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Increased expression of β-amyloid precursor protein, β-APP695 and β-APP751 mRNAs in the thalamus of ageing cynomolgus monkeys
Neuropeptides(1993) 24,2 1 l-22 1 Q Longmsn Group UK Ltd 1993
Session 3: Peptides in Neurological and Psychiatric Disorders Invited speaker - Neuropeptides in Schlzqhrenic Dlsorder and Their Regulation by Antipsychotic Agents
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 ZQR, UK
A. Saria, J. Marksteiner, C. Hurnpel, C. Miller, W. W. Fleischbacker Neurochemical Unit and Biological Psychiatry Research Unit, Department of Psych&y, University Hospital Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria Determination of tissue levels of neuropeptides in human brain haa previously failed to provide conclusive evidence for the involvement of a particular peptide in the pathophysiology of schizophrenia. Therefore, we focused on the investigation of neuropeptides in cerebrospinal fluid (CSF) and the regulation of their biosynthesis in brain after administration of antipsychotic agents in experimental animals. Investigation of immunoreactivities (IR) of substance P (SP), neurokinins (NK), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) in CSF obtained from drug-free, frrst episode schizophrenic patients revealed decreased SP-IR, increased CGRP-IR and unchanged NK-IR and VIP-lR. In experimental animals, treatment with antipsychotic agents lead to differential regulation of the biosynthesis of several neuropeptides in the brain. Thus, haloperidol e.g. decreased the mRNA for the tachykiis SP and neurokinin A. It increased, however, neurokinin B in basal ganglia. Changes of CGRP concentrations and release have been found in the amygdala after haloperidol. Therefore, both CSF studies in humans, as well as studies with antipsychotic agents in experimental animals indicate the participation of particular peptides in the pathophysiology of psychotic conditions.
Inhibition of Electricallyevoked Release of Substance P from Rat Spinal Cord Cl2 (-)Baclofen
M. Malcangio and N. G. Bowery Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, WClN 1AX London, UK
Cl1 Increased Expression of gamyloid Precursor Protein, p-APPm and pAPP,sl mRNAs in the Thalamus of Ageing Cynomolgur Monkeys D. J. S. Sirinat.hainghji, M. Rigby, R. Heavens, Schuligoi, D. Smith, A. Barranco, J. Femandez and S. D. Iversen
Altered expression of the alternatively spliced mRNAs of the p-APP molecule could influence post-translational processing in a manner that promotes Bamyloid deposition in Alzheimer’s disease (AD). To determine if the ageing process could influence these mechanisms, we studied by quantitative in situ hybridization histochemistry the mRNA expression of &APPs95,7~1.77o.714 inthe brains of ageing (17 years) and young (3 years) cynomolgus monkeys (M. fascicularis) using 3%-labelled probes specific to appropriate sequences of the human g-APP gene. Strong hybridization signals for P-APPs~~ and S-APPV~ (but not 770 or 714) were found in several brain regions associated with AD pathology (primary motor cortex, entorhinal cortex, temporal cortex, hippocampus). The ~~-APP&/~-APPz~ ratio was 2: 1 in most regions and this did not differ between the two groups of animals. However, intense labelling for 695 and 75 1 were found in thalamic nuclei (anterior dorsal, anterior ventrolateral, ventrolateral posterior, reticular) of the ageing monkeys. These patterns of labelling were not seen in the young animals. Although no plagues or tangles were detected by immunostaining with antibodies to &A4 or tau epitopes, the discrete mRNA changes may indicate early molecular events associated with the ageing/ neurodegenerative process.
Baclofen, P-parachlorophenylGABA, is antinociceptive in rodents and this effect is prevented by GABAs receptor antagonists including CGP 35348 (3-aminopropyl diethoxymethyl-phosphinic acid). The prolonged depression induced by baclofen on primary afferent neurons in
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211
Session 3: Peptides in Neurological and Psychiatric Disorders Invited speaker - Neuropeptides in Schlzqhrenic Dlsorder and Their Regulation by Antipsychotic Agents
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 ZQR, UK
A. Saria, J. Marksteiner, C. Hurnpel, C. Miller, W. W. Fleischbacker Neurochemical Unit and Biological Psychiatry Research Unit, Department of Psych&y, University Hospital Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria Determination of tissue levels of neuropeptides in human brain haa previously failed to provide conclusive evidence for the involvement of a particular peptide in the pathophysiology of schizophrenia. Therefore, we focused on the investigation of neuropeptides in cerebrospinal fluid (CSF) and the regulation of their biosynthesis in brain after administration of antipsychotic agents in experimental animals. Investigation of immunoreactivities (IR) of substance P (SP), neurokinins (NK), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) in CSF obtained from drug-free, frrst episode schizophrenic patients revealed decreased SP-IR, increased CGRP-IR and unchanged NK-IR and VIP-lR. In experimental animals, treatment with antipsychotic agents lead to differential regulation of the biosynthesis of several neuropeptides in the brain. Thus, haloperidol e.g. decreased the mRNA for the tachykiis SP and neurokinin A. It increased, however, neurokinin B in basal ganglia. Changes of CGRP concentrations and release have been found in the amygdala after haloperidol. Therefore, both CSF studies in humans, as well as studies with antipsychotic agents in experimental animals indicate the participation of particular peptides in the pathophysiology of psychotic conditions.
Inhibition of Electricallyevoked Release of Substance P from Rat Spinal Cord Cl2 (-)Baclofen
M. Malcangio and N. G. Bowery Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, WClN 1AX London, UK
Cl1 Increased Expression of gamyloid Precursor Protein, p-APPm and pAPP,sl mRNAs in the Thalamus of Ageing Cynomolgur Monkeys D. J. S. Sirinat.hainghji, M. Rigby, R. Heavens, Schuligoi, D. Smith, A. Barranco, J. Femandez and S. D. Iversen
Altered expression of the alternatively spliced mRNAs of the p-APP molecule could influence post-translational processing in a manner that promotes Bamyloid deposition in Alzheimer’s disease (AD). To determine if the ageing process could influence these mechanisms, we studied by quantitative in situ hybridization histochemistry the mRNA expression of &APPs95,7~1.77o.714 inthe brains of ageing (17 years) and young (3 years) cynomolgus monkeys (M. fascicularis) using 3%-labelled probes specific to appropriate sequences of the human g-APP gene. Strong hybridization signals for P-APPs~~ and S-APPV~ (but not 770 or 714) were found in several brain regions associated with AD pathology (primary motor cortex, entorhinal cortex, temporal cortex, hippocampus). The ~~-APP&/~-APPz~ ratio was 2: 1 in most regions and this did not differ between the two groups of animals. However, intense labelling for 695 and 75 1 were found in thalamic nuclei (anterior dorsal, anterior ventrolateral, ventrolateral posterior, reticular) of the ageing monkeys. These patterns of labelling were not seen in the young animals. Although no plagues or tangles were detected by immunostaining with antibodies to &A4 or tau epitopes, the discrete mRNA changes may indicate early molecular events associated with the ageing/ neurodegenerative process.
Baclofen, P-parachlorophenylGABA, is antinociceptive in rodents and this effect is prevented by GABAs receptor antagonists including CGP 35348 (3-aminopropyl diethoxymethyl-phosphinic acid). The prolonged depression induced by baclofen on primary afferent neurons in
R.
211