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PubMed1990

Identification of a domain in cytochrome C that displaces [3H]TCP binding from rat brain membrane receptors: synthesis of beta-neuroprotectin.

1. A stereospecific radioreceptor binding assay for the phencyclidine analogue, [3H]TCP, was utilized to screen for inhibition of binding in extracts of rat brain. 2. Extracts were prepared from rat cerebral cortex and hippocampus by methods employing aqueous acid. The extracts were fractionated by reversed phase-HPLC (RP-HPLC) and tested for activity in the radioreceptor assay. Three zones of activity were detected. The middle zone was further purified by high performance-size exclusion chromatography (HP-SEC). 3. Size exclusion chromatography revealed a single zone of activity corresponding to mol. wts of ca 12,000-31,000 daltons. A fraction from this zone was digested with trypsin, and the resulting enzyme fragments, isolated by a combination of HP-SEC and RR-HPLC, were identified as fragments of rat cytochrome C. 4. Horse cytochrome C was digested with trypsin and the fragments were similarly purified on the basis of the [3H]TCP binding displacement assay. The fragments were sequenced and found to be trypsin cleavage products of a single largely invariant domain of the cytochrome C molecule: Lys-Lys-Lys-Asp-Glu-Arg-Ala-Asp-Leu-Ile-Ala-Tyr-Leu-Lys-Lys. 5. beta-neuroprotectin (D)-Ala-Asp-Leu-Ile-Ala-Tyr-Leu-NH2, inhibits [3H]TCP binding and provides protection against NMDA mediated neuronal cell death at low concentrations.

Amino Acid Sequence↗
PubMed1995

NE-100, a novel sigma ligand: effects on [3H]TCP binding to intact primary cultured neuronal cells.

N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), a potent and highly selective sigma ligand, haloperidol, (+)pentazocine, 1-(cyclopropyl-methyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl) piperidine HBr (DuP 734) and 4-(2'-(4"-cyanophenyl)-2'-oxoethyl) 1-(cyclopropylmethyl)piperidine (XJ 448) inhibited carbachol-induced inositol 1,4,5-triphosphate (IP3) formation in a dose-dependent manner. The rank order of potency of the tested drugs for inhibition was: haloperidol > or = (+)pentazocine = NE-100 > DuP 734 = XJ 448. In addition, the effects of NE-100, DuP 734 and XJ 448 upon [3H]TCP binding were examined using primary cultured neuronal cells derived from the fetal rat telencephalon. These drugs inhibited [3H]TCP binding to intact cells. The ability of the test drugs to inhibit [3H]TCP binding to primary cultured neuronal cells was in the order: NE-100 > DuP 734 > XJ 448. These observations suggest that NE-100 indirectly modulates the N-methyl-D-aspartate (NMDA)/phencyclidine (PCP) receptor ion channel complex (NMDA receptor-ion channel), presumably through sigma-1 sites.

Animals↗
PubMed1986

Autoradiographic distribution of phencyclidine receptors in the rat brain using [3H]1-(1-(2-thienyl)cyclohexyl)piperidine ([3H]TCP).

The distribution of phencyclidine (PCP) receptors in the rat brain was determined by autoradiography using 1-(1-(2-thienyl)cyclohexyl)piperidine ([3H]TCP). [3H]TCP appeared to bind to PCP receptors as only PCP-like drugs and sigma-opioids inhibited the binding of [3H]TCP. The areas of the rat brain with the highest density of radiolabeled binding sites were the superficial layers of cerebral cortex, hippocampus and dentate gyrus. Moderate densities of binding sites were found in the medial geniculate nuclei, caudate nucleus, nucleus accumbens, interpeduncular nucleus, superior colliculus, periaqueductal gray and cerebellum. Low densities of binding sites were observed in spinal cord, most of the brainstem, the substantia nigra and most of the hypothalamus.

Animals↗
PubMed1987

[3H]TCP binding sites in Alzheimer's disease.

Quantitative autoradiography was used to determine the density and distribution of [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine ([3H]TCP) binding sites in human hippocampal tissue sections from control and Alzheimer's disease patients. Some Alzheimer's cases showed no changes in binding site density while other cases showed substantial declines in the CA1 region. [3H]TCP binding in the CA1 region from Alzheimer's patients was reduced an average of 40% while the other hippocampal regions were unaffected. It is proposed that the loss of [3H]TCP sites in the hippocampal CA1 region of certain Alzheimer's cases is associated with the greater cell loss observed in cases of severe Alzheimer's disease.

Alzheimer Disease↗
PubMed1987

Loss of hippocampal [3H]TCP binding in Alzheimer's disease.

We have previously demonstrated a marked loss in N-methyl-D-aspartate (NMDA) receptors in the hippocampus and cerebral cortex of patients dying with dementia of the Alzheimer type (DAT). In addition, we have found that the dissociative anesthetic N-(1-[2-thienyl]cyclohexyl)3,4-piperidine ([3H]TCP) binds to a site whose regional distribution is highly correlated with that of NMDA receptor sites. We studied the binding of [3H]TCP to sections of hippocampi from 8 controls, 12 patients with DAT and 7 patients with other dementias. [3H]TCP binding was significantly reduced in strata pyramidalia of CA1/CA2, CA3 and subiculum of DAT hippocampal formation compared to that of control. Labelled dissociative anesthetics could potentially be used with positron emission tomography in the diagnosis of DAT.

Alzheimer Disease↗
PubMed1990

TCP shortens the latency of onset of isoelectricity in hypoglycaemia and fails to protect striatal neurones and dentate gyrus granule cells from hypoglycaemic injury in rats.

Competitive N-methyl-D-aspartate (NMDA) receptor antagonists are known to protect neurones against hypoglycaemic damage. We tested N-[1-(2-thienyl)cyclohexyl]piperidine (TCP), a non-competitive NMDA antagonist, in a recovery model of hypoglycaemic coma in the rat. Administered concomitantly with insulin, TCP shortened the latency of onset of electrocerebral silence, and failed to prevent striatal and dentate gyrus hypoglycaemia-induced injury. This effect is probably related to an increase in glucose consumption of neurones: TCP enhances energy metabolism in several brain structures, which could facilitate, at low blood glucose levels, the onset of isoelectricity, and hamper a putative neuro-protective effect of the drug.

Animals↗
PubMed1991

Autoradiographic visualisation of [3H]DTG binding to sigma receptors, [3H]TCP binding sites, and L-[3H]glutamate binding to NMDA receptors in human cerebellum.

The autoradiographic distributions of [3H]1,3-di-ortho-tolyguanidine ([3H]DTG), [3H]1-[1-(2-thienyl) cyclohexyl] piperidine ([3H]TCP) and L-[3H]glutamate were studied in the human cerebellum. [3H]DTG is a selective label for the sigma receptor, while L-[3H]glutamate binding was carried out under conditions selective for the N-methyl-D-aspartate (NMDA) receptor. [3H]TCP binding sites and sigma receptors showed marked enrichment in the Purkinje cell layer, while L-[3H]glutamate-labelled NMDA receptors showed virtually no binding in the Purkinje cell layer. The results confirm the existence of [3H]TCP binding sites which are not linked to NMDA receptors in the human cerebellum, having a distribution which is more similar to that of the haloperidol-sensitive sigma receptor.

Autoradiography↗
PubMed1989

Excitatory amino acid receptors in the human cerebral cortex: a quantitative autoradiographic study comparing the distributions of [3H]TCP, [3H]glycine, L-[3H]glutamate, [3H]AMPA and [3H]kainic acid binding sites.

The excitatory amino acids are probably the major neurotransmitters in the cerebral cortex, and they act through at least three receptors: the N-methyl-D-aspartate, the quisqualate and the kainic acid receptors. Under the appropriate conditions, [3H]1-(1-(2-thienyl)-cyclohexyl)piperidine [( 3H]TCP), [3H]glycine and L-[3H]glutamate label different sites on the N-methyl-D-aspartate receptor, [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [( 3H]AMPA) labels the quisqualate receptor and [3H]kainic acid the kainic acid receptor. The anatomical localizations of these binding sites were studied in sections of blocks removed from the cerebral cortices of eight post-mortem human brains. The results showed that, in the human cerebral cortex, [3H]TCP, [3H]glycine and L-[3H]glutamate binding sites had congruent distributions, with [3H]AMPA binding sites showing a similar distribution. In the hippocampus, these four ligands had high binding site densities in the CA1 region and the dentate gyrus molecular layer. With the exception of the striate cortex, in the neocortex, a tri-laminar pattern was seen consisting of a high density across laminae I-III, a layer of low density corresponding to the region of lamina IV, and a band of moderate density across laminae V and VI, except for [3H]AMPA where the middle zone of low density was usually wider. [3H]Kainic acid showed a binding pattern which was generally complementary to that of the other four ligands. There were low levels of [3H]kainic acid binding sites in the CA1 region of the hippocampus with higher levels in the CA3 region, the hilus, and the inner third of the dentate gyrus molecular layer. In the neocortex there was a band of high density corresponding to laminae V and VI, with a thin band of moderate binding corresponding to lamina I and the outer region of lamina II. An exception was the motor cortex where the highest level of [3H]kainic acid binding was in laminae I and II. The high degree of congruence between the binding patterns of [3H]TCP, [3H]glycine and L-[3H]glutamate (using conditions appropriate for the N-methyl-D-aspartate receptor) supports data indicating that these ligands bind to different regions of the same receptor complex. The similar distribution of [3H]AMPA binding sites, with the exception of the striate cortex, supports observations made in rodents that N-methyl-D-aspartate receptors and quisqualate receptors have similar distributions and perform different but related functions in excitatory transmission.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Reversible interaction of beta-actin along the channel of the TCP-1 cytoplasmic chaperonin.

The cytoplasm of eukaryotes contains a heteromeric toroidal chaperonin assembled from the t-complex TCP-1 and several other related polypeptides. The structure of the TCP-1 cytoplasmic chaperonin and that of the binary complex formed between this chaperonin and unfolded beta-actin have been studied using electron microscopy and image processing techniques. Two-dimensional averaging of front views reveals a circular stain-excluding mass surrounding a central stain-penetrating region in which the stain is excluded upon actin binding. Sections of a three-dimensional reconstruction of the chaperonin show that the inner core is an empty channel that becomes filled upon binary complex formation with unfolded beta-actin. Upon incubation with Mg-ATP, the beta-actin:chaperonin complex discharges the actin such that the chaperonin central cavity reappears. Side views from different forms of TCP-1 reveals that upon Mg-ATP binding, the cytoplasmic chaperonin undergoes a structural rearrangement that is confirmed using a new classification method.

Actins↗
PubMed2003

Waiting times for radiotherapy: consequences of volume increase for the TCP in oropharyngeal carcinoma.

BACKGROUND AND PURPOSE: Waiting lists for radiotherapy have become longer over the past years. Apart from the psychological distress for the patient we are concerned about tumour growth during this waiting time, which may worsen prognosis. The purpose of this pilot study was to investigate tumour growth in the waiting time and to obtain an indication of its clinical consequences for patients with oropharyngeal carcinoma. A tumour control probability (TCP) model was applied to evaluate consequences for outcome. METHODS AND MATERIALS: Increase in tumour volume was measured for 13 patients with oropharyngeal carcinoma by outlining the tumour on the diagnostic as well as on the treatment planning CT scan. Waiting time was defined as time between histopathological diagnosis and start of radiotherapy. For each tumour we calculated the increase in tumour volume and the tumour doubling time. The potential increase in TCP was calculated for each tumour for the situation without treatment delay. RESULTS: The mean increase in tumour volume was 70%. The mean waiting time was 56 days. Expected TCP with incorporation of delay was 47%, without delay it might have been 63-66%. CONCLUSION: This study shows tumour progression during the time between the diagnostic CT scan and the treatment planning CT scan in oropharyngeal cancer. As a consequence of waiting time, which allows tumour volume increase, there may be an average control loss of 16-19 % for these tumours during the total waiting time before radiotherapy.

Aged↗
PubMed2002

Fixation of the NexGen HA-TCP-coated cementless, screwless total knee arthroplasty: comparison with conventional cementless total knee arthroplasty of the same type.

We performed a 12-month prospective study on 59 patients (92 knees) who underwent NexGen (Zimmer Inc, Warsaw, IN) cruciate-retaining total knee arthroplasty. In the control group, uncoated components were fixed using screws, whereas the hydroxyapatite-tricalcium phosphate (HA-TCP) group underwent screwless fixation of coated components. At 12 months postoperatively, there was a radiographic clear zone around the femoral and tibial components of 56.5% and 32.6% of the knees in the control group. The HA-TCP group showed a clear zone at the medial aspect of the tibial component in only 1 knee. These results suggested that HA-TCP-coated articular components show good initial fixation without using screws. The NexGen coated knee arthroplasty may be useful for solving the problems of cementless fixation.

Aged↗
PubMed2006

Does a local bystander effect necessitate a revision of TCP models that are based on observed clinical data?

It is shown that in order to derive a general model for tumor control probability (TCP) the two assumptions that on the microscopic level (1) clonogens are non-interacting and (2) clonogen killings are uncorrelated events are not necessary. In fact, these two assumptions can be replaced with two weaker ones that only ask that (a) therapy fractions are independent and non-overlapping and (b) the probability of an event only depends on the number of incidents happening during a time interval and the length of this time interval but not on time itself. This change in assumptions implies that TCP models based on clinical data are flexible enough to include interaction of clonogens on the microscopic level and therefore also a possible bystander effect in cell killing. Based on this new set of assumptions the equation for TCP is derived, first for the homogenous case and then for the general case of a heterogeneous ensemble of tumors irradiated in-homogeneously.

Bystander Effect↗
PubMedDate not supplied

Morphometric evaluation of tissue-implant reaction associated with ALCAP and TCP bioceramics in vivo.

The purpose of this investigation was to correlate the thickness of the fibrous capsule and the various histological components surrounding aluminum-calcium phosphate (ALCAP) and tricalcium phosphate (TCP) bioceramics at the subcutaneous (sc) and intraperitoneal (ip) implantation sites. The rational of conducting this investigation is to further elucidate the mechanisms of tissue-implant interaction. Thirteen Sprague-Dawley adult male albino rats were randomly divided into three groups. Animals in groups I and II (n = 5/group) were implanted at both ip and sc implantation sites with either ALCAP or TCP ceramics, respectively. Animals in group III (n = 3) were not implanted and served as the intact control for the comparative purposes. At 90 days postimplantation, the animals in all groups were euthanized (Ketamine/Zylazane) and the fibrous tissue surrounding the ceramic devices was retrieved. After routine histological processing, sections (5 microm) of tissue was stained with hematoxylin and eosin (H&E) and evaluated using light microscopy. With the exception ofneutrophils, at both implantation sites, the fibrous tissues surrounding the TCP bioceramics demonstrated greater capsular thickness, more vascularity, and more macrophages, fibroblasts, and collagen than those surrounding the ALCAP ceramic. Data obtained from this investigation provided further insights into the differences in the tissue-implant responses of calcium-phosphate-based ceramics and the cellular composition of the fibrous tissue reaction found at sc and ip implantation sites.

Abdomen↗
PubMed2003

Evolution of the TCP gene family in Asteridae: cladistic and network approaches to understanding regulatory gene family diversification and its impact on morphological evolution.

In the plant subclass Asteridae, bilaterally symmetrical flowers have evolved from a radially symmetrical ancestral phenotype on at least three independent occasions: in the Boraginaceae, Solanaceae, and Lamiales. Development of bilateral flower symmetry has been shown to be determined by the early-acting cycloidea (cyc) and dichotoma (dich) genes in Antirrhinum, a member of the Lamiales. cyc and dich belong to the TCP gene family of putative transcription factors. TCP gene sequences were isolated from 11 Asteridae taxa using an array of degenerate PCR primers. Closely related species exhibiting either ancestral actinomorphic or derived zygomorphic flowers were sampled for each independent origin of bilateral flower symmetry. Cladistic and network-based analyses were performed to establish viable hypotheses regarding the evolution of bilateral symmetry in Asteridae. For the TCP gene family, the use of cladistic phylogenetic analysis to identify orthologous genes is complicated by a paucity of alignable data, frequent gene duplication and extinction, and the possibility of reticulate evolution via intergenic recombination. These complicating factors can be generalized to many regulatory gene families. As an alternative to cladistic analysis, we propose the use of network analysis for the reconstruction of regulatory gene family phylogenetic and functional relationships. Results of analyses support the hypothesis that the origin of bilaterally symmetrical flowers in the Boraginaceae and Solanaceae did not require orthologs or functional analogs of cyc or dich. This suggests that the genetic mechanism that determines bilateral flower symmetry in these taxa is not homologous to that of the Lamiales. Results of analyses are consistent with the hypothesis that the evolution of bilateral floral symmetry in the Lamiales required the origin of a novel gene function subsequent to gene duplication.

Amino Acid Sequence↗
PubMed1994

Coadministration of atropine, NBQX and TCP against soman-induced seizures.

The ability of relatively low doses of atropine, NBQX and TCP administered in combination to prevent or stop seizures induced by soman, was studied in rats. While these drugs injected together early after soman prevented the onset of seizures, their delayed concomitant administration after 5 or 30 min of epileptic activity only mildly attenuated the intensity of seizures. Conversely, a total arrest of epileptic activity was observed in 80 to 100% of animals when NBQX and TCP were given together after 5 to 50 min of seizures to atropine pretreated rats. The large time-window for antiepileptic effectiveness of this 'three drug treatment', provided that atropine is administered early after soman, is discussed in relation to reciprocal potentiations of the antiepileptic effects of atropine, NBQX and TCP in combination.

Animals↗
PubMed2003

A phylogenomic investigation of CYCLOIDEA-like TCP genes in the Leguminosae.

Numerous TCP genes (transcription factors with a TCP domain) occur in legumes. Genes of this class in Arabidopsis (TCP1) and snapdragon (Antirrhinum majus; CYCLOIDEA) have been shown to be asymmetrically expressed in developing floral primordia, and in snapdragon, they are required for floral zygomorphy (bilaterally symmetrical flowers). These genes are therefore particularly interesting in Leguminosae, a family that is thought to have evolved zygomorphy independently from other zygomorphic angiosperm lineages. Using a phylogenomic approach, we show that homologs of TCP1/CYCLOIDEA occur in legumes and may be divided into two main classes (LEGCYC group I and II), apparently the result of an early duplication, and each class is characterized by a typical amino acid signature in the TCP domain. Furthermore, group I genes in legumes may be divided into two subclasses (LEGCYC IA and IB), apparently the result of a duplication near the base of the papilionoid legumes or below. Most papilionoid legumes investigated have all three genes present (LEGCYC IA, IB, and II), inviting further work to investigate possible functional difference between the three types. However, within these three major gene groups, the precise relationships of the paralogs between species are difficult to determine probably because of a complex history of duplication and loss with lineage sorting or heterotachy (within-site rate variation) due to functional differentiation. The results illustrate both the potential and the difficulties of orthology determination in variable gene families, on which the phylogenomic approach to formulating hypotheses of function depends.

Amino Acid Sequence↗
PubMed1995

Evolution of the chaperonin families (Hsp60, Hsp10 and Tcp-1) of proteins and the origin of eukaryotic cells.

The members of the 10 kDa and 60 kDa heat-shock chaperonin proteins (Hsp10 and Hsp60 or Cpn10 and Cpn60), which form an operon in bacteria, are present in all eubacteria and eukaryotic cell organelles such as mitochondria and chloroplasts. In archaebacteria and eukaryotic cell cytosol, no close homologues of Hsp10 or Hsp60 have been identified. However, these species (or cell compartments) contain the Tcp-1 family of proteins (distant homologues of Hsp60). Phylogenetic analysis based on global alignments of Hsp60 and Hsp10 sequences presented here provide some evidence regarding the evolution of mitochondria from a member of the alpha-subdivision of Gram-negative bacteria and chloroplasts from cyanobacterial species, respectively. This interference is strengthened by the presence of sequence signatures that are uniquely shared between Hsp60 homologues from alpha-purple bacteria and mitochondria on one hand, and the chloroplasts and cyanobacterial hsp60s on the other. Within the alpha-purple subdivision, species such as Rickettsia and Ehrlichia, which live intracellularly within eukaryotic cells, are indicated to be the closest relatives of mitochondrial homologues. In the Hsp60 evolutionary tree, rooted using the Tcp-1 homologue, the order of branching of the major groups was as follows: Gram-positive bacteria--cyanobacteria and chloroplasts--chlamydiae and spirochaetes--beta- and gamma-Gram-negative purple bacteria--alpha-purple bacteria--mitochondria. A similar branching order was observed independently in the Hsp10 tree. Multiple Hsp60 homologues, when present in a group of species, were found to be clustered together in the trees, indicating that they evolved by independent gene-duplication events. This review also considers in detail the evolutionary relationship between Hsp60 and Tcp-1 families of proteins based on two different models (viz. archaebacterial and chimeric) for the origin of eukaryotic cell nucleus. Some predictions of the chimeric model are also discussed.

Amino Acid Sequence↗
PubMed1999

Long-term changes in brain following continuous phencyclidine administration: an autoradiographic study using flunitrazepam, ketanserin, mazindol, quinuclidinyl benzilate, piperidyl-3,4-3H(N)-TCP, and AMPA receptor ligands.

Phencyclidine induces a model psychosis which can persist for prolonged periods and presents a strong drug model of schizophrenia. When given continuously for several days to rats, phencyclidine and other N-methyl-D-aspartate (NMDA) antagonists induce neural degeneration in a variety of limbic structures, including retrosplenial cortex, hippocampus, septohippocampal projections, and piriform cortex. In an attempt to further clarify the mechanisms underlying these degeneration patterns, autoradiographic studies using a variety of receptor ligands were conducted in animals 21 days after an identical dosage of the continuous phencyclidine administration employed in the previous degeneration studies. The results indicated enduring alterations in a number of receptors: these included decreased piperidyl-3,4-3H(N)-TCP (TCP), flunitrazepam, and mazindol binding in many of the limbic regions in which degeneration has been reported previously. Quinuclidinyl benzilate and (AMPA) binding were decreased in anterior cingulate and piriform cortex, and in accumbens and striatum. Piperidyl-3,4-3H(N)-TCP binding was decreased in most hippocampal regions. Many of these long-term alterations would not have been predicted by prior studies of the neurotoxic effects of continuous phencyclidine, and these results do not suggest a unitary source for the neurotoxicity. Whereas retrosplenial cortex, the structure which degenerates earliest, showed minimal alterations, some of the most consistent, long term alterations were in structures which evidence no immediate signs of neural degeneration, such as anterior cingulate cortex and caudate nucleus. In these structures, some of the receptor changes appeared to develop gradually (they were not present immediately after cessation of drug administration), and thus were perhaps due to changed input from regions evidencing neurotoxicity. Some of these findings, particularly in anterior cingulate, may have implications for models of schizophrenia.

Animals↗