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Biomedical subjects

P C May

Publications and source records attributed to P C May.

At least 37 records · Page 2Linked to original sources
PubMed1993

Decrease in amyloid precursor protein precedes hippocampal degeneration in rat brain following transient global ischemia.

We have studied amyloid precursor protein (APP) expression in rat brain following transient global ischemia. Ischemic damage 24 h after 30 min of four-vessel occlusion (4VO) was limited to the caudate nucleus; hippocampal pyramidal neurons appeared histologically normal by light microscopy. Consistent with ongoing neurodegeneration in the caudate nucleus, microtubule-associated protein-2 (MAP-2) levels assessed by immunoblots were significantly reduced in homogenates of caudate nucleus after 4VO. MAP-2 levels In the hippocampus were comparable to control values. In contrast, full length APP levels in both the caudate nucleus and hippocampal homogenates were significantly decreased following 4VO despite normal hippocampal morphology at 24 h. These findings suggest that decrements in full length APP precede overt neuronal damage and may play a role in the subsequent delayed neurodegeneration in the hippocampus.

Amyloid beta-Protein Precursor↗
PubMed1993

GYKI 52466 protects against non-NMDA receptor-mediated excitotoxicity in primary rat hippocampal cultures.

Glutamate excitotoxicity is mediated by both N-methyl-D-aspartate (NMDA)-receptor and non-NMDA receptor (alpha-amino-3-hydroxy-5-methyl-isoxazolepropionate (AMPA)/kainate (KA)) mechanisms but the lack of specific antagonists has limited the characterization of AMPA/KA receptor-mediated excitotoxicity. The 2,3-benzodiazepine GYKI 52466 is a newly described non-competitive AMPA/KA receptor antagonist. We have investigated the neuroprotective efficacy of GYKI 52466 in an embryonic rat hippocampal culture model of non-NMDA receptor-mediated excitotoxicity using KA as an agonist at the AMPA/KA receptor. Overnight treatment with 500 microM KA resulted in prominent neuronal excitotoxicity as assessed by lactate dehydrogenase efflux. GYKI 52466 attenuated KA excitotoxicity in a dose-dependent manner with an IC50 of 9 microM. Together with competitive antagonists (e.g., various quinoxalinediones), non-competitive antagonists like GYKI 52466 can now be used to dissect mechanisms of non-NMDA receptor mediated excitotoxicity.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

Cyclothiazide treatment unmasks AMPA excitotoxicity in rat primary hippocampal cultures.

Mechanisms of non-NMDA receptor-mediated excitotoxicity were studied in embryonic rat hippocampal cultures using kainic acid (KA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) as agonists. Under basal culture conditions, overnight treatment with AMPA resulted in negligible excitotoxicity as assessed by phase-contrast microscopy and measurement of lactate dehydrogenase (LDH) release. In contrast, similar treatment with KA resulted in marked excitotoxic morphologic changes and release of LDH. Cotreatment of cultures with AMPA but not NMDA effectively blocked KA toxicity, suggesting that AMPA-induced rapid desensitization of the AMPA/KA receptor could account for the lack of prominent direct toxicity as well as AMPA's ability to block KA toxicity. To test this hypothesis, cultures were briefly pretreated with 10 microM cyclothiazide, a drug reported to block desensitization of the AMPA/KA receptor, and then exposed overnight to cyclothiazide plus AMPA and/or KA. Cyclothiazide-treated cultures were now vulnerable to AMPA as well as KA; moreover, AMPA was unable to block KA toxicity completely, suggesting that cyclothiazide impaired AMPA/KA receptor desensitization. These and related studies suggest that a regulatory site may exist on the AMPA/KA receptor that modulates non-NMDA receptor-mediated excitotoxicity.

Animals↗
PubMed1993

Neurotoxicity of human amylin in rat primary hippocampal cultures: similarity to Alzheimer's disease amyloid-beta neurotoxicity.

Amylin, a 37-amino-acid amyloidogenic peptide, bears biophysical similarities to the amyloid-beta peptide (A beta) deposited in Alzheimer's disease. Using embryonic rat hippocampal cultures we tested whether amylin induces neurotoxicity similar to that previously observed with A beta(1-40). Treatment with human amylin(1-37) resulted in prominent toxicity as assessed by phase-contrast microscopy and quantification of lactate dehydrogenase in the medium. Amylin-induced neurotoxicity was morphologically similar to that induced by A beta(1-40). In contrast, the nonamyloidogenic rat amylin showed negligible neurotoxicity despite having 95% sequence similarity to human amylin. Only full-length human amylin was toxic; various amylin peptide fragments including amino acid residues 20-29 were nontoxic at similar concentrations. These studies suggest that unrelated amyloidogenic peptides like human amylin and A beta can adopt a similar neurotoxic conformation in vitro. Similar conformation-dependent neurotoxicity may drive the prominent neurite degeneration around compacted but not diffuse deposits of A beta in Alzheimer's disease.

Amino Acid Sequence↗
PubMed1992

Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration.

Sulfated glycoprotein 2 (SGP-2) from rat, and similar molecules from cow, dog, human, pig, ram and quail are known by 11 or more acronyms. SGP-2 is associated with the responses of brain and other tissues to injury; it and related molecules are also normally secreted by the adrenal gland, the liver and the testes. The mRNA of this protein is found in increased levels in Alzheimer's disease. In rats, after perforant path or excitotoxin lesions, levels of the protein or mRNA are elevated in astrocytes, and also in neurons. In rats, brain SGP-2 is regulated by gonadal and adrenal steroids. However, these increases after brain lesions may relate to a function that is associated with the human protein, namely that of inhibiting complement-mediated cell lysis. Other activities suggested for SGP-2 are lipid transport and cell-cell interactions, which are consistent with sequence data that predict binding of dinucleotides, heparin and lipids. The emerging neurobiology of SGP-2 encompasses the subjects of cell death, synaptic remodelling, neuroendocrinology and neurodegenerative diseases.

Animals↗
PubMed1992

Sulfated glycoprotein-2 expression increases in rodent brain after transient global ischemia.

Sulfated glycoprotein-2 (SGP-2) is emerging as a prominent marker of neurodegeneration in mammalian brain. Regulation of brain SGP-2 was studied in adult male Wistar rats subjected to 30 min of forebrain ischemia by four vessel occlusion. By 3 days after the ischemic insult, SGP-2 RNA levels were increased two fold in caudate nucleus and hippocampus. SGP-2 protein levels assessed by immunoblots were markedly increased in both brain regions following ischemia. GFAP RNA levels also increased over 5 fold in caudate nucleus and hippocampus following the ischemic insult. Despite significant elevations in GFAP RNA, protein levels of GFAP assessed by immunoblot were only marginally affected. The elevated expression of SGP-2 in rodent brain following this and other experimental lesion paradigms (e.g., excitotoxic lesions, deafferentation) suggest some general involvement of SGP-2 in neurodegeneration and remodelling following neuronal injury.

Animals↗
PubMed1992

Dopa accumulates in the hypothalamic-hypophysial portal vessels and is taken into the anterior pituitary of NSD-1015-treated rodents.

DOPA was measured in the anterior pituitary and hypothalamic-hypophysial portal blood after treatment with NSD-1015, a DOPA decarboxylase inhibitor. NSD-1015 caused DOPA to accumulate in the anterior pituitary of mice and rats, and increased DOPA in the hypothalamic-hypophysial portal blood of rat. Serum prolactin was also increased. Interruption of the anterior pituitary blood supply from the hypothalamic-hypophysial system by cannulation of the entire pituitary stalk eliminated the NSD-1015-induced DOPA accumulation in the rat pituitary. We conclude that DOPA can be taken into the anterior pituitary from the portal blood of NSD-1015-treated rodents and that the anterior pituitary lacks tyrosine hydroxylase activity in both mice and rats.

Animals↗
PubMed1991

Sulfated glycoprotein-2 is increased in rat hippocampus following entorhinal cortex lesioning.

Thios study showed responses of sulfated glycoprotein-2 (SGP-2) in the rat hippocampus after deafferenting lesion. SGP-2 is a plasma protein that also occurs in many peripheral tissues. In some circumstances, elevations of SGP-2 mRNA are associated with cell degeneration and responses to injury. This study used entorhinal cortex lesions (ECL) to partially deafferent the hippocampus by damaging the perforant path and to induce synaptic remodeling. SGP-2 mRNA is increased in hippocampal astrocytes after ECL. Western blot analysis of soluble hippocampal proteins identified 3 major forms of rat SGP-2 protein: a precursor (61 kDa) and 2 reduced subunits at 39.5 and 35 kDa. These forms increased at 4 days post ECL ipsilaterally to the lesion. By immunocytochemistry (ICC), SGP-2 showed an increased immunoreactivity on the lesioned side by 2 days post ECL that continued through 14 days post ECL. Besides immunopositive astrocytes, punctate immunochemical reaction products occurred among the degenerating fibers of the perforant path. We conclude that changes of SGP-2 protein in the hippocampus after ECL occur roughly in parallel with increases of SGP-2 mRNA. The punctate immuno-deposits could represent secreted SGP-2 and may be useful as a marker for degenerating pathways.

Animals↗
PubMed1991

Cloning of hippocampal poly(A) RNA sequences that increase after entorhinal cortex lesion in adult rat.

Evidence is given for altered gene expression in the hippocampus in response to entorhinal cortex lesioning. Three RNA markers encoding glial fibrillary acidic protein, apolipoprotein E and alpha-tubulin were isolated from a rat hippocampal cDNA library by differential screening with cDNA probes from entorhinal cortex lesioned and control rat hippocampus RNA. By Northern blot analysis, mRNA for apolipoprotein E and alpha-tubulin increased to peak around 6 days after the lesion and returned to near control level at 30 days. The increased synthesis of both mRNAs coincides with the acute phase of synaptogenesis, protein synthesis, and polyribosomes accumulation in the deafferented hippocampal area.

Animals↗
PubMed1991

Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning.

Entorhinal cortex lesions (ECL) that damage the perforant path to the hippocampus induce rapid increases of apolipoprotein E (apo E) mRNA in the hippocampus. Apo E mRNA was localized in astrocytes by in situ hybridization in combination with immunocytochemistry for glial fibrillary acidic protein (GFAP). Unilateral ECL also increased hippocampal GFAP mRNA, with increases preceding those of apo E mRNA. The apo E mRNA and GFAP mRNA responses were transiently bilateral in non-denervated zones. The timing of response in apo E mRNA to deafferentation supports suggestions that apo E has roles in membrane remodelling during responses to neuron injury.

Animals↗
PubMed1990

Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat.

A hippocampal poly(A) RNA, pADHC-9, was cloned by differential screening of a human hippocampal cDNA library. By RNA blot analysis, pADHC-9 was elevated 2-fold in Alzheimer's disease hippocampus. In situ analyses identified pADHC-9 expression in pyramidal and non-pyramidal cells of the hippocampus and entorhinal cortex. Nucleotide sequence analysis identified pADHC-9 as a potential human homolog of rat sulfated glycoprotein 2 (SGP-2). SGP-2 expression increased in rat hippocampus following experimental lesions that mimic intrinsic neuronal loss and/or deafferentation. The function of pADHC-9 in brain has not been defined, but in serum, a similar protein inhibits complement-dependent cytolysis. Increased expression of pADHC-9 in Alzheimer's disease hippocampus may be a compensatory response mounted to retard a complement-driven neurodegenerative cascade.

Alzheimer Disease↗
PubMed1990

Selective alterations of RNA in rat hippocampus after entorhinal cortex lesioning.

In vitro translation products from RNA of rat hippocampus after deafferentation by entorhinal cortex lesions were analyzed by two-dimensional gel electrophoresis. Although hippocampal total RNA yield was not affected 14 days after the lesion, analysis of the gels showed reproducible changes in the steady-state level of several transcripts. Glial fibrillary acidic protein RNA increased 2-fold over control hippocampi RNA. Moreover, seven other transcripts of unknown identity had increased prevalence in the denervated hippocampus. The changes, which ranged from 2- to 20-fold, involved mRNA encoding small slightly acidic polypeptides: 12 kDa (pI 5.6), 13 kDa (pI 6.1), 20 kDa (pI 5.8), 31 kDa (pI 5.7), 33 kDa (pI 5.7), 35 kDa (pI 5.6), and 53 kDa (pI 5.4). These results suggest new molecular markers for analyzing the complex mechanisms of synaptic reorganization in the dentate gyrus after deafferentation.

Actins↗
PubMed1990

The Bath bike for walking rehabilitation.

We describe a new rehabilitation aid for walking and its role in traumatology, discussing its advantages over current aids. Wider applications are suggested in the fields of neurology, rheumatology and spinal injury.

Early Ambulation↗
PubMed1989

The Bath bridge angle-guide.

A device is described which facilitates the accurate location of a guide-pin for the placement of the sliding lag screw when treating fractures of the subtrochanteric zone of the femur with any of the modern sliding hip screw plates.

Equipment Design↗