PubMed Health⌕ Search

Biomedical subjects

R L Faull

Publications and source records attributed to R L Faull.

At least 73 records · Page 4Linked to original sources
PubMed1995

In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes.

To test the hypothesis that apoptosis is involved in human brain neurodegenerative disorders, we investigated whether DNA fragmentation occurs in Alzheimer's disease (AD). Huntington's disease (HD) and Parkinson's disease, as well as in temporal lobe epilepsy, using neurologically normal post-mortem human brain tissue as a control. Using in situ end labelling of DNA, we found evidence of DNA fragmentation in cells in temporal cortex and hippocampus from patients with AD and in striatum from those with HD. In contrast, only scattered DNA fragmentation positive cells were detected in the pial surfaces of some of the neurologically normal human brains. Thus, cells in the HD striatum and AD temporal cortex exhibited DNA fragmentation, suggesting that apoptosis may be involved in these disorders.

Adult↗
PubMed1995

The morphology of human neuroblastoma cell grafts in the kainic acid-lesioned basal ganglia of the rat.

Cells from a human neuroblastoma cell line (SH-SY5Y) have been used to examine their potential suitability as donor cells for neural transplantation. Grafts of SH-SY5Y cells were placed in the basal ganglia of the rat brain 7 days after kainic acid lesions of the striatum. The animals were killed 4 or 8 weeks following grafting, and light and electron microscopic studies showed that the graft formed a well-vascularized compact mass of cells in the host brain. At both time points grafted cells showed evidence of cellular differentiation with process formation, especially at the graft-host interface where there was intermingling of graft and host neuronal process. Electron microscopic studies showed that graft cell processes containing irregularly-shaped, clear vesicles or membrane-bound dense core vesicles, established regions of specialized contact with other graft cells and formed close associations with host neuronal processes. There was little difference between the grafts of different ages, except that in the older grafts there were early signs of neurodegeneration. Since the SH-SY5Y cells used in these grafts express the enzyme tyrosine hydroxylase and synthesize dopamine in vitro, these cells were used in the hope that they may potentially be useful for repairing lesions in the dopamine pathway, such as that seen in Parkinson's disease. Our behavioural studies show that grafting SH-SY5Y cells into the striatum of rats with 6-hydroxydopamine lesions of the median forebrain bundle result in a reduction of amphetamine-induced rotation. However, this was unlikely to be due to dopamine release since there was no tyrosine hydroxylase immunoreactivity seen in the region of the grafts. Thus grafted human neuroblastoma cells survive, establish specialized morphological associations with graft and host processes and improve behavioural deficits resulting from 6-hydroxydopamine lesions. We suggest that grafted differentiated human neuroblastoma cells can interact with cells in the host brain with beneficial effects, and that in the medium-term, neuroblastoma grafts will make useful models for examining graft-host interactions. However, the presence of early degenerative changes in the older grafts suggests that neuroblastoma cells may not be suitable for long-term neural transplantation therapy for neurodegenerative diseases.

Animals↗
PubMed1995

Prolonged expression of Fos-related antigens, Jun B and TrkB in dopamine-denervated striatal neurons.

Previous studies have demonstrated that striatal dopamine-denervation leads to a long-term increase in Fos-related antigen(s) (FRA's) in striatal neurons. Because Fos-family proteins bind to DNA by dimerizing to Jun-family proteins we investigated the expression of Jun B protein 2 weeks and 1 month after striatal dopamine-denervation, produced by medial forebrain bundle transection. We also investigated the effects of this lesion on TrkB-immunoreactivity in the striatum. FRA's (as previously reported) and Jun B were expressed in striatal neurons following dopamine-denervation, and in addition, there was an increase in expression of TrkB in the striatum on the dopamine-denervated side. These results show that striatal dopamine depletion leads to a long-term up-regulation of FRA's and Jun B in the striatum, and this may be related to other biochemical changes previously reported to occur in striatal neurons (e.g.: D2-dopamine receptor up-regulation) after dopamine depletion. In addition, FRA and Jun B expression may induce increased production of TrkB after dopamine-denervation.

Animals↗
PubMed1995

Dopamine D1 receptor, D2 receptor, proenkephalin A and substance P gene expression in the caudate nucleus of control and schizophrenic tissue: a quantitative cellular in situ hybridisation study.

The cellular expression of the mRNAs encoding the dopamine D1 receptor, dopamine D2 receptor and the neuropeptides enkephalin and substance P was determined in fresh frozen sections of human post-mortem caudate nucleus from control and schizophrenic brains using the technique of radioactive in situ hybridisation coupled with computer-assisted image analysis. Measurements of silver grain densities and mean cross-sectional somatic areas revealed no significant differences in the expression of any of these four gene transcripts. Further, cell count estimates revealed that each of these four mRNAs was expressed by approximately 20% of caudate cells (neurones and glia) in both control and schizophrenic tissue. These data demonstrate that the cellular expression of the dopamine D1 and D2 receptors and the neuropeptides enkephalin and substance P mRNAs are stable post mortem and that the relative cellular abundance of these mRNAs is not altered in the caudate nucleus of schizophrenic brains when compared to controls. These findings draw into focus the possible sites of action of clinically prescribed neuroleptics and suggest that chronic neuroleptic treatment of patients displaying negative schizophrenic symptoms may 're-set' an underlying neurochemical imbalance within the caudate nucleus.

Aged↗
PubMed1995

Repeated asphyxia causes loss of striatal projection neurons in the fetal sheep brain.

Repeated episodes of cerebral hypoxia-ischemia can cause primarily striatal neuronal loss in the developing brain. We investigated the effect of repeated episodes of asphyxia on specific neuronal sub-populations of the basal ganglia in late-gestation fetal sheep. Asphyxia was induced in 10 fetal sheep (118-126 days gestation) by occluding the umbilical cord for 5 min. This procedure was repeated four times at 30 min intervals and the brains were fixed 3 days later for histopathology. Immunohistochemical markers were used to identify various populations of neurons in the striatum. Antibodies to calbindin were used to stain the GABAergic medium-sized striatal projection neurons and antibodies to somatostatin and parvalbumin to identify striatal interneurons. Striatal projection neurons to the globus pallidus were recognized by enkephalin immunoreactivity, while the striatonigral terminals were identified in the substantia nigra pars reticulata by substance P immunohistochemical labelling. The results showed a marked loss of calbindin staining in the striatum, evident by both reduced cell numbers and a decrease in neuropil staining. The number of parvalbumin immunoreactive cells was also reduced in the striatum, while somatostatin interneurons were selectively preserved. In addition, immunostaining for enkephalin in the globus pallidus and for substance P in the substantia nigra was markedly reduced. These results show that the stiatal GABAergic medium-sized projection neurons are severely affected by recurrent episodes of asphyxia. These findings are confirmed and extended by the results demonstrating that both the enkephalin/GABA striatopallidal and the substance P/GABA stiatonigral pathways are affected. The results of this study therefore suggest that the efferent striatal projections to the globus pallidus and to the substantia nigra may be involved in asphyxial episodes resulting in cerebral palsy.

Animals↗
PubMed1995

GABA and GABAA receptor changes in the substantia nigra of the rat following quinolinic acid lesions in the striatum closely resemble Huntington's disease.

GABA and GABAA receptors have been studied in the substantia nigra of the rat following quinolinic acid lesions in the striatum. The regional distribution of GABA and GABAA receptors was investigated using immunohistochemical techniques with monoclonal antibodies to GABA and to the beta 2.3 subtypes of the GABAA receptor complex. The distribution, density and cellular localization of GABAA receptors were studied using quantitative receptor autoradiography and 6-hydroxydopamine-induced degeneration of dopaminergic pars compacta neurons. The subunit configuration of GABAA receptors was investigated using in situ hybridization histochemistry and subunit subtype-specific oligonucleotide probes. The results showed that in the normal substantia nigra GABA and GABAA receptors were mainly localized within the pars reticulata. GABAA receptors were mainly of the BZI variety, had a subunit subtype configuration that included alpha 1 and beta 2.3 subtypes, and showed a rostrocaudal gradient in the density of receptors; the density of receptors in the caudal third was 56% higher than that in the rostral third of the pars reticulata. Following quinolinic acid-induced degeneration of the striatonigral pathway, there was a marked loss of GABA immunoreactivity and a 59% increase in the density of GABAA receptors in the substantia nigra pars reticulata. There was a corresponding regional topography in the pattern of loss of GABA immunoreactivity and in the pattern of increase in GABAA receptors in the pars reticulata; the topography varied with the size and placement of the lesion in the striatum and correlated with the known topographical organization of the striatonigral projection. The quantitative autoradiographic results showed that following quinolinic acid lesions in the striatum: (i) the greatest increase in the density of GABAA receptors occurred in the middle third (91% increase) of the pars reticulata; (ii) the receptors were mainly of the GABAA/BZI variety; and (iii) 6-hydroxydopamine-induced degeneration of the dopaminergic pars compacta neurons did not significantly affect the density of receptors, indicating that the increased receptor binding was mainly localized on non-dopaminergic pars reticulata neurons. The immunohistochemical and in situ hybridization studies showed that, as in the normal substantia nigra, GABAA receptors in the substantia nigra pars reticulata on the lesioned side contained the alpha 1 and beta 2.3 GABAA receptor subtypes; the alpha 1 and beta 2.3 subtypes (but not the alpha 2) were increased after quinolinic acid lesions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

GABA, muscarinic cholinergic, excitatory amino acid, neurotensin and opiate binding sites in the octavolateralis column and cerebellum of the skate Raja nasuta (Pisces: Rajidae).

As part of a study of signal processing in the electro- and mechanosensory systems we have screened the octavolateralis column of the skate for GABAA, muscarinic cholinergic, excitatory amino acid, neurotensin and opiate binding sites using autoradiography following in vitro labelling of cryostat sections with tritiated ligands. The presence and distribution of these binding sites is compared between the octavolateralis column and the corpus cerebellum. GABAA binding sites were located in high concentrations in the granule cell regions of the cerebellum and octaval columns, with much lower concentrations in the Purkinje cell layer of the corpus cerebellum. Little or no labelling was evident in all molecular layer areas. Displacement studies using the discriminating ligand CL218,872 indicated that the GABAA binding sites were predominantly of the GABAA/benzodiazepine Type II variety. M1 muscarinic cholinergic binding sites were found in high concentrations in all granule cell areas and in lower concentrations in the molecular layer of the octavolateralis column, with an absence of labelling in the molecular layer of the corpus cerebellum. Kainic acid and AMPA binding sites were present in very high concentrations in all molecular layer areas. Glutamate binding was present in the molecular layer of the octavolateralis column and in some restricted regions of the dorsal granular ridge, whereas phencyclidine binding sites were sparse or absent. Neurotensin binding sites were strongly present in all granule cell areas and evident in the molecular layer of the octavolateralis column. There was evidence for opiate binding sites in the molecular layer of both the dorsal and medial octavolateralis nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Interaction of felbamate with [3H]DCKA-labeled strychnine-insensitive glycine receptors in human postmortem brain.

The dicarbamate felbamate has been shown to be capable of competing for the binding of 5,7-[3H]dichlorokynurenic acid ([3H]DCKA) to strychnine-insensitive glycine receptors in sections of human postmortem brain. The IC50 for this interaction was 305.8 microM and the inhibition was complete at 1 mM. Autoradiographic localization of [3H]DCKA binding revealed many regions of human brain in which strychnine-insensitive glycine receptors are manifest. The specific binding in most of these areas was markedly reduced in the presence of 625 microM felbamate. In many regions, [3H]DCKA binding was reduced to background in the presence of felbamate, but some areas retained binding by as much as 41% (i.e., the CA2 region of the hippocampus). This is in contrast to the binding of [3H]DCKA in the presence of carbamazepine, phenytoin, or valproic acid. The binding of the glycine receptor antagonist was not affected by any of these latter agents to the same degree as felbamate. Strychnine-insensitive glycine receptors represent a site of action of felbamate in the human brain.

Adult↗
PubMed1994

Use of [3H]5,7 dichlorokynurenic acid to identify strychnine-insensitive glycine receptors in human postmortem brain.

[3H]5,7 Dichlorokynurenic acid ([3H]DCKA) was used to define conditions for obtaining selective binding to strychnine-insensitive glycine receptors. The parameters were established in sections of human brain prior to localizing the receptors sites by autoradiography. The binding of [3H]DCKA was of high affinity (Kd = 14.5 nM), readily reversible (K-1 = 0.216 min-1), and specific (60% specific binding determined by inhibition with 100 microM glycine or D-serine). High levels of strychnine-insensitive glycine receptors were identified in several brain areas including portions of the cerebral cortex (Bmax in middle temporal gyrus: 174.0 fmol/mg tissue), basal ganglia, hippocampal formation, and midbrain. These results identify regions where glycine receptors may be involved in modulating NMDA-mediated channel activity.

Autoradiography↗
PubMed1993

Loss of sigma binding sites in the CA1 area of the anterior hippocampus in Alzheimer's disease correlates with CA1 pyramidal cell loss.

The densities of [3H]1,3-di-o-tolylguanidine ([3H]DTG) binding to sigma binding sites in the CA1 stratum pyramidale region in 7 hippocampi affected by Alzheimer's disease, were compared with densities in 7 normal hippocampi. There was an average reduction of 26% in [3H]DTG binding in this area, which was correlated with an average 29% pyramidal cell loss in the same region. These results are consistent with experiments in animals indicating that sigma binding sites are preferentially associated with the somata of large cells.

Aged↗
PubMed1993

Compartmentalization of parvalbumin immunoreactivity in the human striatum.

The distribution of parvalbumin in the basal ganglia was studied in eight human brains using immunohistochemical techniques and the pattern of staining was compared to the distribution of enkephalin immunoreactivity in adjacent sections. The results showed a heterogeneous pattern of parvalbumin immunoreactivity in the caudate nucleus and putamen; this pattern of staining was characterized by irregularly shaped patches of low parvalbumin immunoreactivity dispersed against a background matrix of moderate-to-high immunoreactive staining. These parvalbumin-poor patches in the caudate nucleus and putamen aligned with the enkephalin-rich striosomes. These results show that parvalbumin immunoreactivity in the human striatum has the same compartmental mosaic organization as other neurochemical markers in the mammalian striatum.

Adolescent↗
PubMed1993

Compartmental loss of NADPH diaphorase in the neuropil of the human striatum in Huntington's disease.

The distribution of NADPH diaphorase staining in the human basal ganglia was compared in five cases who were neurologically normal with five cases who died with Huntington's disease. The normal cases showed an intense staining for NADPH diaphorase throughout all regions of the neuropil in the striatum (caudate nucleus, putamen and nucleus accumbens); the staining in the neuropil was largely homogeneous although a heterogeneous distribution was evident at rostral levels of the head of the caudate nucleus and in the nucleus accumbens where patches of reduced staining aligned with acetylcholinesterase-poor regions. The globus pallidus showed a moderately intense homogeneous pattern of staining for NADPH diaphorase. In comparison with control cases, sections of the striatum from the five cases with Huntington's disease showed a dramatic decrease in the intensity of NADPH diaphorase staining in the neuropil, especially in the caudate nucleus and putamen. In cases of early Huntington's disease where no discernible loss of neurons was seen [grade 0 using the grading criteria of Vonsatell et al. (1985) J. Neuropath. exp. Neurol. 44, 559-577], there was a marked heterogeneous pattern of staining in the caudate nucleus and putamen showing a patchy loss of NADPH diaphorase in the neuropil. This resulted in clearly delineated islands of greatly reduced staining surrounded by a matrix of moderately reduced staining; the patches of greatly reduced staining corresponded with acetylcholinesterase-poor striosomes. In cases of more advanced neuropathology (grades 1 and 2) the loss of NADPH diaphorase staining in the neuropil was even more marked, affecting both acetylcholinesterase-poor and acetylcholinesterase-rich regions of the caudate nucleus and putamen and resulting in an almost homogeneous loss of staining in these striatal regions. Despite this marked loss of staining in the neuropil, the numbers of NADPH diaphorase-stained neuronal somata in the striatum in Huntington's cases appeared comparable to those in the control cases. In the globus pallidus of one of the advanced Huntington's disease cases there appeared to be a minimal loss of NADPH diaphorase staining; however, staining in the other regions of the brain which were examined was similar to that in the control cases. These findings demonstrate a progressive compartmental loss of NADPH diaphorase in the neuropil of the human striatum in Huntington's disease which correlates with the extent of neurodegeneration; early in the disease the loss of neuropil staining is first evident in the striosome compartment, then followed by an additional loss in the matrix compartment in more advanced cases of the disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗
PubMed1993

Loss of cannabinoid receptors in the substantia nigra in Huntington's disease.

Previous autoradiographic studies in rats using [3H]CP55,940 have demonstrated the cannabinoid receptor to be located on the axon terminals of striatal efferent neurons projecting to the globus pallidus and substantia nigra. Because these neurons are selectively lost in Huntington's disease, a loss of [3H]CP55,940 binding is predicted in the substantia nigra of the Huntington's disease brain. We have used autoradiography to compare the binding of [3H]CP55,940 in the substantia nigra of Huntington's disease and neurologically normal brains. The results have demonstrated that cannabinoid receptors in the normal human substantia nigra are discreetly localized within the substantia nigra pars reticulata. In contrast, the Huntington's disease brains show a massive loss (97.5%) of cannabinoid receptor binding in the substantia nigra pars reticulata. These results show that in the substantia nigra of the human brain cannabinoid receptors are located on striatonigral terminals which degenerate in Huntington's disease.

Aged↗
PubMed1992

The regional, cellular and subcellular localization of GABAA/benzodiazepine receptors in the substantia nigra of the rat.

The regional, cellular and subcellular distribution of GABAA/benzodiazepine receptors was investigated by light and electron microscopy in the rat substantia nigra. The regional distribution and density of GABAA/benzodiazepine receptor subtypes (Type I and II) was studied using quantitative receptor autoradiography following in vitro labelling of cryostat sections with tritiated ligands. This was followed by a detailed study of the cellular and subcellular distribution and localization of GABAA/benzodiazepine receptors by light and electron microscopy using immunohistochemical techniques with a monoclonal antibody (bd-17) to the beta 2,3 subunits of the GABAA/benzodiazepine receptor complex. Finally, in situ hybridization histochemistry using 35S-labelled oligonucleotide probes was used to demonstrate the cellular distribution of mRNA for the alpha 1 and alpha 2 GABAA receptor subunits in the substantia nigra. The results of the autoradiographic and immunohistochemical studies showed a close correspondence in the regional distribution of GABAA/benzodiazepine receptors in the substantia nigra. A moderate-to-high density of receptors was present throughout the full extent of the substantia nigra pars reticulata with a very low density of receptors in the substantia nigra pars compacta. Quantitative autoradiographic studies showed that: (i) the pars reticulata contained mainly central Type I receptors; (ii) the highest density of receptors was present in the caudal pars reticulata (200 +/- 38 fmol/mg) with successively lower densities of receptors in the middle (176 +/- 31 fmol/mg) and rostral (150 +/- 26 fmol/mg) levels of the pars reticulata; and (iii) the density of receptors in the pars reticulata was reduced by 34% following 6-hydroxydopamine-induced degeneration of dopaminergic pars compacta neurons. At the cellular level, GABAA/benzodiazepine receptor immunoreactivity was localized in a punctate fashion on dendrites and neuronal cell bodies in the pars reticulata. At the subcellular level, GABAA/benzodiazepine receptor immunoreactivity was associated with the pre- and postsynaptic membranes of axodendritic synaptic complexes along the length of small-to-large sized smooth dendrites in the pars reticulata. Two types of immunoreactive axodendritic synaptic complexes were identified: most (about 80%) immunopositive synapses showed equal staining of the pre- and postsynaptic membranes and were associated with small (less than 1.0 micron) axon terminals containing few mitochondria and small, round-to-pleomorphic vesicles in synaptic contact with small, peripheral dendrites; less frequently (about 20%) immunopositive synapses showed a marked immunoreactive thickening of the postsynaptic membrane and were associated with large (greater than 1.0 micron) axon terminals containing numerous mitochondria and mainly pleomorphic vesicles in synaptic contact with large mainstem dendrites.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗