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Biomedical subjects

A Adem

Publications and source records attributed to A Adem.

At least 73 records · Page 4Linked to original sources
PubMed1994

Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis.

Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous system. The regional distribution of insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by immunohistochemistry and quantitative autoradiography. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. IGF-1 receptor immunoreactivity showed a similar pattern to that for 125I-IGF-1 binding, with immunoreactivity being found in the gray matter of the spinal cord and enhanced immunoreactivity occuring in ALS patients compared to controls. In agreement with the distribution of IGF-1 receptors, IGF-1 immunoreactivity was found within the gray matter of the spinal cord. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.

Aged↗
PubMed1994

A novel anticholinesterase THB013: biochemical and behavioural studies.

Clinical trials with tacrine (THA) have resulted in elevations of liver enzymes in Alzheimer patients that showed improvement. In an effort to minimize these side effects several THA analogues were synthesized. These analogues were compared to THA in biochemical as well as behavioural studies. In this study, the biochemical effects of THA and one of these analogs, THB 013, on plasma cholinesterase activity, cholinergic receptors as well as the effect of these drugs on spatial learning in adult rats were examined. THB 013 was, at lower concentration, more efficacious in inhibiting plasma cholinesterase as well as blocking the scopolamine induced disruption of spatial learning when administered 10 min before the scopolamine injection. It is possible that THB 013 with more potent cholinergic effects than THA might be useful in the treatment of Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

Sex differences in binding of human growth hormone to rat brain.

The binding of 125I-human growth hormone (125I-hGH) to membranes from female and male rat brain was studied. The binding was time-, pH- and protein concentration-dependent. The binding capacities calculated for the hormone were higher in the female brain (12.1 fmol/mg protein) than in the male brain (4.5 fmol/mg protein). In the female brain, saturation isotherms yielded dissociation constants (Kd) of 6.2 x 10(-10) and 4.5 x 10(-8) M and maximal binding (Bmax) of 2.9 and 8.4 fmol/mg protein for the high and low affinity binding sites, respectively, and in the male brain a Kd of 2.3 x 10(-9) M and a Bmax of 3.5 fmol/mg protein. Displacement studies indicated that in the female brain the binding of 125I-hGH was inhibited in a dose-dependent manner more potently by lactogenic than by somatogenic hormones. The rank order of potencies of these hormones to inhibit the binding of 125I-hGH was hGH > hPRL > rPRL > oGH > rGH. However, in the male brain the inhibition of 125I-hGH binding was found to be most pronounced by somatogenic hormones with the rank order of hGH > oGH > rGH > hPRL > rPRL. These findings indicate the presence of specific binding sites for hGH in the rat brain. The level as well as the properties of these sites vary in the two sexes, with higher levels in the female brain as compared to the male brain. Moreover, these sites display predominantly lactogenic characteristics in the female brain and almost exclusively somatogenic characteristics in the male brain.

Animals↗
PubMed1994

Somatogenic and lactogenic binding sites in rat brain and liver: quantitative autoradiographic localization.

The distribution of somatogenic and lactogenic binding sites in female and male rat brain as well as in liver was studied by quantitative receptor autoradiography using 125I-human growth hormone (125I-hGH) as a ligand. Quantitative measurement of binding sites for 125I-hGH showed differences in the levels of these sites in the female and male brain and liver. Moreover, regional differences in the brain were also observed in each sex. In the female brain high levels of 125I-hGH binding sites were found in the choroid plexus. Intermediate levels were observed in the striatum, the hypothalamus and the hippocampus, whereas low levels of these sites were found in the central gray, the temporal, the piriform and the entorhinal cortices. In the male brain high levels of 125I-hGH binding sites were detected in the choroid plexus. Intermediate levels were observed in the parietal cortex, the hypothalamus and the hippocampus, whereas low levels were found in the tegmentum, the temporal cortex and the striatum. Quantification of 125I-hGH binding sites in the liver revealed higher levels in the female than in the male liver. In general, higher levels of binding sites (16%-77%) were observed in the female than in the male tissues. The quantification of rat growth hormone (rGH) by radioimmunoassay was also performed in this study. Varying amounts of rGH immunoreactivity were detected in the different brain regions, with the highest levels of rGH-like material being found in the midbrain and cortex of both sexes. Moreover, higher levels of rGH-like material were observed in the female than in the male brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Decrease of somatostatin receptor binding in the rat cerebral cortex after ibotenic acid lesion of the nucleus basalis magnocellularis: a quantitative autoradiographic study.

The specific binding of 125I-Tyr11-somatostatin-14 (125I-Tyr11-SS-14) was measured in different cortical regions after unilateral ibotenic acid lesion of the rat nucleus basalis magnocellularis (NBM). A marked loss of acetylcholinesterase-positive fibers was observed in the frontal, parietal, temporal and occipital cortices ipsilateral to the lesion. The loss of cholinergic cell bodies in the NBM was further investigated with choline-acetyltransferase (ChAT) immunohistochemistry which indeed demonstrated a loss of ChAT-positive magnocellular perikarya. Autoradiographic analyses of specific binding of 125I-Tyr11-SS-14 demonstrated a significant reduction in binding density in the denervated parts of the neocortex. The decrease in specific binding was most pronounced (40-50%) in the superficial layers (I-III) of the frontal, parietal and temporal cortices 2 and 4 weeks after lesion. A significant loss in 125I-Tyr11-SS-14 binding in the deeper layers was only observed in the frontal cortex after 2 and 4 weeks. In the occipital cortex a significant decrease was measured in the superficial layers only after 4 weeks. The specific binding in all cortical regions returned to normal after 6 weeks. The results suggested that 125I-Tyr11-SS-14 binding sites are localized on cholinergic afferents in the rat neocortex and that an up-regulation of number of binding sites, alternatively an increased binding affinity occurred with time after lesion.

Animals↗
PubMed1993

Different regulatory patterns of M1 and M2 muscarinic receptor subtype RNA in SH-SY5Y human neuroblastoma induced by phorbol ester or DMSO.

The human neuroblastoma cells SH-SY5Y were treated with the differentiation agents 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or dimethyl sulfoxide (DMSO) and the muscarinic receptor subtype M1 and M2 RNA levels analyzed. After a decrease induced by both agents, the M1 level gradually returned to normal in the presence of TPA but remained minimal with DMSO. As for M2, several phases were observed with TPA, while DMSO caused a drastic increase. The data obtained with TPA were tentatively correlated with the amounts of immunoreactive PKC alpha. In conclusion, our results reveal: (a) differential regulation of M1 and M2 muscarinic receptor subtypes by either treatment; (b) opposing effects of TPA and DMSO on both subtypes.

Blotting, Northern↗
PubMed1993

Effects of nucleus basalis lesion on muscarinic receptor subtypes.

The cholinergic system in the central nervous system is an important component of the neural circuitry of learning, memory and cognition. A decline of cholinergic innervation in the human brain is a characteristic feature of dementia of Alzheimer's type. In this study, changes in cholinergic markers were studied after a unilateral lesion of the nucleus basalis magnocellularis (nbM). Acetylcholinesterase (AChE) histochemistry showed a loss of cortical AChE-containing neurons, and choline acetyltransferase (ChAT) immunohistochemistry demonstrated a loss of cholinergic cells in nbM. The localizations of muscarinic M1 and M2 receptors using [3H]pirenzepine ([3H]PZ) and [3H]AF-DX 384, respectively, were studied by quantitative autoradiography 1, 2, 4 and 6 weeks following unilateral ibotenic acid lesion of nbM. A significant decrease in [3H]PZ binding sites was observed at postlesion week 1 in the parietal and temporal cortices. The decrease in [3H]AF-DX 384 binding sites on the lesioned side was observed throughout frontal, parietal and temporal cortices after postlesion week 1, with a significant increase after 6 weeks, possibly as result of loss of presynaptic receptors and upregulation of postsynaptic ones. Moreover, laminar distribution after nbM lesion shows that M1 and M2 receptor binding sites are more affected in superficial layers (I,II,III) than in the deep layers (IV,V,VI), depending on ligand, postlesion period and cortical region. Furthermore, nbM lesion causes a higher deficit of M2 receptors than of M1 receptors. These data suggest the existence of a presynaptic population as well as a postsynaptic population of M1 and M2 receptors which are differently affected after unilateral nbM lesion.

Acetylcholinesterase↗
PubMed1993

The next generation of cholinesterase inhibitors.

Clinical trials with tacrine (THA) have resulted in elevations of liver enzymes in Alzheimer patients that showed improvement. In an effort to minimize these side effects several THA analogues were synthesized. These analogues were compared to THA in biochemical as well as behavioural studies. The biochemical effects of these drugs on plasma cholinesterase activity and cholinergic receptors as well as the effect of these drugs on spatial learning in adult rats were examined. It is possible that some of these analogues with more potent cholinergic effect than THA might be the next generation of cholinesterase inhibitors which can be useful in the treatment of Alzheimer's disease.

Acetylcholine↗
PubMed1992

Characterisation of dopamine and serotonin uptake inhibitory effects of tetrahydroaminoacridine in rat brain.

The effects of 1,2,3,4-tetrahydro-9-aminoacridine (THA) on uptake rates of radioactive 5-hydroxytryptamine (5-HT) and dopamine were investigated in rat diencephalon and striatal homogenates, respectively. Six and eight microM of THA were needed to inhibit 50% of dopamine and 5-HT uptake rates. Kinetic parameters, Km and Vmax, using six different concentrations of dopamine and 5-HT were estimated in the presence or absence of THA. A significant decrease in Vmax without any change in Km values was observed for both dopamine and 5-HT in the presence of THA. The results show that THA is a non-competitive uptake inhibitor of dopamine and 5-HT in the nerve terminals. The re-uptake blocking effect of THA on dopaminergic and serotonergic neurones, following THA treatment, might lead to increased levels of these monoamines in brains of Alzheimer patients and contribute in the therapeutic effects of the drug.

Analysis of Variance↗
PubMed1992

Pharmacokinetics of tetrahydroaminoacridine: relations to clinical and biochemical effects in Alzheimer patients.

The pharmacokinetics of tetrahydroaminoacridine (THA) was studied in patients suffering from Alzheimer's dementia. Single doses of the drug were administered by intravenous (15 mg), oral (50 mg) and rectal routes (25 mg). Pharmacokinetic parameters were related to clinical and biochemical effects in patients who, in a separate study, participated in a clinical trial of oral THA. The bioavailability of THA was low and varied considerably between subjects. Clinical improvement and occurrence of elevated liver enzymes correlated positively with drug bioavailability. Acetyl and butyryl cholinesterase activities in the plasma did not change following THA administration. Rectally administered THA had a higher bioavailability than orally administered THA in three subjects who were given the drug by both routes. These results indicate that a clinical trial of rectal THA would be justified as this administration route may improve resorption and diminish first-pass metabolism of the drug in the liver compared with oral administration.

Administration, Oral↗
PubMed1991

A comparison of the binding of nicotine and nornicotine stereoisomers to nicotinic binding sites in rat brain cortex.

Both stereoisomers of nicotine and nornicotine were tested for their ability to competitively displace 3H-(-)-nicotine and 3H-acetylcholine (in the presence of atropine), in rat cortex tissue. 3H-acetylcholine was displaced from two binding sites, super-high and high, by (+)-nicotine, (-)-nornicotine and (+)-nornicotine but from a high affinity site by (-)-nicotine. 3H-nicotine was displaced from two sites, high and low affinity by nicotine and nornicotine stereoisomers. The high-affinity 3H-(-)-nicotine binding site showed similar binding characteristics to one of the sites labelled by 3H-acetylcholine. IC50 values showed (-)-nicotine to be 13 and 25-fold more potent than (+)-nicotine for displacing 3H-(-)-nicotine and 3H-acetylcholine, respectively, but no difference was observed for nornicotine stereoisomers. While (-)-nicotine preferentially bound to the high affinity site of 3H-(-)-nicotine (+)-nicotine preferred the low affinity site. The study provides further evidence for multiple nicotine receptors in brain.

Animals↗
PubMed1991

Amino acid sequence of a snake venom toxin that binds to the muscarinic acetylcholine receptor.

The green mamba, Dendroaspis angusticeps, has two protein toxins that bind to the muscarinic acetylcholine receptor. The sequence of muscarinic toxin 2 was determined with an automatic gas phase sequencer. The C-terminal residue is Asp as determined by hydrazinolysis and amino acid analysis. Toxin 2 has 65 amino acid residues and a formula weight of 7040. It is homologous to a large number of other snake venom toxins as short alpha-neurotoxins, cardiotoxins/cytotoxins and angusticeps-type toxins of mamba venoms. The sequence is confirmed in the accompanying article (Ducancel, F., Rowan, E.G., Cassart, E., Harvey, A. L., Menez, A. and Boulain, J.-C. Toxicon 29, 516-520, 1991).

Amino Acid Sequence↗
PubMed1990

Multiple effects of tetrahydroaminoacridine on the cholinergic system: biochemical and behavioural aspects.

9-Amino-1,2,3,4-tetrahydroaminoacridine (THA) in combination with lecithin has been reported to improve the memory of Alzheimer's disease patients. We have examined some properties of THA in vitro and in vivo so as to define some of the mechanism(s) by which THA might produce its therapeutic effects. In vitro, THA was more potent at inhibiting human plasma cholinesterase (IC50 = 0.03 microM) than human erythrocyte acetylcholinesterase (IC50 = 0.3 microM) and rat brain acetylcholinesterase (IC50 = 0.32 microM). Radioligand binding studies indicated that THA binds reversibly and competitively to primary M1 and M2 human cortical muscarinic receptors with similar affinities. Moreover, THA showed similar affinity for temporal cortices muscarinic receptors from Alzheimer and non-Alzheimer (control) brains. In vivo, subcutaneous administration of THA (1-8 mg/kg body weight) to adult rats (6 months old) produced a dose dependent decrease in general activity compared to saline-treated rats. However, at a concentration of 0.5 mg/kg body weight, the general activity of the rats was increased compared to saline-treated rats. The cognitive function of the THA-treated adult rats (subcutaneously 2 mg/kg body weight) was not significantly improved compared to saline-treated rats. It is concluded that the mechanisms of action of THA on the cholinergic system involve reversible inhibition of cholinesterases and reversible and competitive interaction with muscarinic acetylcholine receptors. These effects might be of therapeutic value in the treatment of Alzheimer's disease.

Aged↗
PubMed1989

Tetrahydroaminoacridine inhibits human and rat brain monoamine oxidase.

The inhibitory effects of 1,2,3,4-tetrahydro-9-aminoacridine (THA) on monoamine oxidase (MAO; EC 1.4.3.4) enzyme activities in human hippocampal and rat striatal homogenates have been studied. The activities of MAO-A and MAO-B were estimated radiochemically, in-vitro, in human hippocampus and rat striatum in the presence of various concentrations of THA with [2-14C]hydroxytryptamine binoxalate (100 microM) and beta-[ethyl-14C]phenylethylamine hydrochloride (20 microM) as substrates for the respective enzyme form. THA was found to inhibit both MAO-A and MAO-B activities reversibly and competitively, with inhibition constants (Ki) of 12.5 microM and greater than 500 microM respectively, of the rat striatal enzymes. From this it can be extrapolated that at therapeutic tissue concentrations of THA (10(-8) to 10(-6) M), more than 20% of the MAO-A activity should be inhibited. Thus it is possible that inhibition of MAO may be involved in the therapeutic action of THA in Alzheimer's disease.

Aged↗
PubMed1989

Insulin-like growth factor 1 (IGF-1) receptors in the human brain: quantitative autoradiographic localization.

The distribution of Insulin-like growth factor 1 (IGF-1) receptors in large cryosections of human brain hemispheres (80-microns) was studied by quantitative autoradiography using 125I-IGF-1 as ligand. Postmortem tissue only from individuals free from neurological diseases was used. The highest densities of IGF-1 receptors were found in the hippocampus, amygdala and parahippocampal gyrus. Intermediate densities were observed in the cerebellum, cerebral cortex and caudate nucleus, whereas low densities of IGF-1 receptors were obtained in the substantia nigra, red nucleus, white matter and cerebral pedunculus. The cartography of IGF-1 receptors in the normal human brain will hopefully be of use in the study of the alteration of these receptors in diseased brain.

Aged↗
PubMed1989

Quantitative autoradiography of nicotinic receptors in large cryosections of human brain hemispheres.

In vitro quantitative autoradiography was used to visualize nicotinic receptors in large cryosections of human brain hemispheres. Sections 80 microns thick of human brain hemispheres were incubated with (-)-[3H]nicotine and the distribution of nicotinic receptors in human brain was studied. Increasing numbers of nicotinic binding sites were observed in the: hippocampus less than cortex less than cerebellum less than substantia nigra less than putamen less than periaqueductal gray. The cartography of nicotinic receptors in the normal human brain will hopefully be of use in the study of the alteration of these receptors in diseased brain.

Aged↗