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Biomedical subjects

C W Cotman

Publications and source records attributed to C W Cotman.

At least 145 records · Page 8Linked to original sources
PubMed1995

Low-dose propranolol reduces aggression and agitation resembling that associated with orbitofrontal dysfunction in elderly demented patients.

Although several reports suggest that intermediate to high doses of propranolol (80-160 and 200-600 mg/day) can effectively treat aggressive behavior in dementia, significant side effects can occur at these doses. To minimize these side effects, we treated and followed-up a series of 12 demented patients, whose caregivers sought medical help for their disruptive, aggressive behavior, with low-dose propranolol monotherapy (10-80 mg/day). Assessment measures obtained at baseline and during treatment by caregiver interview included ordinal ratings of aggression severity, the Cohen-Mansfield Agitation Inventory (CMAI), and the California Behavior Questionnaire (CBQ). The aggression ratings showed that low-dose propranolol effectively reduced aggression in eight of 12 patients (67%) within 2 weeks of treatment and remained effective for the duration of follow-up (1 to 14 months). Subscales of the CMAI showed responders to have significant reductions in physical and verbal aggression/agitation and in pacing/wandering. These results suggest that low-dose propranolol should be further studied for treating aggression or agitation in demented patients.

Aged↗
PubMed1994

Protease nexin-1, a potent thrombin inhibitor, is reduced around cerebral blood vessels in Alzheimer's disease.

The clotting protease thrombin might contribute to the pathophysiology of central nervous system (CNS) injury and certain diseases by its ability to retract processes on neurons and astrocytes and to stimulate astrocyte proliferation. Protease nexin-1 (PN-1) is a 43 kDa thrombin inhibitor found predominantly in the brain where much of it resides around capillaries and large blood vessels. This location of PN-1 prompted the hypothesis that it may play a protective role against extravasated thrombin released following cerebrovascular injury or under certain pathological conditions. Recent studies indicated that the levels of PN-1 are markedly reduced in the postmortem brains of patients with Alzheimer's disease (AD). It was suggested that this reduction in PN-1 levels was due to the sequestration of PN-1 by extravasated thrombin. In the present study we examined the specific nature of this reduction by immunohistochemical staining of sections from control and AD brains using PN-1 specific antibodies. We show that the levels of PN-1 immunoreactivity around blood vessels and the number of blood vessels exhibiting PN-1 immunoreactivity were markedly reduced in the brains of patients with AD compared to age-matched controls; this reduction was reflected by a decrease in the levels of PN-1 activity and PN-1 protein. Thus an imbalance between PN-1 and thrombin may be a contributing factor in the pathology of AD.

Aged↗
PubMed1994

Immunohistochemical evidence for apoptosis in Alzheimer's disease.

Recently, in vitro studies conducted in our laboratory and others have suggested that apoptosis may have a role in the neuronal cell death associated with Alzheimer's disease (AD). To evaluate this hypothesis, the hippocampi and entorhinal cortices of AD, aged control, and surgical biopsy tissue were examined using the ApopTag system for the detection of DNA fragmentation and DNA strains to reveal nuclear morphology. Numerous neuronal nuclei displaying distinct morphological characteristics of apoptosis were present within tangle-bearing neurons as well as non-tangle-bearing neurons in AD brain, whereas few or no such nuclei were detected in control brain. Our in vivo results support the hypothesis that apoptosis may be one mechanism leading neuronal cell death in AD.

Aged↗
PubMed1994

Early phosphorylation of tau in Alzheimer's disease occurs at Ser-202 and is preferentially located within neurites.

Within the neurofibrillary tangles (NFTs) and dystrophic neurites (DNs) of Alzheimer's disease (AD), the cytoskeletal protein tau is abnormally hyperphosphorylated. In this study we evaluate the phosphorylation of specific residues on tau within different phases of the formation of NFTs. Two monoclonal antibodies, AT8 and PHF-1, were used to selectively recognize phosphorylated Ser-202 and Ser-396 of PHF-tau protein, respectively. We found that abnormal phosphorylation of tau appears to occur first at Ser-202 in DNs, then at Ser-202 in the soma and finally at Ser-396 in DNs and NFTs. These results suggest that abnormal phosphorylation at Ser-202 of PHF-tau in DNs represents one of the earliest neuropathological changes within the neurites of vulnerable neurons and may have a pivotal role in the initial pathogenesis of AD.

Aged↗
PubMed1994

Ultrastructural analysis of beta-amyloid-induced apoptosis in cultured hippocampal neurons.

Following treatment with the beta-amyloid (A beta) 25-35 analog, scanning and transmission electron microscopy were used to investigate the morphological changes in cultured hippocampal neurons during the course of degeneration. Ultrastructural analysis revealed focal cell surface blebbing and rapid condensation of nuclear chromatin. Changes in cytoplasmic morphology included prominent vacuole formation, dispersal of polyribosome rosettes and the disappearance of the golgi complex, smooth endoplasmic reticulum and microtubules with increased cytoplasmic electron density. Mitochondria and limited rough endoplasmic reticulum remained intact throughout the process of cell death. These results provide additional evidence suggesting A beta-induced cell death in vitro occurs via an apoptotic mechanism.

Amyloid beta-Peptides↗
PubMed1994

Pharmacological dissociation of glutamatergic metabotropic signal transduction pathways in cortical astrocytes.

Using cultured cortical astrocytes we demonstrate differential activation of metabotropic signal transduction pathways with 1-aminocyclopentane-trans-1S3R-dicarboxylic acid (1S3R-ACPD) and the glutamate transport inhibitor trans-2,4-pyrrolidine dicarboxylic acid (trans-2,4-PDC). Phosphoinositide hydrolysis was more potently stimulated by 1S3R-ACPD than by L-trans-2,4-PDC; however, L-trans-2,4-PDC was far more efficacious than 1S3R-ACPD at inhibiting cyclic AMP accumulation. The metabotropic receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG) inhibited 1S3R-ACPD stimulation of phosphoinositide hydrolysis but not its ability to inhibit cyclic AMP accumulation thereby demonstrating a means to pharmacologically dissociate these two metabotropic signal transduction pathways in astrocytes. (+)-MCPG produced similar antagonism of the metabotropic agonist properties of L-trans-2,4-PDC. The metabotropic effects of L-trans-2,4-PDC could not be reduced with enzymatic treatment of the cultures to remove extracellular glutamate, suggesting that these effects are not secondary to the ability of this compound to inhibit glutamate uptake. Taken together the findings indicate the presence of multiple glutamatergic signal transduction pathways in astrocytes and suggest a similarity in the pharmacophores for metabotropic receptors and glutamate transporters.

Animals↗
PubMed1994

Down regulation of nestin by TGF-beta or serum in SFME cells accompanies differentiation into astrocytes.

The serum-free mouse embryo (SFME) cell line, derived from 16-day-old mouse embryos in medium in which serum was replaced by growth factors and other supplements, has been cultured for more than 200 generations. SFME cells are nontumorigenic, lack gross chromosomal abnormalities, and display characteristics of CNS progenitor cells. SFME cells show reversible induction of the astrocyte-specific marker glial fibrillary acidic protein when cultured in the presence of TGF-beta or serum. In order to determine if SFME cells exhibit further characteristics of CNS progenitor cells we investigated the expression of the gene encoding nestin, an intermediate filament protein expressed by neuroepithelial stem cells of the CNS. SFME cells express nestin in serum-free medium, and nestin expression is reversibly down-regulated by TGF-beta or serum. These results demonstrate that nestin expression is regulated by factors present in serum and support the hypothesis that SFME cells represent a CNS progenitor cell.

Animals↗
PubMed1994

Exposure to hydrogen peroxide induces cell death via apoptosis in cultured rat cortical neurons.

To investigate whether direct oxidative damage may induce neuronal death via an apoptotic cell suicide pathway, we exposed cultured cortical neurons to the prooxidant hydrogen peroxide. Our experiments demonstrate that brief exposures to low concentrations of hydrogen peroxide can induce neuronal cell death via apoptosis as demonstrated by toxicity assays, specific DNA staining, and the appearance of DNA laddering on agarose gels. These results suggest that direct oxidative injury may serve as a general trigger for apoptosis in the CNS, and that other apoptotic stimuli, such as exposure to amyloid-beta peptides, may also involve oxidative injury. Peroxide-induced apoptosis may serve as a valuable model for further studies of apoptosis in neurons.

Animals↗
PubMed1994

A conformationally constrained competitive inhibitor of the sodium-dependent glutamate transporter in forebrain synaptosomes: L-anti-endo-3,4-methanopyrrolidine dicarboxylate.

A series of L-3,4-methanopyrrolidine dicarboxylate isomers were investigated as potential inhibitors of the high affinity, sodium-dependent glutamate transporter in rat forebrain synaptosomes. Of the isomers tested, only L-anti-endo-3,4-methanopyrrolidine dicarboxylate (L-anti-endo-MPDC) blocked the uptake of [3H]D-aspartate, a non-metabolized substrate. Kinetic analysis demonstrated that L-anti-endo-MPDC is a potent competitive inhibitor (Ki = 5 microM) comparable to that of L-glutamate and L-trans-2,4-pyrrolidine dicarboxylate (L-trans-2,4-PDC). Conformational analysis of L-glutamate, L-trans-2,4-PDC and L-anti-endo-MPDC are used to refine the pharmacophore model of the transporter binding site.

Amino Acid Transport System X-AG↗
PubMed1994

beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain.

beta-amyloid peptides that accumulate within the brain of individuals with Alzheimer's disease bind to C1q and activate the classical C pathway via a specific interaction with a site within the collagen-like domain of C1q (C1q-CLF). Synthetic analogues of beta-amyloid peptides, beta 1-42 and beta 1-40, bound to C1q and were strong activators of C as assessed by both total C consumption and C4 consumption. beta 1-42 was significantly more effective than beta 1-40 in binding to C1q and triggering C activation, whereas beta 1-28 demonstrated little or no binding or C activation. This C-activating capacity seems to be largely correlated with the assembly of the beta 1-42 into low speed sedimentable aggregates and/or macromolecular fibrils. Radiolabeled C1q and C1q-CLF bind specifically to these aggregates or amyloid fibrils. In addition, using synthetic C1q peptides in a solid phase binding assay, the major binding site of beta 1-42 to C1q was localized to the C1q A chain collagen-like residues 14-26, a region previously described as a novel interaction site for Ab-independent activators of C1. C1q A chain peptide 14-26 blocked the ability of beta-amyloid peptides to activate the classical C pathway, providing evidence that this relatively unrecognized mechanism of C activation (via binding to the C1q-CLF) may have crucial physiologic consequences. Finally, these observations provide further support for the hypothesis that C activation and inflammation may be a component in the pathogenesis of AD and suggest possibilities for modulating the progression of AD.

Alzheimer Disease↗
PubMed1994

Subpopulations of dystrophic neurites [correction of neuritis] in Alzheimer's brain with distinct immunocytochemical and argentophilic characteristics.

Using two monoclonal antibodies, tau-1 and PHF-1, and a sequential staining method combining double-labeling immunofluorescence and Bielschowsky silver staining, we have demonstrated the presence of two populations of dystrophic neurites (DNs) with distinct immunocytochemical and argentophilic characteristics. Tau-1 and PHF-1 immunoreactivity were co-localized in many DNs. However, approximately 20% of the DNs were immunoreactive for PHF-1 only. PHF-1 single-labeled DNs were not visible or very weak with Bielschowsky silver stain. Of DNs continuous with neurofibrillary tangles (NFTs), tau-1/PHF-1 double-labeled DNs were continuous with intracellular NFTs only, while PHF-1 single-labeled DNs were continuous with extracellular NFTs only. Furthermore, the population of DNs that cluster around extracellular NFTs is different from those that cluster around or within senile plaques. The combined use of tau-1 and PHF-1 immunocytochemistry may provide a more accurate indication of the number of extracellular DNs and extracellular NFTs, which may aid in the diagnosis of severe and advanced AD cases.

Aged↗
PubMed1994

Increased immunoreactivity for Jun- and Fos-related proteins in Alzheimer's disease: association with pathology.

The protein products of the Jun and Fos immediate early gene (IEG) families are cooperative transcriptional regulatory factors implicated in regulating the expression of many genes. The levels of a variety of proteins such as the amyloid precursor protein and basic fibroblast growth factor are altered in Alzheimer's disease (AD), thus the events regulating these changes are of interest. Both of these genes contain an activator protein-1 consensus sequence which may be responsive to regulation by immediate early genes. In order to evaluate the potential involvement of IEGs in AD pathology, we have examined Jun- and Fos-related protein immunoreactivity in control and AD brain. Specifically, we investigated the correspondence of immunoreactivity for Jun and Fos proteins with immunoreactivity for paired helical filament-1 (PHF-1), a marker for neurofibrillary tangles which recognizes abnormally phosphorylated tau, glial fibrillary acidic protein (GFAP), and thioflavine staining in double-labeling experiments. An intensification of both Jun and Fos immunoreactivity was observed in AD cases; in addition, both Jun and Fos immunoreactivity were colocalized with PHF-1 in some neurons in AD brain. Jun and Fos immunoreactivity were also colocalized with GFAP-positive astrocytes distributed in the cortex of AD and control cases, and surrounding thioflavine-stained plaques in AD brain. These observations suggest that members of the Jun and Fos IEG families may play a role in AD pathology.

Aged↗
PubMed1994

Seizure-associated induction of basic fibroblast growth factor and its receptor in the rat brain.

In order to assess the role of neuronal activity in the regulation of the fibroblast growth factor system, we examined changes in levels of basic fibroblast growth factor and the expression of its receptor-1 following seizures. Epileptiform activity was induced by kainate injection and the rats displaying seizures were killed 3, 6, 12 and 24 h after injection. To identify basic fibroblast growth factor and fibroblast growth factor receptor-1 immunoreactivity, we used a monoclonal antibody that binds to the biological active form of basic fibroblast growth factor and a monoclonal antibody that recognizes fibroblast growth factor receptor-1. In normal brain tissue, fibroblast growth factor staining was widely distributed throughout the brain and appeared to be localized within the nucleus of astrocytes. Starting 6 h after seizures, there was a progressive increase in basic fibroblast growth factor immunoreactivity. The seizure-induced effect on basic fibroblast growth factor immunoreactivity was expressed in astrocytes as an enlargement of the nucleus and a spreading of the staining to the processes. This phenomenon was particularly strong in the cerebral cortex and hippocampus. The fibroblast growth factor receptor-1 immunoreactivity was virtually absent in control brain tissue. By 3 h post-seizure induction, there was an increase in fibroblast growth factor receptor-1 immunoreactivity in the molecular layer of the dentate gyrus. After 6 h, fibroblast growth factor receptor-1-positive cells appeared in the stratum oriens along the CA1, CA2 and CA3 hippocampal subfields. This effect gradually expanded to other brain regions and by 24 h fibroblast growth factor receptor-1 immunoreactivity was distributed throughout the hippocampus and cerebral cortex. Fluorescent double labelling indicated that the fibroblast growth factor receptor-1 immunoreactivity was expressed in astrocytes. At 24 h, some fibroblast growth factor receptor-1 immunoreactivity was also observed in neuron-like cells located throughout the cerebral cortex and hippocampus. Since our results indicate that seizure activity modulates the expression of basic fibroblast growth factor and fibroblast growth factor receptor-1 levels, it is also possible that physiological stimulation might have similar effects. In addition, our results suggest that the fibroblast growth factor system may have a role in plasticity events triggered by physiological activity.

Animals↗
PubMed1994

Distribution of basic fibroblast growth factor in the developing rat brain.

Previous studies in vitro indicate that basic fibroblast growth factor participates in the survival, proliferation and differentiation of immature neural cells, predicting that it may have the same types of roles in vivo. In order to evaluate a possible role of basic fibroblast growth factor in neural development, we have examined its localization in the rodent brain at critical stages of development. We characterized basic fibroblast growth factor immunoreactivity at embryonic days 13 and 18, and postnatal days 1, 4, 6, 10, 20 and 90. Our results showed that basic fibroblast growth factor was transiently expressed by different cellular phenotypes throughout development. At embryonic day 13, basic fibroblast growth factor immunoreactivity was sparsely distributed in various cell phenotypes. At embryonic day 18, the primitive cerebral cortex showed basic fibroblast growth factor immunoreactivity within its emerging laminar structure, including the cortical plate and subplate regions. At postnatal day 1, basic fibroblast growth factor immunoreactivity was mostly concentrated in the hippocampal subfields cornu Ammon 1, cornu Ammon 2 and cornu Ammon 3, and neurons of the medical septum and the vertical limb of the diagonal band nuclei. At postnatal days 4-6, astrocyte-like cells showed basic fibroblast growth factor immunoreactivity for the first time during development. At this stage, basic fibroblast growth factor in the hippocampus was mostly shown within subfields cornu Ammon 2 and cornu Ammon 1. In the medical septum, just a few neuronal profiles were weakly stained, and basic fibroblast growth factor positive astrocytes appeared to accumulate around these basic fibroblast growth factor-stained neurons. At postnatal day 20, the adult pattern of basic fibroblast growth factor immunoreactivity was fully established. Astrocytes throughout the brain expressed basic fibroblast growth factor, and neuronal basic fibroblast growth factor was restricted to particular populations such as cingulate cortex and hippocampus. The cornu Ammon 2 subfield was the main neuronal location for basic fibroblast growth factor in the mature hippocampus. Our results showed that the cellular location of basic fibroblast growth factor changes during development, suggesting that basic fibroblast growth factor has multiple and evolving roles during histogenesis and differentiation of the CNS.

Animals↗
PubMed1994

Beta-amyloid-induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer's disease.

One neuropathological characteristic of Alzheimer's disease is an abundance of reactive astrocytes, particularly in association with senile plaques. Neither the factor(s) responsible for initiating the reactive astrocytosis nor the effects of this event on disease progression are known. We investigated the possibility that beta-amyloid protein, the primary constituent of plaques, contributes to reactive astrocytosis by comparing results derived from both culture studies and immunohistochemical analyses of Alzheimer brain tissue. We report that beta-amyloid peptides, in an aggregation-dependent manner, rapidly induce a reactive phenotype in cultured rat astrocytes. Reactive morphological changes are accompanied by increased immunoreactivities for glial fibrillary acidic protein and basic fibroblast growth factor. Although toxic to other types of central nervous system cells, aggregated beta-amyloid peptides do not significantly decrease astrocyte viability. Rather, the processes of cultured astrocytes envelop aggregated deposits of beta-amyloid peptide. In Alzheimer brain, the processes of reactive astrocytes were also observed to engulf beta-amyloid deposits. Similar to the in vitro findings, the astrocytic response was associated only with beta-amyloid plaques exhibiting an aggregated structure. Further, the plaque-associated reactive astrocytes showed enhanced immunoreactivities for glial fibrillary acidic protein and basic fibroblast growth factor. These data suggest that beta-amyloid which has assembled into beta-sheet fibrils significantly contributes to the reactive astrocytosis characteristic of Alzheimer's disease. Thus, in addition to its hypothesized direct effects on neuronal viability, beta-amyloid may also influence disease progression indirectly via reactive astrocytosis.

Aged↗
PubMed1994

Ca2+ channel blockers attenuate beta-amyloid peptide toxicity to cortical neurons in culture.

Deposit of beta-amyloid protein (A beta) in Alzheimer's disease brain may contribute to the associated neurodegeneration. We have studied the neurotoxicity of A beta in primary cultures of murine cortical neurons, with the aim of identifying pharmacologic ways of attenuating the injury. Exposure of cultures to A beta (25-35 fragment; 3-25 microM) generally triggers slow, concentration-dependent neurodegeneration (over 24-72 h). With submaximal A beta-(25-35) exposure (10 microM), substantial (> 40% within 48 h) degeneration often occurs and is markedly attenuated by the presence of the Ca2+ channel blockers nimodipine (1-20 microM) and Co2+ (100 microM) during the A beta exposure. However, A beta neurotoxicity is not affected by the presence of glutamate receptor antagonists. We suggest that Ca2+ influx through voltage-gated Ca2+ channels may contribute to A beta-induced neuronal injury and that nimodipine and Co2+, by attenuating such influx, are able to attenuate A beta neurotoxicity.

Amyloid beta-Peptides↗