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PubMed1986

Rapid down regulation of hippocampal adenosine receptors following brief anoxia.

Adenosine A1 receptors, as demonstrated by [3H]cyclohexyladenosine (CHA) binding to cryostat sections of the brain, were studied utilizing quantitative autoradiographic techniques. A brief period of global CNS anoxia resulted in the rapid and persistent down regulation of [3H]CHA binding sites in the hippocampus but not in the neocortex or striatum. The density of adenosine A1 receptors in a given brain region has previously been shown to be a critical factor in determining the strength of the inhibitory action of adenosine. Since the down regulation of these sites is correlated temporally with the onset of hyperactivity following transient anoxia, it is suggested that a reduction in the strength of the neuromodulatory action of adenosine contributes to the postanoxic hyperactivity of CA1 pyramidal cells and perhaps to their selective vulnerability.

Adenosine↗

PubMed1988

MPTP produces a pattern of nigrostriatal degeneration which coincides with the mosaic organization of the caudate nucleus.

In the normal dog we have found that cholinesterase and tyrosine hydroxylase (TH) histochemistry define a mosaic structure of the caudate nucleus that is similar to that described in other species. To determine if nigrostriatal afferents interlocked with this mosaic we injected dogs with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin specific to dopaminergic nigrostriatal cells. Alternate sections in the caudate nucleus stained for acetylcholinesterase, TH, and terminal degeneration revealed that the areas of densest degeneration were localized to the matrix, thereby outlining areas of much lighter degeneration which were coincident with the patches. This pattern of terminal degeneration suggests the existence of subcomponents of the dopaminergic nigrostriatal pathway, at least one of which might be selectively vulnerable to MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1988

Depth profile of local oxygen tension and blood flow in rat cerebral cortex, white matter and hippocampus.

Microregional oxygenation and blood flow were measured in rat cerebral cortical lamina, subcortical white matter and hippocampus. This was done to examine relationships between oxygenation and blood flow at a local level, to determine effects of craniotomy, and to consider whether flow/oxygenation relationships might be predictive of selective vulnerability known to accompany anoxia or ischemia. Blood flow and oxygen tension were measured with closely apposed polarographic microelectrodes. Oxygen tension was highest in white matter, lower in the region of cortical laminae IV-V and lowest in the hippocampus. Blood flow in the hippocampus was higher than that in white matter or laminae IV-V of cerebral cortex. Ratios of blood flow to oxygenation were similar throughout the cortex, higher in white matter but oxygenation in hippocampus was significantly less than expected from measurement of hippocampal blood flow reflecting increased oxygen consumption or relative hypoxia due to increased diffusion distances for oxygen in hippocampus. Comparison of data from closed vs opened skull animals indicated that diffusion of oxygen and hydrogen influenced data to approximately 1000 micron below the cerebral surface.

Animals↗

PubMed1989

Ischemia triggers NMDA receptor-linked cytoskeletal proteolysis in hippocampus.

Transient forebrain ischemia is followed within minutes by accelerated proteolysis of the cytoskeletal protein, spectrin. This effect is most pronounced in the selectively vulnerable CA1 region of hippocampus which also experiences a second proteolytic phase during the terminal stages of neuronal degeneration. Both proteolytic phases are suppressed by MK-801, an NMDA receptor antagonist. Cytoskeletal disruption, via NMDA receptor-linked proteolytic events, is suggested to predispose vulnerable neurons to delayed cell death.

Animals↗

PubMed1989

Neuronal damage following repeated brief ischemia in the gerbil.

The effect of repetition of brief ischemia, which causes no morphological brain damage when given as a single insult, was studied. Two-minute forebrain ischemia was induced in gerbils singly and 3 or 5 times at 60-min intervals. Although 2-min ischemia induced no neuronal damage, 3 or 5 repeated ischemic insults caused neuronal damage in the selectively vulnerable regions, the severity being dependent on the number of episodes.

Animals↗

PubMed1990

Excitatory amino acid receptor subtype binding following traumatic brain injury.

Sprague-Dawley rats were subjected to a moderate level (2.2 atm) of traumatic brain injury (TBI) using fluid percussion. Injured animals were allowed post-trauma survival periods of 5 min, 3 and 24 h. Regional glutamate receptor subtype binding was assessed with quantitative autoradiography in each group for N-methyl-D-aspartate (NMDA), quisqualate and kainate receptor subpopulations at approximately the -3.8 bregma level and compared to a sham control group. [3H]glutamate binding to the NMDA receptor was significantly (P less than 0.05) decreased at 3 h post-TBI in the hippocampal CA1 stratum radiatum, the molecular layers of the dentate gyri and the outer (layers 1-3) and inner (layers 5 and 6) overlying neocortex. NMDA receptor binding was significantly reduced in layers 5 and 6 of the neocortex at all post-trauma survival times but no further differences were seen in the hippocampi. No significant changes were observed with [3H]AMPA binding to quisqualate receptors and [3H]KA binding was significantly reduced only in layers 5 and 6 of the neocortex at 24 h after TBI. These data further confirm the pathological involvement of the NMDA receptor complex in brain regions selectively vulnerable to moderate levels of TBI in this model.

Animals↗

PubMed1990

Brain ischemia alters the density of binding sites for glibenclamide, a specific blocker of ATP-sensitive K+ channels.

Transient ischemia in normoglycemic animals leads to delayed neuronal damage which is confined to selectively vulnerable regions. In at least one of these, the CA1 sector of the hippocampus, cell death is preceded by neuronal hyperactivity, presumed to be caused by loss of inhibitory control. Hyperglycemic subjects develop postischemic seizures, and show enhanced damage. The ATP-sensitive K+ channel, which may be important in inhibitory control, is the target of antidiabetic sulfonylureas. We determined densities of sulfonylurea binding sites in rat brain after forebrain ischemia. Normoglycemic animals showed a decrease of glibenclamide receptor binding in the CA3 field, hilus and dentate gyrus of the hippocampus after 1 day of recovery. After 4 days of recovery, levels of sulfonylurea binding sites decreased mainly in the CA1 field and in the hilus, as well as in the substantia nigra. After 1 day of recovery, hyperglycemic animals did not show any significant variations of densities of sites compared to control animals. It is proposed that reduction of inhibitory control by ATP-sensitive K+ channels may be associated with delayed neuronal death.

Adenosine Triphosphate↗

PubMed1990

Postischemic glucose utilization in rat hippocampal layers.

The influence on hippocampal glucose utilization was determined in male Wistar rats 7 days after a 10-min forebrain ischemia. Ischemia was induced by clamping of the carotid arteries and lowering blood pressure to 40 mm Hg. Despite severe neuronal damage as assessed by histological techniques, local cerebral glucose utilization (LCGU) was significantly increased in the pyramidal and radiatum layer of the CA1 sector, while in layers of the CA2, CA3 and CA4 sector and dentate gyrus. LCGU was reduced compared to non-ischemic controls. The increases in LCGU are suggested to reflect long-lasting hyperexcitation in the selectively vulnerable CA1 sector, implicating a correlation between cellular hypermetabolism and neuronal damage.

Animals↗

PubMed1990

Protective effect of adenosine and a novel xanthine derivative propentofylline on the cell damage after bilateral carotid occlusion in the gerbil hippocampus.

The role of adenosine in the development of ischemia induced pathological changes has been examined in Mongolian gerbils. A dramatic increase in the concentrations of adenosine, inosine and hypoxanthine was detected by microdialysis in the dorsal part of hippocampus and in the striatum immediately after 5 min bilateral occlusion of the carotid arteries. From a resting value of about 0.5 microM the concentration of adenosine increased to more than 10 microM. The adenosine levels became normalized within 30 min after ischemia. Inosine and hypoxanthine levels were higher and they increased and also returned towards control somewhat later than adenosine. A second occlusion resulted in a similar but somewhat smaller increase in purine levels. Carotid occlusion for up to 12 min had no major, lasting effect on the binding to adenosine A1-receptors in the CA-regions of the hippocampus, as determined by autoradiography. Neuronal and vascular changes (degeneration of neurons, mitochondrial destruction and ribosomal disaggregation, astroglial oedema) due to ischemia (3-12 min, followed by 48 h recirculation) was studied with light and electron microscopy in the selectively vulnerable CA1 area of hippocampus. In one series of experiments the adenosine antagonist theophylline (20 mg/kg i.p.), given 15 min prior to a 5 min occlusion, significantly enhanced the ischemia induced changes. In another experiment the adenosine uptake inhibitor propentofylline (HWA 285, 10 mg/kg), injected 15 min before a 12 min carotid occlusion, reduced the neuronal (90%) and astroglial changes (84%) due to ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1990

The quantification of brain lesions with an omega 3 site ligand: a critical analysis of animal models of cerebral ischaemia and neurodegeneration.

Previous investigations have indicated that the detection and quantification of omega 3 (peripheral type benzodiazepine) binding site densities that are associated with reactive astroglia and macrophages could be of widespread applicability in the localization and indirect assessment of neural tissue damage in the central nervous system. In the present study, we analyze the usefulness of this approach in a number of experimental models that are characterized by (or putatively involve) neuronal degeneration. One week after the systemic administration of the excitotoxin, kainate, a marked increase in omega 3 site densities (as assessed by [3H]PK 11195 binding) was noted, an increase that was most prominent in known regions of selective vulnerability (hippocampus and septum). However, the kainate-induced omega 3 site proliferation was not a function of the dose administered, a marked interstudy variation was observed, and the binding increase was prevented by the administration of the anticonvulsant, clonazepam. The densities of omega 3 sites were studied, by autoradiography (using [3H]PK 11195 or [3H]PK 14105 as ligands), in 4 groups of Fischer 344 rats aged 3, 12, 22 and 30 months. No age-related changes were noted except in the 30-month-old group in which discrete and focal increases (reflecting tumoral processes) were observed in various brain regions. In spontaneously hypertensive, stroke-prone rats, omega 3 binding increases were observed concomitant with the development of stroke-related neurological signs. With autoradiography, the omega 3 site increase was localized to focal increases in the boundary zones between major cerebral arteries (and corresponding to regions of ischaemic or haemorrhagic infarction). Focal cerebral ischaemia was studied in rats and mice. Subsequent to middle cerebral artery occlusion in normotensive (Wistar/Kyoto) and spontaneously hypertensive rats, the density of omega 3 sites in the ipsilateral hemisphere was markedly elevated, the increase being greater in the spontaneously hypertensive rats. The increases in omega 3 labelling in these two strains matched the absolute volumes of infarctions, determined previously. Middle cerebral artery occlusion in the mouse also increased hemispheric levels of omega 3 sites; the maximum values were obtained between 4 and 8 days following the induction of focal ischaemia. These results demonstrate the feasibility of using omega 3 sites as a marker of excitotoxic, ischaemic and proliferative damage in the rodent brain. Binding measurement in tissue homogenates is an economic and time-efficient approach, whereas the autoradiographic detection of omega 3 sites allows the localization of brain lesions with a macroscopic or microscopic level of anatomical resolution.(ABSTRACT TRUNCATED AT 400 WORDS)

Affinity Labels↗

PubMed1991

Transient ischemia attenuates neuronal afterdischarges induced in the absence of synaptic transmission.

In vitro hippocampal slices were prepared from animals previously subjected to a 10-min period of transient forebrain ischemia. Electrophysiological responses were examined in the selectively vulnerable CA1 region in the presence of standard (2.0 mM) and reduced (0.2 mM) calcium concentrations. Synaptic responses evoked by orthodromic stimulation in standard calcium were intact following ischemia. In contrast, repetitive neuronal discharges, which are normally evoked by antidromic stimulation in the presence of low calcium concentrations, were attenuated or eliminated following ischemia. The possible contributions of presynaptic and postsynaptic mechanisms to post-ischemic hyperexcitability are discussed.

Animals↗

PubMed1991

The quantitative autoradiographic distribution of [3H]MK-801 binding sites in the normal human spinal cord.

The distribution of NMDA receptors in the normal human spinal cord has been investigated using the non-competitive channel blocking agent MK-801. Specific [3H]MK-801 binding was present throughout the spinal grey matter at all segmental levels, the greatest density of binding being found in the substantia gelatinosa. Focal areas of high binding were also found in a distribution corresponding to lower motor neurones in the ventral horns. This study provides anatomical evidence that NMDA receptors are likely to be important in motor as well as sensory spinal synaptic transmission. The anatomical distribution of NMDA receptors in relation to motor neurone somata may have important implications in selective vulnerability to excitotoxic injury.

Aged↗

PubMed1992

Reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) profiles in the amygdala of human and New World monkey (Saimiri sciureus).

The topographic distribution of nicotinamide adenine dinucleotide-diaphorase (NADPH-d) stained profiles in the amygdala of the human and new world monkey (Saimiri sciureus) were studied histochemically. Fiber and terminal staining were heterogeneously distributed within the amygdala. The most intense staining occurred in the basolateral subdivision, consisting of the lateral, basolateral and accessory basal nuclei. Moderate staining intensity was observed throughout the cortical and media nuclei and cortical transition area, constituents of the corticomedial subdivision. The central amygdaloid area was characterized by minimal NADPH-d histochemical reactivity. NADPH-d positive neurons were pleomorphic and divisible into two classes based on their staining characteristics: intensely or lightly stained neurons. Their distribution was generally complementary, with the majority of intensely stained neurons occupying the basolateral subdivision. There were no appreciable species differences in the patterns of neuronal, fiber and terminal staining between monkey or human amygdala. These results may be relevant to our understanding of the selective vulnerability of neural systems within the human amygdala in neurodegenerative diseases.

Acetylcholinesterase↗

PubMed1992

The quantitative autoradiographic distribution of [3H]MK-801 binding sites in the normal human brainstem in relation to motor neuron disease.

The distribution of N-methyl-D-aspartate (NMDA) receptors in the normal human brainstem has been investigated using MK-801. Specific [3H]MK-801 binding showed a heterogeneous distribution, the greatest density of binding sites being found in the substantia nigra, locus coeruleus, and the hypoglossal and inferior olivary nuclei. Brainstem motor nuclei subserving eye movements, which tend to be spared in motor neuron disease (MND), had significantly lower densities of binding compared to other cranial nerve motor nuclei (V, VII, X, XII) which tend to be affected. The anatomical distribution of NMDA receptors may be one factor determining selective vulnerability to excitotoxic injury.

Adult↗

PubMed1993

Autoradiographic comparison of the distribution of [3H]MK801 and [3H]CNQX in the human cerebellum during development and aging.

The autoradiographic distribution of N-methyl-D-aspartate (NMDA) and D,L-a-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid/quisqualate (AMPA/QUIS) receptors was determined in cerebellum obtained at autopsy from 37 human individuals, aged from 24 weeks gestation to 95 years. [3H]MK801 was used to label the NMDA receptor and [3H]CNQX to label the AMPA/QUIS receptor. AMPA/QUIS receptors were concentrated in the cerebellar molecular layer, and NMDA receptors in the granular layer. Significant (3- to 4-fold) increases in binding were seen for both ligands from the fetal to neonatal periods in the molecular layer (CNQX) and in both molecular and granular layers (MK801). MK801 binding in the molecular layer continued to increase with age up to the tenth decade and together with binding in the granular layer, increased 2-fold between 10-40 years. The Purkinje cell layer was negative for MK801 binding until the 6-7th decade when it became positive. [3H]CNQX binding in the molecular layer increased significantly with age between the fetal period and the tenth decade, whereas in the granular layer binding increased from neonate to 40 years, but then decreased significantly from 60 years to the tenth decade. Lamination of the molecular and granular layers was absent during the fetal period and appeared with both ligands during the neonatal period. These marked differences in age-related expression of ligand binding sites in the granular layer during development and aging are of potential significance in relation both to selective vulnerability to ischemia, and synaptic plasticity and remodelling related to neuronal loss in senescence.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1993

Aminooxyacetic acid produces excitotoxic brain injury in neonatal rats.

Impairment of cellular energy metabolism plays an important role in the expression of brain injury resulting from a variety of acute neurologic disorders. The role of mitochondrial energy metabolism in excitotoxic perinatal brain injury was assessed by studying the toxicity of aminooxyacetic acid (AOAA), an inhibitor of mitochondrial malate-aspartate shunt, in postnatal (PND) 7 rats. Intrastriatal injection of AOAA produced seizures and dose-dependent excitotoxic injury. The neuronal damage was attenuated by pyridoxine suggesting involvement of pyridoxal dependent mechanisms. The lesion was selectively blocked by the NMDA antagonist MK-801 but not the AMPA antagonist GYKI-52466. Furthermore, AOAA potentiated NMDA, but not AMPA or 1S,3R-ACPD, induced brain injury. The data suggest that regional impairment of cellular energy metabolism is an important determinant of selective vulnerability to excitotoxic injury in perinatal rats. Furthermore, the role of impaired energy metabolism is particularly relevant to NMDA receptor mediated brain injury.

Aminooxyacetic Acid↗

PubMed1993

Biochemical and histological alterations induced by fluid percussion brain injury in the rat.

In the present study we have characterized the time-course of the histopathological and biochemical alterations resulting from mechanical brain injury caused by lateral fluid percussion centered over the parietal cortex in the rat. The injury device used was an HPLC pump coupled to a solenoid valve which delivered a constant and short lasting (10 ms) impact pressure (1.6 atm). This traumatic procedure resulted in an accumulation of blood in the subarachnoid space and cortical edema at 4-24 h post-trauma. From 4 h after injury, cortical neurons exhibited a pathologic appearance and phagocytic cells invaded the brain parenchyma. At 3 and 7 days post-injury, complete neuronal loss was observed in the parietal cortex around the impact site. In the ipsilateral cortex, the time-course of histologically assessed neuronal loss and phagocytic/glial activation paralleled the time-course of the loss of omega 1-2 (benzodiazepine) sites (a neuronal marker) and of the increase in p sites (peripheral-type benzodiazepine binding sites; a glial/macrophage marker). Neuronal loss and increase in the density of the glial/macrophage biochemical marker were also observed in the hippocampus but not in the contralateral cortex or in other subcortical structures, suggesting a selective vulnerability of the hippocampus to this traumatic procedure. There was a very good spatial correlation between the histological alterations and the changes in the density of the neuronal and glial/macrophage biochemical markers (as assessed by autoradiography). The volume of the lesion, integrated from the surface of the lesion measured at 10 coronal levels cut at a 1 mm interval and stained with haemalum and eosin, represented 32.9 +/- 1.7 mm3.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Exposure to sub-lethal ischemia failed to prevent subsequent ischemic death of dentate hilar neurons, as estimated by laminin immunohistochemistry.

The CA1 pyramidal cells and dentate hilar neurons are selectively vulnerable to forebrain ischemia. Although brief ischemia induces tolerance to subsequent ischemia in the CA1 pyramidal neurons, a protective effect of preceding brief ischemia on the dentate hilar neurons has not been established. We observed that vulnerable dentate hilar neurons were strongly laminin-immunopositive and used laminin immunohistochemistry to estimate the fate of dentate hilar neurons after ischemia. Pretreatment of brief sublethal ischemia, which effectively protects the CA1 neurons, failed to prevent the death of dentate hilar neurons. These results indicate that brief ischemia failed to induce tolerance to subsequent longer ischemia in the dentate hilar neurons.

Animals↗