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Neurotrophic factors: Biology & clinical potential
S-34 Neurotrophic Factors: Neuropsychiatric Implications
96 inositol reduction in rat cortex after therapeutic doses or chronic Li is small and that PI levels are not affected. We recently found that chronic Li in rats did not reduce cortical inositol levels but did so markedly in hippocampus. Thus regional specificity may be important in investigating the inositol depletion hypothesis. Jope and Williams (1995) recently reported that effects of inositol to antagonize behavioral effects of Li also occur with epi-inosirol, a stereoisomer not usually thought to have biological activity. Further studies of biological effects of epi-inositol are necessary to evaluate the meaning of this finding. We have found that oral inositol 12 gm daily had significant therapeutic effects in depression, panic and obsessivecompulsive disorder in controlled double-blind trials. Moreover, we found that post-mortem cortical inositol levels are significantly reduced in bipolar patients and suicides compared with controls. These results suggest that Li does not simply reduce inositol levels, but that inositol may be involved in a more complex manner in affective disorder and Li action. Batty and Downes (1995) recently reported that inositol levels modulate phospholipase C activity in a complex manner independent of PI levels.
I8-33-51Lithium Effects on Protein Phosphorylation in Bipolar and Healthy Subjects
R. Zanardi, G. Racagni, E. Smeraldi, J. Perez. Dpt of Neuropsychiatric Sciences HSR, Milan, Italy
Several lines of evidence indicate that protein phosphorylation system is involved in the regulation of almost all neuronal functions. Moreover, cAMP-dependent phosphorylation system is a target in the action of antidepressant drugs and lithium. We have investigated basal and cAMPdependent endogenous phosphorylation in platelets fromeuthymic bipolar patients and from healthy volunteers before and after 15 days of lithium treatment. The major polypeptides stimulated by cAMP had apparent molecular weights of 22 and 38 kDa. cAMP-dependent phosphorylation of the 22 kDa protein band was significantly increased in euthymic bipolar patients with respect to controls. Lithium significantly enhanced basal and cAMP-dependent phosphorylation of both 22 and 38 kDa proteins in euthymic bipolar patients, while no significant difference was observed in healthy volunteers. This study could provide a better understaining of the involvement of cAMP-signaling in the pathophysiology of mood disorders and in the action of lithium salts.
15-341 Neurotrophic Factors: Neuropsychiatric Implications
I8-34-1 I NGF, Howit all Began and HowModern
Technologies Confirm and Expand the Original Hypothesis
E. Shooter. Department of Neurolbiology. Stanford University School of Medicine, Stanford, USA
Early studies in neuroembryology showed that the size of a peripheral field determined the density of its innervation. This led to the idea that the target provided molecules for nerve growth and differentiation. The first of these, NGF, was discovered in a mouse sarcoma which, when transplanted near the leg bud of a chick embryo, induced massive fiber ingrowth from spinal and sympathetic ganglia (I ]. The serendipitous discovery of NGF in snake venom and the adult mouse submaxillary gland permitted its partial purification, the preparation of an antibody against NGF and the demonstration that neutralizing endogenous NGF in the new born rat with the antibody prevented the development of all sympathetic neurons. The subsequent demonstration of the retrograde flow of NGF in sympathetic and sensory fibers firmly established the hypothesis that target derived neurotrophins control neuronal cell death during development. The phenotypes of mice in which the genes for either a neurotrophin or its trk receptor have been knocked out fully support this hypothesis at least for peripheral neurons. Recent extensions of the hypothesis come from the findings that neurons can switch neurotrophin dependency early in development, but still rely on one specific neutrophin
to control cell death, and that an autocrine or paracrine supply of a second neurotrophin can support a neuron in adult life. [I ] Levi-Montalcini R. Hamburger V, J. Exp . Zool. 116 (1951) 32l-362.
I 8-34-21Modulation of Activity-Dependent Neuronal Plasticity: A New Facet of Neurotrophin Action H. Thoenen. Dept. of Neurochemistry, Max Planck Institute fo r Psychiatry, Maninsried, Gennany
The function of neurotrophins was, to date, predominantly considered under the aspect of the regulation of survival and differentiation of specific populations of neurons during embryonic development and the maintenance of their characteristic neuronalfunctions in adulthood. However, there is increasing evidence that neurotrophins are also involved in neuronal plasticity. The evidence for this evolves from different sets of experiments in vivo and ill vitro. In rats and kittens, the local administration of NGF, BDNF, NT-4/5 and the corresponding blocking antibodies dramatically influence the activity-dependent developmental changes of the visual cortex, in particular ocular dominance. The shortcoming of this system is that it does not allow to analyze the underlying mechanisms at a cellular and molecular level. However, there is complementary information from various in vitro and in vivo systems, indicating that neurotrophins are rapidly and highly specifically regulated by neuronal activity, that neurotrophins are released in an activity-dependent manner not only from the neuronal cell body, but also from dendritic processes, and that neurotrophins initiate the release of conventional transmitters, such as acetylcholine, glutamate and dopamine from neurons which express the appropriate signal-transducing tyrosine kinase trk receptors. This is a scenario which is compatible with the interpretation that neurotrophins modulate the strength and stability of specific subsets of synapses in an activity-dependent manner. This interpretation is strongly supported by the observation that, in hippocampal slices of BDNF deficient mice, LTP in the CA3/CA I system is strongly impaired, and that LTPcan be restored by adenovirus-mediated BDNF gene transfer into the CAI neurons.
I8-34-31 Neurotrophic Factors: Biology & Clinical Potential R.M. Lindsay. Regeneron Inc, Tarrytown, N YI0591 . USA Recent analyses of mutant mice bearing null mutations in genes expressing various neurotrophic factors or their receptors have elegantly confirmed the vital role that such factors play in neural development. A much broader of role of neurotrophic factors in maintenance and regeneration is also emerging, largely as a consequence of the molecular characterization of a significant number of novel neurotrophic factors in the last few years. In my talk I will describe in vitro and in vivo experiments which have focused (a) on elucidation of the biology and specificity of the neurotrophins (NGF. BDNF, NT-3 & NT-4/5 ) and Cl\'TF for distinct neuronal populations, especially neuronal populations that are compromised in peripheral neuropathies or lost in central neurodegenerative disorders such as ALS and Parkinson's disease, (b) syne rgistic actions between neurotrophic factors as observed towards motor neurons in vitro and in vivo, using combinations of BDl'.'F and CNTF and (c) the neuroprotective actions of individual neurotrophins or CNTF in animal models of nerve injury, peripheral neuropathy or CNS neurodegenerative disorders. Finally, I will highlight the therapeutic potential of neurotrophic factors that emerges from these studies, and the status of current or projected clinical trials in motor neuron disease, peripheral neuropathies, Parkinson's and Huntington's disease.
I8-34-41 Opposing Effects of Stress and Antidepressants of Neurotrophic Factors R.M. Post, M. Smith, S.R.B. Weiss, S. Beaulieu, D.-M. Chuang. Biological Psychiatry Branch. NIMH, Bethesda, Mary/a nd, USA
Acute and chronic stressors ate capable of inducing decrease in BDNFmRNA and, with chronic stress only, increases in NT3-mRNA in hippocampus and locus coeruleus. ECT and chronic, but not acute, treatment with antidepressants such as DMI show the opposite pattern; i.e.,
96 inositol reduction in rat cortex after therapeutic doses or chronic Li is small and that PI levels are not affected. We recently found that chronic Li in rats did not reduce cortical inositol levels but did so markedly in hippocampus. Thus regional specificity may be important in investigating the inositol depletion hypothesis. Jope and Williams (1995) recently reported that effects of inositol to antagonize behavioral effects of Li also occur with epi-inosirol, a stereoisomer not usually thought to have biological activity. Further studies of biological effects of epi-inositol are necessary to evaluate the meaning of this finding. We have found that oral inositol 12 gm daily had significant therapeutic effects in depression, panic and obsessivecompulsive disorder in controlled double-blind trials. Moreover, we found that post-mortem cortical inositol levels are significantly reduced in bipolar patients and suicides compared with controls. These results suggest that Li does not simply reduce inositol levels, but that inositol may be involved in a more complex manner in affective disorder and Li action. Batty and Downes (1995) recently reported that inositol levels modulate phospholipase C activity in a complex manner independent of PI levels.
I8-33-51Lithium Effects on Protein Phosphorylation in Bipolar and Healthy Subjects
R. Zanardi, G. Racagni, E. Smeraldi, J. Perez. Dpt of Neuropsychiatric Sciences HSR, Milan, Italy
Several lines of evidence indicate that protein phosphorylation system is involved in the regulation of almost all neuronal functions. Moreover, cAMP-dependent phosphorylation system is a target in the action of antidepressant drugs and lithium. We have investigated basal and cAMPdependent endogenous phosphorylation in platelets fromeuthymic bipolar patients and from healthy volunteers before and after 15 days of lithium treatment. The major polypeptides stimulated by cAMP had apparent molecular weights of 22 and 38 kDa. cAMP-dependent phosphorylation of the 22 kDa protein band was significantly increased in euthymic bipolar patients with respect to controls. Lithium significantly enhanced basal and cAMP-dependent phosphorylation of both 22 and 38 kDa proteins in euthymic bipolar patients, while no significant difference was observed in healthy volunteers. This study could provide a better understaining of the involvement of cAMP-signaling in the pathophysiology of mood disorders and in the action of lithium salts.
15-341 Neurotrophic Factors: Neuropsychiatric Implications
I8-34-1 I NGF, Howit all Began and HowModern
Technologies Confirm and Expand the Original Hypothesis
E. Shooter. Department of Neurolbiology. Stanford University School of Medicine, Stanford, USA
Early studies in neuroembryology showed that the size of a peripheral field determined the density of its innervation. This led to the idea that the target provided molecules for nerve growth and differentiation. The first of these, NGF, was discovered in a mouse sarcoma which, when transplanted near the leg bud of a chick embryo, induced massive fiber ingrowth from spinal and sympathetic ganglia (I ]. The serendipitous discovery of NGF in snake venom and the adult mouse submaxillary gland permitted its partial purification, the preparation of an antibody against NGF and the demonstration that neutralizing endogenous NGF in the new born rat with the antibody prevented the development of all sympathetic neurons. The subsequent demonstration of the retrograde flow of NGF in sympathetic and sensory fibers firmly established the hypothesis that target derived neurotrophins control neuronal cell death during development. The phenotypes of mice in which the genes for either a neurotrophin or its trk receptor have been knocked out fully support this hypothesis at least for peripheral neurons. Recent extensions of the hypothesis come from the findings that neurons can switch neurotrophin dependency early in development, but still rely on one specific neutrophin
to control cell death, and that an autocrine or paracrine supply of a second neurotrophin can support a neuron in adult life. [I ] Levi-Montalcini R. Hamburger V, J. Exp . Zool. 116 (1951) 32l-362.
I 8-34-21Modulation of Activity-Dependent Neuronal Plasticity: A New Facet of Neurotrophin Action H. Thoenen. Dept. of Neurochemistry, Max Planck Institute fo r Psychiatry, Maninsried, Gennany
The function of neurotrophins was, to date, predominantly considered under the aspect of the regulation of survival and differentiation of specific populations of neurons during embryonic development and the maintenance of their characteristic neuronalfunctions in adulthood. However, there is increasing evidence that neurotrophins are also involved in neuronal plasticity. The evidence for this evolves from different sets of experiments in vivo and ill vitro. In rats and kittens, the local administration of NGF, BDNF, NT-4/5 and the corresponding blocking antibodies dramatically influence the activity-dependent developmental changes of the visual cortex, in particular ocular dominance. The shortcoming of this system is that it does not allow to analyze the underlying mechanisms at a cellular and molecular level. However, there is complementary information from various in vitro and in vivo systems, indicating that neurotrophins are rapidly and highly specifically regulated by neuronal activity, that neurotrophins are released in an activity-dependent manner not only from the neuronal cell body, but also from dendritic processes, and that neurotrophins initiate the release of conventional transmitters, such as acetylcholine, glutamate and dopamine from neurons which express the appropriate signal-transducing tyrosine kinase trk receptors. This is a scenario which is compatible with the interpretation that neurotrophins modulate the strength and stability of specific subsets of synapses in an activity-dependent manner. This interpretation is strongly supported by the observation that, in hippocampal slices of BDNF deficient mice, LTP in the CA3/CA I system is strongly impaired, and that LTPcan be restored by adenovirus-mediated BDNF gene transfer into the CAI neurons.
I8-34-31 Neurotrophic Factors: Biology & Clinical Potential R.M. Lindsay. Regeneron Inc, Tarrytown, N YI0591 . USA Recent analyses of mutant mice bearing null mutations in genes expressing various neurotrophic factors or their receptors have elegantly confirmed the vital role that such factors play in neural development. A much broader of role of neurotrophic factors in maintenance and regeneration is also emerging, largely as a consequence of the molecular characterization of a significant number of novel neurotrophic factors in the last few years. In my talk I will describe in vitro and in vivo experiments which have focused (a) on elucidation of the biology and specificity of the neurotrophins (NGF. BDNF, NT-3 & NT-4/5 ) and Cl\'TF for distinct neuronal populations, especially neuronal populations that are compromised in peripheral neuropathies or lost in central neurodegenerative disorders such as ALS and Parkinson's disease, (b) syne rgistic actions between neurotrophic factors as observed towards motor neurons in vitro and in vivo, using combinations of BDl'.'F and CNTF and (c) the neuroprotective actions of individual neurotrophins or CNTF in animal models of nerve injury, peripheral neuropathy or CNS neurodegenerative disorders. Finally, I will highlight the therapeutic potential of neurotrophic factors that emerges from these studies, and the status of current or projected clinical trials in motor neuron disease, peripheral neuropathies, Parkinson's and Huntington's disease.
I8-34-41 Opposing Effects of Stress and Antidepressants of Neurotrophic Factors R.M. Post, M. Smith, S.R.B. Weiss, S. Beaulieu, D.-M. Chuang. Biological Psychiatry Branch. NIMH, Bethesda, Mary/a nd, USA
Acute and chronic stressors ate capable of inducing decrease in BDNFmRNA and, with chronic stress only, increases in NT3-mRNA in hippocampus and locus coeruleus. ECT and chronic, but not acute, treatment with antidepressants such as DMI show the opposite pattern; i.e.,