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Willem Hendrik Gispen - One of the best experts on this subject based on the ideXlab platform.
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Neurotrophic ACTH4–9 analogue therapy normalizes electroencephalographic alterations in chronic experimental allergic encephalomyelitis
The European journal of neuroscience, 1998Co-Authors: Henricus J. Duckers, J. Verhaagen, R P Van Dokkum, F.h. Lopes Da Silva, E.l.j.m. Van Luijtelaar, Anton M.l. Coenen, Willem Hendrik GispenAbstract:Chronic experimental allergic encephalomyelitis (CEAE) is an established experimental model for multiple sclerosis (MS). The demyelinating lesions in the white matter of the central nervous system observed in CEAE and in MS are accompanied by various neurophysiological alterations. Among the best defined electrophysiological abnormalities are the changes in event-related potentials, in particular evoked potentials involving the spinal cord, i.e. motor and sensory evoked potentials. Less familiar are the changes observed in the electroencephalogram of CEAE-affected animals, which are also encountered in the human equivalent, MS. In the present experiment we evaluated the therapeutic value of a Neurotrophic Peptide treatment [H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH, an ACTH4-9 analogue] and its effect on the delayed flash visual evoked potentials (VEP) and power spectra of the electroencephalogram, during a 17-week follow-up of CEAE. CEAE animals treated with the Neurotrophic Peptide were protected against the development of neurological symptoms during the course of the demyelinating syndrome. VEPs of animals suffering from CEAE showed a delay of the latencies of the late components which was significantly counteracted by Peptide treatment. The peak-to-peak amplitude of the VEP afterdischarge recorded from CEAE animals was significantly increased during the course of CEAE and correlated closely with the progression of the myelinopathy. Furthermore, CEAE animals showed an increase of electroencephalogram (EEG) beta activity of up to 500% as compared with the age-matched control group. This increase in beta power mainly consisted of a prevailing 20-21 Hz peak, a frequency that normally is not dominant in control EEG recordings of the rat during passive wakefulness. All these electrophysiological phenomena were absent in ACTH4-9 analogue-treated animals. The present findings underscore the potential importance of a Neurotrophic Peptide treatment in the pharmacotherapy of central demyelinating syndromes, and possibly of MS.
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Functional and neurophysiological evidence of the efficacy of trophic pharmacotherapy using an adrenocorticotrophic hormone4–9 analog in experimental allergic encephalomyelitis, an animal model of multiple sclerosis
Neuroscience, 1996Co-Authors: Henricus J. Duckers, J. Verhaagen, R P Van Dokkum, F.h. Lopes Da Silva, Willem Hendrik GispenAbstract:Chronic experimental allergic encephalomyelitis (CEAE) is a well-established animal model for the human syndrome, multiple sclerosis. CEAE has striking histological, electrophysiological and clinical analogies with multiple sclerosis and is a valuable animal model for the preclinical pharmacotherapeutical development of new putative therapeutic agents. In this paper, we describe a Neurotrophic repair approach in Lewis rats suffering from CEAE. The Neurotrophic Peptide used is a degradation resistant adrenocor- ticotrophic hormone,_ 9 analog. The development of CEAE was examined using a combination of clinical, functional and electrophysiological parameters including somatosensory and motor evoked potentials. The latencies and amplitudes of the various evoked potentials can provide quantitative, objective data regarding the involvement of different nerve tracts in CEAE and the effectiveness of the Neurotrophic Peptide. Repeated subcutaneous injections of the Neurotrophic Peptide suppressed the development of CEAE- related clinical symptoms, markedly improved motor performance and reduced the reaction time upon thermal stimulation as compared to saline-treated CEAE animals during a 17 week follow-up study. Prolonged onset latencies of corticomotor evoked potentials and peak latencies of somatosen- sory evoked potentials due to the demyelination were normalized upon Peptide treatment. In addition, Peptide treatment substantially prevented total blocking of the corticomotor pathway in CEAE-animals and reduced the attenuation of sensory evoked potentials-related peak amplitudes as compared to saline-treated animals. The functional and electrophysiological improvements observed in CEAE-animals treated with the adrenocorticotrophic hormone4_ 9 analog, suggest that a Neurotrophic repair approach could be of great value to promote the restoration of function in a disabling demyelinating disorder.
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Effective use of a neutrophic ACTH4–9 analogue in the treatment of a peripheral demyelinating syndrome (experimental allergic neuritis)
Brain, 1994Co-Authors: Henricus J. Duckers, J. Verhaagen, E De Bruijn, Willem Hendrik GispenAbstract:Summary Demyelinating syndromes are an important group of nerve disorders for which no effective therapy exists and which are life threatening in a substantial proportion of the patients. In the present experiments we assessed the ameliorative effect of Org 2766, a degradation resistant ACTH4–9 analogue devoid of corticotrophic and melanotrophic action in experimental allergic neuritis (EAN), an animal model for a human demyelinating disease, the Guillain-Barre syndrome (GBS). In order to mimic the clinical situation, Peptide treatment was initiated at the first appearance of neurological symptoms in each animal. The ACTH4–9 analogue treatment substantially suppressed the neurological symptoms in animals with EAN, as assessed by clinical scoring and resulted in a significant improvement of motor performance. Furthermore, histological examination of the sural nerve provided a morphological basis for the beneficial functional effect of Peptide treatment: more myelinated fibres were present in EAN animals treated with the ACTH4–9 analogue in comparison with EAN animals treated with saline. Further analysis of the sural nerve indicated a complete preservation of the diameter distribution of myelinated fibres in sural nerves of Peptide-treated animals. In contrast, saline-treated EAN animals exhibited a significant loss of small and intermediate size myelinated fibres in the sural nerves. This study provides first evidence for the amelioration of the functional and anatomical deficits in an animal model of the GBS syndrome by an interventive synthetic Neurotrophic Peptide treatment.
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The Neurotrophic analogue of ACTH(4-9), Org 2766, protects against experimental allergic neuritis
Brain, 1993Co-Authors: Henricus J. Duckers, J. Verhaagen, Willem Hendrik GispenAbstract:SUMMARY Demyelinating diseases such as multiple sclerosis or the Guillain-Barre syndrome originate from an autoimmune response resulting in the degradation of myelin and impaired neuronal function. Prophylactic administration of the Neurotrophic Peptide, H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH (an ACTH(4–9) analogue), to rats with experimental allergic neuritis, a model for the Guillain-Barre syndrome, markedly suppresses the clinical symptoms, protects against loss of motor coordination and prevents the degeneration of myelinated axons in the affected peripheral nerve. Therefore, this Peptide may provide a new approach to the therapy of peripheral demyelinating polyneuropathies.
Eliezer Masliah - One of the best experts on this subject based on the ideXlab platform.
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Chronic administration of the Neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia.
Journal of neuroscience research, 2011Co-Authors: Rubén Antonio Vázquez-roque, Edward Rockenstein, Anthony Adame, Fidel De La Cruz, Sergio Zamudio, Ismael Juárez, Brenda Ramos, Carolina Tecuatl, Raúl Mena, Eliezer MasliahAbstract:Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (Cbl), a Neurotrophic Peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether Cbl was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in Cbl-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in Cbl-treated nVHL rats. Cbl treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that Cbl promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that Cbl may have Neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that Cbl has beneficial effects in the management of schizophrenia symptoms.
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Neurotrophic effects of Cerebrolysin in the Mecp2^308/Y transgenic model of Rett syndrome
Acta Neuropathologica, 2008Co-Authors: Edith Doppler, Edward Rockenstein, Kiren Ubhi, Michael Mante, Anthony Adame, Herbert Moessler, Chandra Inglis, Leslie Crews, Monika Hitzl, Eliezer MasliahAbstract:Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG-binding protein (MeCP2). Neuropathological studies in patients with Rett syndrome and in MeCP2 mutant models have shown reduced dendritic arborization and abnormal neuronal packing. We have previously shown that Cerebrolysin (CBL), a Neurotrophic Peptide mixture, ameliorates the synaptic and dendritic pathology in models of aging and neurodegeneration. This study aimed to determine whether CBL was capable of reducing behavioral and neuronal alterations in Mecp2^308/Y mutant mice. Two sets of experiments were performed, the first with 4-month-old male Mecp2^308/Y mutant mice treated with CBL or vehicle for 3 months (Group A) and the second with 1-month-old mice treated for 6 months (Group B). Behavioral analysis showed improved motor performance with CBL in Group A and a trend toward improvement in Group B. Consistent with behavioral findings, neuropathological analysis of the basal ganglia showed amelioration of dendritic simplification in CBL-treated Mecp2^308/Y mutant mice. CBL treatment also ameliorated dendritic pathology and neuronal loss in the hippocampus and neocortex in Mecp2^308/Y mutant mice. In conclusion, this study demonstrates that CBL promotes recovery of dendritic and neuronal damage and behavioral improvements in young adult Mecp2^308/Y mutant mice and suggests that CBL may have Neurotrophic effects in this model. These findings support the possibility that CBL may have beneficial effects in the management of Rett syndrome.
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Neurotrophic effects of Cerebrolysin in the Mecp2(308/Y) transgenic model of Rett syndrome.
Acta neuropathologica, 2008Co-Authors: Edith Doppler, Edward Rockenstein, Kiren Ubhi, Michael Mante, Anthony Adame, Herbert Moessler, Chandra Inglis, Leslie Crews, Monika Hitzl, Eliezer MasliahAbstract:Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG-binding protein (MeCP2). Neuropathological studies in patients with Rett syndrome and in MeCP2 mutant models have shown reduced dendritic arborization and abnormal neuronal packing. We have previously shown that Cerebrolysin (CBL), a Neurotrophic Peptide mixture, ameliorates the synaptic and dendritic pathology in models of aging and neurodegeneration. This study aimed to determine whether CBL was capable of reducing behavioral and neuronal alterations in Mecp2308/Y mutant mice. Two sets of experiments were performed, the first with 4-month-old male Mecp2308/Y mutant mice treated with CBL or vehicle for 3 months (Group A) and the second with 1-month-old mice treated for 6 months (Group B). Behavioral analysis showed improved motor performance with CBL in Group A and a trend toward improvement in Group B. Consistent with behavioral findings, neuropathological analysis of the basal ganglia showed amelioration of dendritic simplification in CBL-treated Mecp2308/Y mutant mice. CBL treatment also ameliorated dendritic pathology and neuronal loss in the hippocampus and neocortex in Mecp2308/Y mutant mice. In conclusion, this study demonstrates that CBL promotes recovery of dendritic and neuronal damage and behavioral improvements in young adult Mecp2308/Y mutant mice and suggests that CBL may have Neurotrophic effects in this model. These findings support the possibility that CBL may have beneficial effects in the management of Rett syndrome.
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Amelioration of the cerebrovascular amyloidosis in a transgenic model of Alzheimer's disease with the Neurotrophic compound cerebrolysin.
Journal of neural transmission (Vienna Austria : 1996), 2004Co-Authors: Edward Rockenstein, Anthony Adame, Herbert Moessler, Leslie Crews, M. Mante, G. Larrea, M. Windisch, Eliezer MasliahAbstract:Increased production and reduced clearance of amyloid β (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease (AD). We have recently shown that the Neurotrophic Peptide mixture Cerebrolysin™ (Cbl) has the ability of improving synaptic functioning and reducing amyloid deposition in a transgenic (tg) animal model of Alzheimer’s disease (AD). Since in AD, potentially toxic Aβ aggregates accumulate not only around neurons but also in the blood vessels, then it is important to investigate whether bioactive compounds such as Cbl might have the capacity to ameliorate the age-related cerebral amyloid angiopathy (CAA) in tg models. To this end, tg mice expressing mutant human amyloid precursor protein (APP) under the Thy1 promoter were treated with Cbl or saline alone starting at 7 or 12 months of age for a total of three months. Neuropathological analysis with an antibody against Aβ showed that Cbl decreased amyloid deposition around the blood vessels in a time dependant manner. These effects were accompanied by a reduction in perivascular microgliosis and astrogliosis and increased expression of markers of vascular fitness such as CD31 and ZO-1. No lymphocytic infiltration was observed associated with Aβ in the vessels. Consistent with these findings, ultrastructural analysis showed that while in tg mice treated with saline alone there was an abundant accumulation of amyloid fibers in the vascular wall accompanied by thickening of the basal membrane and endothelial cell damage, in Cbl-treated mice there was considerable reduction in the subcellular alterations of endothelial and smooth muscle cells with preservation of basal membranes and intercellular junctions. Taken together, these results suggest that Cbl treatment might have beneficial effects in patients with cognitive impairment due to cerebrovascular amyloidosis by reducing Aβ accumulation and promoting the preservation of the cerebrovasculature.
J. Verhaagen - One of the best experts on this subject based on the ideXlab platform.
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Neurotrophic ACTH4–9 analogue therapy normalizes electroencephalographic alterations in chronic experimental allergic encephalomyelitis
The European journal of neuroscience, 1998Co-Authors: Henricus J. Duckers, J. Verhaagen, R P Van Dokkum, F.h. Lopes Da Silva, E.l.j.m. Van Luijtelaar, Anton M.l. Coenen, Willem Hendrik GispenAbstract:Chronic experimental allergic encephalomyelitis (CEAE) is an established experimental model for multiple sclerosis (MS). The demyelinating lesions in the white matter of the central nervous system observed in CEAE and in MS are accompanied by various neurophysiological alterations. Among the best defined electrophysiological abnormalities are the changes in event-related potentials, in particular evoked potentials involving the spinal cord, i.e. motor and sensory evoked potentials. Less familiar are the changes observed in the electroencephalogram of CEAE-affected animals, which are also encountered in the human equivalent, MS. In the present experiment we evaluated the therapeutic value of a Neurotrophic Peptide treatment [H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH, an ACTH4-9 analogue] and its effect on the delayed flash visual evoked potentials (VEP) and power spectra of the electroencephalogram, during a 17-week follow-up of CEAE. CEAE animals treated with the Neurotrophic Peptide were protected against the development of neurological symptoms during the course of the demyelinating syndrome. VEPs of animals suffering from CEAE showed a delay of the latencies of the late components which was significantly counteracted by Peptide treatment. The peak-to-peak amplitude of the VEP afterdischarge recorded from CEAE animals was significantly increased during the course of CEAE and correlated closely with the progression of the myelinopathy. Furthermore, CEAE animals showed an increase of electroencephalogram (EEG) beta activity of up to 500% as compared with the age-matched control group. This increase in beta power mainly consisted of a prevailing 20-21 Hz peak, a frequency that normally is not dominant in control EEG recordings of the rat during passive wakefulness. All these electrophysiological phenomena were absent in ACTH4-9 analogue-treated animals. The present findings underscore the potential importance of a Neurotrophic Peptide treatment in the pharmacotherapy of central demyelinating syndromes, and possibly of MS.
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Functional and neurophysiological evidence of the efficacy of trophic pharmacotherapy using an adrenocorticotrophic hormone4–9 analog in experimental allergic encephalomyelitis, an animal model of multiple sclerosis
Neuroscience, 1996Co-Authors: Henricus J. Duckers, J. Verhaagen, R P Van Dokkum, F.h. Lopes Da Silva, Willem Hendrik GispenAbstract:Chronic experimental allergic encephalomyelitis (CEAE) is a well-established animal model for the human syndrome, multiple sclerosis. CEAE has striking histological, electrophysiological and clinical analogies with multiple sclerosis and is a valuable animal model for the preclinical pharmacotherapeutical development of new putative therapeutic agents. In this paper, we describe a Neurotrophic repair approach in Lewis rats suffering from CEAE. The Neurotrophic Peptide used is a degradation resistant adrenocor- ticotrophic hormone,_ 9 analog. The development of CEAE was examined using a combination of clinical, functional and electrophysiological parameters including somatosensory and motor evoked potentials. The latencies and amplitudes of the various evoked potentials can provide quantitative, objective data regarding the involvement of different nerve tracts in CEAE and the effectiveness of the Neurotrophic Peptide. Repeated subcutaneous injections of the Neurotrophic Peptide suppressed the development of CEAE- related clinical symptoms, markedly improved motor performance and reduced the reaction time upon thermal stimulation as compared to saline-treated CEAE animals during a 17 week follow-up study. Prolonged onset latencies of corticomotor evoked potentials and peak latencies of somatosen- sory evoked potentials due to the demyelination were normalized upon Peptide treatment. In addition, Peptide treatment substantially prevented total blocking of the corticomotor pathway in CEAE-animals and reduced the attenuation of sensory evoked potentials-related peak amplitudes as compared to saline-treated animals. The functional and electrophysiological improvements observed in CEAE-animals treated with the adrenocorticotrophic hormone4_ 9 analog, suggest that a Neurotrophic repair approach could be of great value to promote the restoration of function in a disabling demyelinating disorder.
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The Neurotrophic Peptide Org 2766 does not influence the expression of the immediate early gene c-fos following sciatic nerve crush in the rat
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 1994Co-Authors: L.c. Plantinga, J. Verhaagen, S.l. Wong, P.m. Edwards, Peter R. Bär, W.h. GispenAbstract:Abstract The Neurotrophic Peptide Org 2766 accelerates the regeneration of peripheral nerves. Although the mechanism of action of this neuroPeptide is not yet understood, functional, pharmacological, and morphological evidence has demonstrated that Org 2766 exerts its beneficial effect during the early stages of nerve regeneration. The induction of some members of the Immediate Early Gene (IEG) family such as c-jun and c-fos is one of the first molecular events following peripheral nerve damage. The Fos and Jun proteins act as a transcription factor and may stimulate the expression of a number of genes implicated in nerve regeneration. We examined whether Org 2766 stimulates nerve regeneration by enhancing or prolonging the expression of c-fos mRNA. Following a crush lesion of the sciatic nerve, the expression of c-fos mRNA was induced in the spinal cord and in the damaged nerve at 30 min following injury in untreated animals as demonstrated with Northern blot. No effect of the crush lesion was observed in dorsal root ganglia (DRG). The induction of c-fos mRNA in the damaged nerve was more robust as compared to the relatively small induction observed in the spinal cord. With in situ hybridization an increase in c-fos mRNA expression both in the dorsal and in the ventral horn of the spinal cord was demonstrated at 30 min post-lesion. In the distal sciatic nerve portion the expression of c-fos mRNA was predominantly localized around Schwann cell nuclei at 30 min after nerve crush. The effect of Org 2766 treatment on the expression of c-fos mRNA was investigated using semiquantitative dot blots. Dot blots containing RN A samples of DRG, spinal cord or sciatic nerve of control animals, saline treated and Org 2766 treated animals isolated 15 min, 30 min, l hr, 1 day and 2 days following nerve crush were scanned densitometrically. No significant effect of Org 2766 on the expression of c-fos mRNA was detected. We conclude that Org 2766 does not stimulate peripheral nerve regeneration by affecting the expression of the c-fos mRNA following sciatic nerve crush. The putative effect of Org 2766 on other immediate early transcription factors of the fos and jun family is currently under investigation.
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Effective use of a Neurotrophic ACTH4-9 analogue in the treatment of a peripheral demyelinating syndrome (experimental allergic neuritis). An intervention study.
Brain : a journal of neurology, 1994Co-Authors: H J Duckers, J. Verhaagen, E De Bruijn, W.h. GispenAbstract:Demyelinating syndromes are an important group of nerve disorders for which no effective therapy exists and which are life threatening in a substantial proportion of the patients. In the present experiments we assessed the ameliorative effect of Org 2766, a degradation resistant ACTH4-9 analogue devoid of corticotrophic and melanotrophic action in experimental allergic neuritis (EAN), an animal model for a human demyelinating disease, the Guillain-Barré syndrome (GBS). In order to mimic the clinical situation, Peptide treatment was initiated at the first appearance of neurological symptoms in each animal. The ACTH4-9 analogue treatment substantially suppressed the neurological symptoms in animals with EAN, as assessed by clinical scoring and resulted in a significant improvement of motor performance. Furthermore, histological examination of the sural nerve provided a morphological basis for the beneficial functional effect of Peptide treatment: more myelinated fibres were present in EAN animals treated with the ACTH4-9 analogue in comparison with EAN animals treated with saline. Further analysis of the sural nerve indicated a complete preservation of the diameter distribution of myelinated fibres in sural nerves of Peptide-treated animals. In contrast, saline-treated EAN animals exhibited a significant loss of small and intermediate size myelinated fibres in the sural nerves. This study provides first evidence for the amelioration of the functional and anatomical deficits in an animal model of the GBS syndrome by an interventive synthetic Neurotrophic Peptide treatment.
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Effective use of a neutrophic ACTH4–9 analogue in the treatment of a peripheral demyelinating syndrome (experimental allergic neuritis)
Brain, 1994Co-Authors: Henricus J. Duckers, J. Verhaagen, E De Bruijn, Willem Hendrik GispenAbstract:Summary Demyelinating syndromes are an important group of nerve disorders for which no effective therapy exists and which are life threatening in a substantial proportion of the patients. In the present experiments we assessed the ameliorative effect of Org 2766, a degradation resistant ACTH4–9 analogue devoid of corticotrophic and melanotrophic action in experimental allergic neuritis (EAN), an animal model for a human demyelinating disease, the Guillain-Barre syndrome (GBS). In order to mimic the clinical situation, Peptide treatment was initiated at the first appearance of neurological symptoms in each animal. The ACTH4–9 analogue treatment substantially suppressed the neurological symptoms in animals with EAN, as assessed by clinical scoring and resulted in a significant improvement of motor performance. Furthermore, histological examination of the sural nerve provided a morphological basis for the beneficial functional effect of Peptide treatment: more myelinated fibres were present in EAN animals treated with the ACTH4–9 analogue in comparison with EAN animals treated with saline. Further analysis of the sural nerve indicated a complete preservation of the diameter distribution of myelinated fibres in sural nerves of Peptide-treated animals. In contrast, saline-treated EAN animals exhibited a significant loss of small and intermediate size myelinated fibres in the sural nerves. This study provides first evidence for the amelioration of the functional and anatomical deficits in an animal model of the GBS syndrome by an interventive synthetic Neurotrophic Peptide treatment.
Shoei Furukawa - One of the best experts on this subject based on the ideXlab platform.
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ALTERED PRODUCTION OF NERVE GROWTH FACTOR IN CULTURED VASCULAR SMOOTH MUSCLE CELLS FROM GENETICALLY HYPERTENSIVE RATS
Clinical and experimental pharmacology & physiology. Supplement, 1995Co-Authors: Takashi Ueyama, Masanori Hamada, Takuzo Hano, Ichiro Nishio, Shoei FurukawaAbstract:Summary 1. Nerve growth factor (NGF) is a Neurotrophic Peptide for peripheral sympathetic nerves. Hypotrophy of sympathetic nerve ganglia and reduced content of neuroPeptide Y were reported in genetically hypertensive (GH) rats. These facts led us to consider that production of NGF might be altered in GH rat cells. 2. Vascular smooth muscle cells (VSMC) were prepared from the aortic media of 12 week old GH rats and age-matched normotensive (NT) rats by enzyme digestion method. Growth rates and the maximum cell densities were fairly equivalent between GH cells and NT cells. 3. The NGF content in the medium was measured using an enzyme immunoassay against mouse beta NGF. The amount of NGF secreted from VSMC of GH were 1.2pg/104 cells per 48 h in the progressive phase and 0.7 pgj 104 cells per 48 h in the quiescent phase, while those of NT were 8 pg/104 cells per 48 h and 1pg/104 cells per 48 h, respectively. The levels of NGF secretion per cells were greater in NT cells. In summary, NGF secretion from VSMC were reduced in GH. 4. These results suggested that a reduced production of NGF from VSMC might be involved in the reported hypotrophy of sympathetic nerve cells in GH.
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Increased nerve growth factor levels in spontaneously hypertensive rats.
Journal of hypertension, 1992Co-Authors: Takashi Ueyama, Masanori Hamada, Takuzo Hano, Ichiro Nishio, Yoshiaki Masuyama, Shoei FurukawaAbstract:OBJECTIVE Increased sympathetic innervation has been reported in spontaneously hypertensive rats (SHR); however, the precise mechanisms involved are not yet clear. Nerve growth factor (NGF), a Neurotrophic Peptide in peripheral sympathetic neurons, is believed to contribute to this phenomenon. METHODS We measured the content of NGF in SHR and control Wistar-Kyoto (WKY) rats during development. Mesenteric artery, spleen, heart and sciatic nerve were isolated and homogenized. NGF content in the supernatant fractions was measured using a highly sensitive and specific two-site enzyme immunoassay. RESULTS At 3 weeks of age, SHR had a greater NGF content in the spleen, the sciatic nerve and the mesenteric artery than WKY rats. However, these differences disappeared completely at 12 weeks of age. Cardiac NGF content was slightly lower in 3-week-old SHR and, conversely, higher in 12-week-old SHR than in age-matched WKY rats. CONCLUSIONS These findings suggest that, except for the heart, the SHR tissues observed overproduce NGF at a young age, leading to enhancement of peripheral sympathetic nervous system activity and the production of vasoconstrictive catecholamines.
Mutsumi Maruyama - One of the best experts on this subject based on the ideXlab platform.
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Identification and Molecular Cloning of a Novel Brain-specific Receptor Protein That Binds to Brain Injury-derived Neurotrophic Peptide
2001Co-Authors: Tokiko Hama, Mutsumi Maruyama, Ritsuko Katoh-semba, Mari Takizawa, Makio Iwashima, Kiyomitsu Nara, Mitsubishi KagakuAbstract:Brain injury-derived Neurotrophic Peptide (BINP) is a synthetic 13-mer Peptide that supports neuronal survival and protects hippocampal neurons in primary cultures from cell death caused by glutamate. We have developed a monoclonal antibody named mAb 6A22 against the 40-kDa BINP-binding protein, p40BBP. mAb 6A22 inhibits binding between BINP and rat brain synaptosomes and abolishes the protective effect of BINP. The antigen of mAb 6A22 should be the BINP-binding protein that mediates the neuroprotective action of BINP. Using an expression cloning approach with mAb 6A22, we isolated a cDNA encoding a novel receptor protein that shows binding activity of BINP. COS7 cells transfected with the cloned cDNA show binding of BINP and cell surfaces that are stained by 6A22. The mRNA for p40BBP is specific for the rat brain and is increased after birth. From immunohistochemical studies using mAb 6A22, p40BBP increased after kainic acid treatment in rat hippocampal neurons.
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Development of an antibody against a 40,000 mol. wt brain injury-derived Neurotrophic Peptide-binding protein and identification of a 40,000 mol. wt brain injury-derived Neurotrophic Peptide-binding protein in hippocampal neurons.
Neuroscience, 2000Co-Authors: Tokiko Hama, Mutsumi MaruyamaAbstract:Abstract Brain injury-derived Neurotrophic Peptide is a 13-amino acid Peptide derived from a 15,000 mol. wt Neurotrophic factor released from sites of mechanical injury in neonatal rat brain. This Peptide promotes survival of septal cholinergic neurons and mesencephalic dopaminergic neurons, and protects hippocampal neurons from glutamate-induced neurotoxicity. In this study, we have developed a monoclonal antibody against a brain injury-derived Neurotrophic Peptide-binding protein by immunizing mice with septal synaptosomes from five-week-old rat brain. Monoclonal antibodies were screened for inhibition of the binding of a 125 I-labeled analogue of brain injury-derived Neurotrophic Peptide to rat brain synaptosomes. The monoclonal antibody 6A22 suppressed the biological activity of brain injury-derived Neurotrophic Peptide and abolished the protective effect of the Neurotrophic Peptide against glutamate-induced neurotoxicity. This monoclonal antibody recognized a 40,000 mol. wt brain injury-derived Neurotrophic Peptide-binding protein, which was also identified by cross-linking experiments. Immunohistochemical studies showed that the 6A22 antibody bound to the cell surfaces of a subpopulation (about 60%) of hippocampal neurons in culture. These results are consistent with the possibility that the 40,000 mol. wt protein belongs to brain injury-derived Neurotrophic Peptide receptors.
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Characteristics of brain injury-derived Neurotrophic Peptide-binding sites on rat brain synaptosomes and neurons in culture.
Neuroscience, 1999Co-Authors: Mutsumi Maruyama, Kazuki Sato, A. Ohtake, Akihiko Ogura, Tokiko HamaAbstract:Abstract Brain injury-derived Neurotrophic Peptide is the fragmental 13-mer Peptide of the novel Neurotrophic factor which was extracted and purified from Sponge Gelform made of gelatin implanted at the mechanically-induced injury site in neonatal rat brains. Brain injury-derived Neurotrophic Peptide supports survival of septal cholinergic and mesencephalic dopaminergic neurons in culture, and rescues hippocampal neurons in culture from glutamate neurotoxicity. Here we studied the binding characteristics of brain injury-derived Neurotrophic Peptide to synaptosomes from normal adult rat brains and neurons in culture from neonatal rat brains. [ 125 I]Asp-[Tyr 11 ]-brain injury-derived Neurotrophic Peptide binding to rat brain synaptosomes was specific and saturable. Equilibrium binding studies revealed that [ 125 I]Asp-[Tyr 11 ]-brain injury-derived Neurotrophic Peptide bound to 1.1 pmol/mg protein with a K d (dissociation constant) of 0.17 μM in hippocampal synaptosomes and to 2.0 pmol/mg protein with a K d of 0.38 μM in septal synaptosomes. [ 125 I]Asp-[Tyr 11 ]-brain injury-derived Neurotrophic Peptide could bind to a subpopulation of hippocampal neurons in culture from embryonic rat brains. Affinity cross-linking with the car☐yl-reactive cross-linking reagent I-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl and [ 125 I]Asp-[Tyr 11 ]-brain injury-derived Neurotrophic Peptide produced radiolabeled bands corresponding to 100,000, 50,000 and 40,000 mol. wt molecules on hippocampal neurons in culture. These results suggest that the 13-mer sequence of brain injury-derived Neurotrophic Peptide plays a crucial role in expressing the Neurotrophic properties of the factor.