consumption. Ethanol was administered to the experimental group ad libitum (10% v/v in drinking water) from 3 months to 28 months of age, the average ethanol intake being 6.4-5.4 g/kg per day. The sympathetic neurons of the ethanol consuming rats showed several signs of enhanced degeneration, e.g. decreased neuronal packing density, increased amount of age-pigment and decreased intensity of catecholamine histofluorescence and tyrosine hydroxylase immunoreactivity. The results may indicate a selective vulnerability of peripheral sympathetic neurons rather than a universal accelerated aging due to chronic ethanol exposure.

Aging↗

PubMed1987

Comprehension in aphasia: a cross-linguistic study.

Broca's aphasics and normal controls were tested to determine relative sparing and impairment of word order, grammatical morphology, and semantic information in a sentence interpretation task. Patients were native speakers of English, German, or Italian, languages that vary drastically in the "cue validity" or information value of these three sources of information. Word order was selectively spared while grammatical morphology was selectively impaired in all three languages. Nevertheless, language-specific patterns of sentence interpretation remained in Broca's aphasics, even within the impaired morphological component, supporting an interpretation in terms of "accessing" rather than a "loss." Testing with Wernicke's aphasics, anomics, and some additional age-matched controls suggested that the selective vulnerability of morphology is not specific to agrammatic patients, at least in this paradigm.

Adolescent↗

PubMed1991

Sentence comprehension in aphasia in two clear case-marking languages.

Studies of aphasia in Indo-European languages point to a selective vulnerability of morphological case marking in sentence comprehension. However, in case-marking languages such as German and Serbo-Croatian, the use of case marking to express formal grammatical gender diminishes the clarity of grammatical role marking. In Hungarian and Turkish, there are simple and reliable markings for the direct object. These markings are not linked to grammatical gender. Compared to Hungarian, the Turkish accusative marking is somewhat lower in availability, but somewhat higher in detectability. The processing of these cues by aphasics was tested using the design of MacWhinney, Pléh, and Bates (1985. Cognitive Psychology, 17, 178-209). Simple sentences with two nouns and one transitive verb were read to Broca's and Wernicke's aphasics, anomics, and control subjects in both Turkey and Hungary. The main effect of case marking was extremely strong. However, this was not true for all groups. The aphasics used the case cue far less than the normals, with the Hungarian Wernicke's group showing the greatest loss. Word order variations were largely ignored in all groups whenever the case-marking cue was present. When case marking was absent, Turkish subjects had a clear SOV interpretation for NNV sentences and Hungarians had a clear SVO interpretation for NVN sentences, in accord with basic patterns in their languages. When there was a contrast between the animacy of the two nouns, subjects choose the animate nouns significantly more often. The effect of animacy was particularly strong in Turkish, in accord with basic facts of Turkish grammar. In Hungarian, VNN sentences without case marking were interpreted as VOS when the first noun was inanimate. In Turkish, VNN sentences without case marking were often interpreted as VSO. In general, the aphasic subjects showed a clear preservation of virtually all aspects of their native languages, albeit in a much noisier form. Despite the high reliability of the case-marking cue, it was damaged more than the word order cue in English subjects. The near-chance processing of the case cue by the Wernicke's aphasics in Hungarian can probably be attributed to the relatively greater difficulty involved in detecting the Hungarian accusative suffix.

Anomia↗