- Email: [email protected]
A functional framework for neurotrophic activities
Neurobiologyof Aging, Vol. 10. pp. 537-539. * Pergamon Press plc, 1989. Printed in the U.S.A. 8. Mattson, M. P. Neurotransmitters in the regulation of neuronal cytoarchitecture. Brain Res. Rev. 13:179-212; 1988. 9. Sandrock, A. W., Jr.; Matthew, W. D. An in vitro neurite-promoting antigen functions in axonal regeneration in vivo. Science 237: 1605-1608; 1987. 10. Sporn, M. B.; Roberts, A. Peptide growth factors are multifunctional.
0197-4580/89 $3.00 + .00
Nature 332:217-219; 1988. 11. Walicke, P. A. Novel neurotrophic factors, receptors and oncogenes. Annu. Rev. Neurosci. 12:103-126; 1989. 12. Whitson, J. S.; Selkoe, D. J.; Cotman, C. W. Amyloid B protein enhances the survival of hippocampal neurons in vitro. Science 243:1488-1490; 1989.
A Functional Framework for Neurotrophic Activities
L A N N Y J. H A V E R K A M P
Department of Neurology, Baylor College of Medicine, Houston, TX 77030
In attempts to understand the diverse roles which trophic activities exert in neuronal development and maintenance, it is useful to define some framework from within which to view their function. An example of such an outline is presented, sufficiently broad to avoid excluding by definition agents with clearly neurotrophic effect.
DRS. Hefti, Hartikka, and Knusel have provided a remarkably complete overview of the field of neurotrophic factors. As is made apparent in the latter half of this review, the number of factors with identified in vitro neurotrophic effects has expanded rapidly over the last few years, and it can be safely predicted that their number will continue to substantially increase. I would suggest, however, that Hefti et al.'s definition of a neurotrophic factor as an "endogenous freely diffusible protein able to promote survival, growth and function of developing or adult neurons" is too limiting. Excluding activities based on their means of presentation, size, or structure may be necessary to the formation of a coherent and detailed review. However, if we are to attempt an understanding of the mechanisms by which neurons develop and are maintained, I think it a better strategy to provisionally compartmentalize trophic activities, rather than to exclude some by definition. Requisite to such an exercise is an indication of how a factor, identified as neurotrophic in vitro, acts within the animal. What follows, therefore, is something of a functional framework of types of neurotrophic activities from within which one might view that data which will reflect upon neurotrophic factors' modes of actions and sources of in vivo supply. First is a "classical" view of a neurotrophic molecule; that it be synthesized and exported by the neuronal target in limiting supply, that it be specifically taken up at the innervating nerve terminal, and transported back to the cell body to have genomic effect. A most obvious candidate phenomenon to rely upon this sort of activity is that of naturally occurring neuronal cell death. A great deal of data has been generated evincing the necessity of interaction of neurons with their targets in controlling neuronal survival during this period. A favored hypothesis for describing the mechanism by which it occurs is one of competition by neurons for a limited supply of trophic factor [or a competition for sites of uptake (24)]. Indeed, control of survival of NGF-sensitive peripheral neurons by supply or withdrawal of NGF during this period, as reviewed by Hefti et al., is the strongest evidence that such is a mechanism for naturally occurring cell death in both these and other neuronal populations. The seemingly straightforward requirement for, and all-or-nothing response to, neuro-
trophic factors during this period is such that Barde has proposed (5), as Hefti et al. note, that only those factors acting during the naturally occurring cell death period be considered neurotrophic. A second type of trophic activities which may not share all the defined properties noted above must undoubtedly exist, however. And while these activities may not, in a specific cell type, be regulated by the molecule for which a competition is waged during the cell death period, they nevertheless influence the development, differentiation, and maintenance of neurons. Such substances are supplied either by the support cells of the neuron, or by diffusing freely from sources other than the innervated target cell. Demonstrations of effects on cultured neurons by glial conditioned media (8) for example, clearly indicate that cells other than the neuronal target are capable of providing neurotrophic substances. Such growth factors as ubiquitous in distribution as FGF (14), yet for which neuronal receptors have been demonstrated (33), would seem most likely to fall within this class. Also included here are the obviously trophic actions of such hormones as insulin (25), which should not be ignored for having effects on many other cell types, and also the steroid hormones such as androgens, which have very specific trophic effects on some classes of neurons (3). Thirdly, there are substances which have primarily a local action on neuronal form and function. Activities during outgrowth of neurites, by proteases and protease inhibitors (22), are undoubtedly of initially local influence. A primarily local site of action again seems most likely in the trophic regulation of synapse elimination at polyinnervated neuromuscular junctions, where specific proteases (10) and insulin-like growth factor-lI (18) have been implicated as controlling. Also included under this class of actions are those of the proteins composing, or bound to, the extracellular matrix, such as the neuronal integrin-class receptors' interactions with Schwann cell secreted basal lamina components (7). These latter activities, often summarily described as "cell adhesion" interactions, can have most profound effects on neuronal form and subsequent function (20). A fourth, and final, category of trophic activities are those arising from afferent neural sources. These activities may either be related to neurotransmitter release and action, or be based on the
538
HAVERKAMP
release or recognition of substances without effect on membrane polarization. For example, unique patterns of neuronal death may result from surgical deafferentation (23), while neuronal morphology is influenced (13) and transmitter choice effected (11) by neurotransmitters and peptides. While such a functional categorization may have some utility, it should not be implied that any one trophic factor can act in only one manner. Indeed, NGF appears to act by all of the first three means, for besides its definitive action during the naturally occurring cell death period (16), it is also produced by Schwann cells and can be taken up and transported by intact axons (4,26), and can act in a distinctly local manner on the neurites of cultured cells (9,15). It should also be noted that there are probably multiple trophic factors acting upon a neuron at any one time (2). For example, both NGF and FGF can rescue axotomized medial forebrain neurons (1,17), and in culture the cholinergic development of spinal motoneurons is stimulated by both FGF and the purified skeletal muscle derived factor, CDF (21). It may be that, in vivo, if the source of one factor is lost, supply with an abundance of another may suffice for the neuron's maintenance. A final point to consider is, that while a neuron's requirement for atrophic factor may change with maturation, there may also be developmental regulation of sensitivity to, and supply of, additional trophically acting molecules (29). The developmental decline in sensitivity to NGF of some neurons (12), as well as the decreased likelihood that axotomy of maturing neurons will result in death (27), is often viewed as a decrease in neuronal dependence on a target-derived factor. Alternatively, however, these
maturational changes in response to withdrawal of target-derived factors may reflect an increased availability of this factor from other sources, or a developmental increase in sensitivity to other neurotrophic molecules. An analogous situation to these changes with development are the changes in metabolism of regenerating peripheral neurons. After axotomy, sensitivity to target-derived factor (e.g., NGF) may play a major role in survival and regeneration (19), but additional moieties with trophic activity may also act under the specific requirements of regrowth (28,321. While the levels of, or access to, target-derived neurotrophic factors may be controlling at some stages of development, their effects are continually a portion of the neuron's total trophic environment. As our understanding of the identity, actions, and interactions of neurotrophic factors proceeds, we may come to learn that the trophic response is a symphonic one. It has become apparent that neuronal afferent communication is a complex blend of neurotransmitter, -modulator, and -regulator action (6,30). The overlapping and interactive nonneuronal effects of peptide growth factors have become apparent (31). With an equally sophisticated understanding of neurotropbic activities, we can hope to someday understand and intervene in the processes which control neuronal maintenance and survival. ACKNOWLEDGEMENTS l thank Jim McManaman, Ron Oppenheim, and Stan Appel for much helpful discussion and comment.
REFERENCES 1. Anderson, K. J.; Dam, D.; Lee, S.; Cotman, C. W. Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo. Nature 332:360-361; 1988. 2. Appel, S. H.; Bostwick, J. R.; Haverkamp, L. J.; McManaman, J. L. Multiple trophic factors influence neuronal cholinergic activity. In: Biggio, G., ed. Symposia in neumscience, vol. 7. Neuronal plasticity and trophic factors. Padova, Italy: Liviana Press; 1988:1-8. 3. Arnold, A. P.; Gorski, R. A. Gonadal steroid induction of structural sex differences in the central nervous system. Annu. Rev. Neurosci. 7:413--442; 1984. 4. Bandtlow, C. E.; Hedmann, R.; Schwabb, M. E.; Thoenen, H. Cellular localization of nerve growth factor synthesis by in situ hybridization. EMBO J. 6:891-899; 1987. 5. Barde, Y. A. What, if anything, is a neurotrophic factor? Trends Neurosci. 11:343-346; 1988. 6. Barker, J. L.; Smith, T. G., Jr. Three modes of communication in the nervous system. Adv. Exp. Med. Biol. 116:3-25; 1979. 7. Bixby, J. L.; Lilien, J.; Reichardt, L. F. Identification of the major proteins that promote neuronal process outgrowth on Schwann cells in vitro. J. Cell Biol. 107:353-361; 1988. 8. Brenneman, D. E.; Neale, E. A.; Foster, G. A.; d'Autremont, S. W.; Westbrook, G. L. Nonneuronal cells mediate neurotrophic action of vasoactive intestinal peptide. J. Cell Biol. 104:1603-1610; 1987. 9. Campenot, R. B. Development of sympathetic neurons in compartmentalized cultures. II. Local control of neurite survival by nerve growth factor. Dev. Biol. 93:13-21; 1982. 10. Connold, A. L.; Evers, J. V.; Vrbova, G. Effect of low calcium and protease inhibitors on synapse elimination during postnatal development in the rat soleus. Dev. Brain Res. 28:99-107; 1986. 11. Friedman, W. J.; Dreyfus, C. F.; McEwen, B.; Black, I. B. Presynaptic transmitters and depolarizing influences regulate development of the substantia nigra in culture. J. Neurosci. 8:3616-3623; 1988. 12. Goedert, M.; Otten, U.; Thoenen, H. Biochemical effects of antibodies against nerve growth factor on developing and differentiated sympathetic ganglia. Brain Res. 148:264-268; 1978. 13. Goldberg, J. I.; Kater, S. B. Expression and function of the neurotransmitter serotonin during development of the Helisoma nervous
system. Dev. Biol. 131:483-495; 1989. 14. Gospodarowicz, D.; Neufeld, G.; Schweigerer, L. Fibroblast growth factor: Structural and biological properties. J. Cell. Physiol. Suppl. 5:15-26; 1987. 15. Gundersen, R. W.; Barrett, J. N. Neuronal chemotaxis: Chick dorsal-root axons turn toward high concentrations of nerve growth factor. Science 206:1079-1080; 1979. 16. Hamburger, V.; Brunso-Bechtold, J. K.; Yip, J. W. Neuronaldeath in the spinal ganglia of the chick embryo and its reduction by nerve growth factor. J. Neurosci. 1:60-71; 1981. 17. Hefti, F.; Montero, C. N.; Mash, D. C. Nerve growth factor rescues septal cholinergic neurons and promotes reinnervation of the hippocampus in rats with partial fimbrial transections. In: Reier, P. J.; Bunge, R. D.; Seil, F. J., eds. Current issues in neural regeneration research. New York: Alan R. Liss Inc.; 1988:105-115. 18. Ishii, D. N. Relationship of insulin-like growth factor I/ gene expression in muscle to synaptogenesis. Proc. Natl. Acad. Sci. USA 86:2898-2902; 1989. 19. Johnson, E. M., Jr.; Rich, K. M.; Yip, H. K. The role of NGF in sensory neurons in vivo. Trends Neurosci. 9:33-37; 1986. 20. Landmesser, L.; Dahm. L. M.; Schultz, K.; Rutishauser, U. Distinct roles for adhesion molecules during innervation of embryonic chick muscle. Dev. Biol. 130:645-670; 1988. 21. McManaman, J. L.; Crawford, F.; Clark, R.; Richker, J.: Fuller, F. Multiple neurotrophic factors from skeletal muscle: Demonstration of effects of bFGF and comparisons with the 22-k dalton CAT development factor, J. Neurochem., m press: 1989. 22. Monard, D. Cell-derived proteases and protease inhibitors as regulators of neurite outgrowth. Trends Neurosci. l 1:541-544; 1988. 23. Okado, N.; Oppenheim, R. W. Cell death of motoneurons in the chick embryo spinal cord. IX. The loss of motoneurons following removal of afferent inputs. J. Neurosci. 4:1639-1652; 1984. 24. Oppenheim, R. W. The neurotrophic theory and naturally occurring motoneuron death. Trends Neurosci.. in press: 1989. 25. Recio-Pinto, E.; Rechler, M. M.; Ishii. D. N. Effects of insulin. insulin-like growth factor-I/, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J. Neurosci. 6:1211-1219; 1986.
Neurobiologyof Aging. Vol. 10, pp. 539-540. e Pergamon Press plc, 1989. Printed in the U.S.A. 26. Richardson, P. M.; Riopelle, R. J. Uptake of nerve growth factor along peripheral and spinal axons of primary sensory neurons. J. Neurosci. 4:1683-1689; 1984. 27. Schmalbruch, H. Motonueron death after sciatic nerve section in newborn rats. J. Comp. Neurol. 224:252-258; 1984. 28. Sjoberg, J.; Kanje, M. Insulin-like growth factor (IGF-1) as a stimulator of regeneration in the freeze-injured rat sciatic nerve. Brain Res. 485:102-108; 1989. 29. Smith, R. G.; McManaman, J. L.; Appel, S. H. Trophic effects of skeletal muscle extracts on ventral spinal cord neurons in vitro: Separation of a protein with morphologic activity from proteins with cholinergic activity. J. Cell Biol. 101:1608-1621; 1985.
0197-4580/89 $3.00 + .00
30. Snyder, S. H. Brain peptides as neurotransmitters. Science 209: 976-983; 1980. 31. Sporn, M. B.; Roberts, A. B. Peptide growth factors are multifunctional. Nature 332:217-219; 1988. 32. Van der Neut, R.; Bar, P. R.; Sodaar, P.; Gispen, W. H. Trophic influences of alpha-MSH and ACTH4_~o on neuronal outgrowth in vitro. Peptides 9:1015-1020; 1988. 33. Walicke, P. A.; Feige, J.-J.; Baird, A. Characterization of the neuronal receptor for basic fibroblast growth factor and comparison to receptors on mesenchymal cells. J. Biol. Chem. 264:4120-4126; 1989.
Towards Trophic Factor Pharmacology? A. C L A U D I O C U E L L O
Department of Pharmacology and Therapeutics, Mclntyre Medical Sciences Building, 3655 Drummond Street, McGill University, Montreal, PQ, Canada H3G 1 Y6
Recent developments in neurobiology have lent support to the idea that neural degeneration can be prevented, if not reverted, by the judicious application of substances which specifically affect the trophism of neurones in the adult. A great many of these substances have been proposed and some fully identified chemically. In addition to well characterized neurotrophic factors, other molecules can bring about equally dramatic effects in experimental animals. These investigations are leading us to a new field in neuropharmacology, that of "trophic factor pharmacology." Clinical expectations are high and the anticipation felt in the laboratory equally so.
THE timely review of Franz Hefti on "Functions of neurotrophic factors in the adult and aging brain and their possible uses in the treatment of neurodegenerative diseases" has assembled a remarkable amount of information on the neurobiology of substances capable of "stimulating mechanisms necessary for survival, neurite growth, and functions related to transmitter production and release." More importantly, Franz Hefti has managed to stimulate excitement in a field which has its foundations in biochemistry, and cell and molecular biology and which is now moving towards pharmacological clinical applications aimed at the prevention of neuronal cell degeneration and death. Hefti's review emphasizes the compelling evidence for the role of trophic factors, in particular NGF, on neuronal cell survival in the adult. From this base, the case is presented for potential therapeutic applications of neurotrophic factors in human neurodegenerative disease. Although the idea is not new (1,4) clinical evidence for the involvement of trophic factors in diseases of the nervous system is not yet available. Nevertheless, there is a great deal of interest in the possible therapeutic scenario where putative trophic substances may be applied. Much of this interest is being generated by dramatic observations in the laboratory. Thus, nourished by the excitement of the laboratory, and the great hope of potential therapeutic possibilities, "trophic factor pharmacolog y , " a new branch in neuropharmacology, has been conceived. It is difficult to anticipate the extent of the practical benefits medicine and society at large will obtain from this intensive and exciting research exercise, but I would venture to say positive developments should be expected. Even if no " m i r a c l e " drugs are developed from the effort, it is highly likely that these investigations will provide us with a clearer understanding of the underlying
mechanisms of brain repair, involution and aging well beyond our most optimistic expectations. Subsequently, clues may be uncovered for therapeutic intervention to prevent or limit the decline in brain functions as a consequence of disease, trauma or aging. The current status of basic research on neuronal cell survival, for which Hefti himself has been a pioneer, is comprehensively covered in this review. In addition to providing sufficient arguments for the serious consideration of potential therapeutic applications, it indicates present ambiguities and possible directions for future research. Ambiguities in the field are caused by a lack of consensus in defining what constitutes a neurotrophic factor in the adult. The lack of guiding principles can be explained by the fact that investigations into the effects of these factors are presently being carried out in mature animals while, historically, the intellectual input in this area had its basis in the field of developmental neurobiology. Hefti provides a fairly open definition of what constitutes a neurotrophic factor. This is probably wise since our understanding of the biological scope of these substances is still extremely limited. Some neurotrophic factors might be strictly target derived, while others might be produced and secreted in a more diffuse manner. Others could be restricted or may act preferentially on transmitter or pathway specific systems, e.g., NGF actions on subsets of CNS cholinergic neurones. Still others may be almost universal trophic agents acting on many different cell types, i.e., neurones, glia, etc. Finally, it is very clear we know little about the circumstances in which these factors alone, or in combination, might affect the injured, diseased or aged nervous system. The review excludes as neurotrophic factors substances which can directly or indirectly elicit some or all of the effects such as
0197-4580/89 $3.00 + .00
Nature 332:217-219; 1988. 11. Walicke, P. A. Novel neurotrophic factors, receptors and oncogenes. Annu. Rev. Neurosci. 12:103-126; 1989. 12. Whitson, J. S.; Selkoe, D. J.; Cotman, C. W. Amyloid B protein enhances the survival of hippocampal neurons in vitro. Science 243:1488-1490; 1989.
A Functional Framework for Neurotrophic Activities
L A N N Y J. H A V E R K A M P
Department of Neurology, Baylor College of Medicine, Houston, TX 77030
In attempts to understand the diverse roles which trophic activities exert in neuronal development and maintenance, it is useful to define some framework from within which to view their function. An example of such an outline is presented, sufficiently broad to avoid excluding by definition agents with clearly neurotrophic effect.
DRS. Hefti, Hartikka, and Knusel have provided a remarkably complete overview of the field of neurotrophic factors. As is made apparent in the latter half of this review, the number of factors with identified in vitro neurotrophic effects has expanded rapidly over the last few years, and it can be safely predicted that their number will continue to substantially increase. I would suggest, however, that Hefti et al.'s definition of a neurotrophic factor as an "endogenous freely diffusible protein able to promote survival, growth and function of developing or adult neurons" is too limiting. Excluding activities based on their means of presentation, size, or structure may be necessary to the formation of a coherent and detailed review. However, if we are to attempt an understanding of the mechanisms by which neurons develop and are maintained, I think it a better strategy to provisionally compartmentalize trophic activities, rather than to exclude some by definition. Requisite to such an exercise is an indication of how a factor, identified as neurotrophic in vitro, acts within the animal. What follows, therefore, is something of a functional framework of types of neurotrophic activities from within which one might view that data which will reflect upon neurotrophic factors' modes of actions and sources of in vivo supply. First is a "classical" view of a neurotrophic molecule; that it be synthesized and exported by the neuronal target in limiting supply, that it be specifically taken up at the innervating nerve terminal, and transported back to the cell body to have genomic effect. A most obvious candidate phenomenon to rely upon this sort of activity is that of naturally occurring neuronal cell death. A great deal of data has been generated evincing the necessity of interaction of neurons with their targets in controlling neuronal survival during this period. A favored hypothesis for describing the mechanism by which it occurs is one of competition by neurons for a limited supply of trophic factor [or a competition for sites of uptake (24)]. Indeed, control of survival of NGF-sensitive peripheral neurons by supply or withdrawal of NGF during this period, as reviewed by Hefti et al., is the strongest evidence that such is a mechanism for naturally occurring cell death in both these and other neuronal populations. The seemingly straightforward requirement for, and all-or-nothing response to, neuro-
trophic factors during this period is such that Barde has proposed (5), as Hefti et al. note, that only those factors acting during the naturally occurring cell death period be considered neurotrophic. A second type of trophic activities which may not share all the defined properties noted above must undoubtedly exist, however. And while these activities may not, in a specific cell type, be regulated by the molecule for which a competition is waged during the cell death period, they nevertheless influence the development, differentiation, and maintenance of neurons. Such substances are supplied either by the support cells of the neuron, or by diffusing freely from sources other than the innervated target cell. Demonstrations of effects on cultured neurons by glial conditioned media (8) for example, clearly indicate that cells other than the neuronal target are capable of providing neurotrophic substances. Such growth factors as ubiquitous in distribution as FGF (14), yet for which neuronal receptors have been demonstrated (33), would seem most likely to fall within this class. Also included here are the obviously trophic actions of such hormones as insulin (25), which should not be ignored for having effects on many other cell types, and also the steroid hormones such as androgens, which have very specific trophic effects on some classes of neurons (3). Thirdly, there are substances which have primarily a local action on neuronal form and function. Activities during outgrowth of neurites, by proteases and protease inhibitors (22), are undoubtedly of initially local influence. A primarily local site of action again seems most likely in the trophic regulation of synapse elimination at polyinnervated neuromuscular junctions, where specific proteases (10) and insulin-like growth factor-lI (18) have been implicated as controlling. Also included under this class of actions are those of the proteins composing, or bound to, the extracellular matrix, such as the neuronal integrin-class receptors' interactions with Schwann cell secreted basal lamina components (7). These latter activities, often summarily described as "cell adhesion" interactions, can have most profound effects on neuronal form and subsequent function (20). A fourth, and final, category of trophic activities are those arising from afferent neural sources. These activities may either be related to neurotransmitter release and action, or be based on the
538
HAVERKAMP
release or recognition of substances without effect on membrane polarization. For example, unique patterns of neuronal death may result from surgical deafferentation (23), while neuronal morphology is influenced (13) and transmitter choice effected (11) by neurotransmitters and peptides. While such a functional categorization may have some utility, it should not be implied that any one trophic factor can act in only one manner. Indeed, NGF appears to act by all of the first three means, for besides its definitive action during the naturally occurring cell death period (16), it is also produced by Schwann cells and can be taken up and transported by intact axons (4,26), and can act in a distinctly local manner on the neurites of cultured cells (9,15). It should also be noted that there are probably multiple trophic factors acting upon a neuron at any one time (2). For example, both NGF and FGF can rescue axotomized medial forebrain neurons (1,17), and in culture the cholinergic development of spinal motoneurons is stimulated by both FGF and the purified skeletal muscle derived factor, CDF (21). It may be that, in vivo, if the source of one factor is lost, supply with an abundance of another may suffice for the neuron's maintenance. A final point to consider is, that while a neuron's requirement for atrophic factor may change with maturation, there may also be developmental regulation of sensitivity to, and supply of, additional trophically acting molecules (29). The developmental decline in sensitivity to NGF of some neurons (12), as well as the decreased likelihood that axotomy of maturing neurons will result in death (27), is often viewed as a decrease in neuronal dependence on a target-derived factor. Alternatively, however, these
maturational changes in response to withdrawal of target-derived factors may reflect an increased availability of this factor from other sources, or a developmental increase in sensitivity to other neurotrophic molecules. An analogous situation to these changes with development are the changes in metabolism of regenerating peripheral neurons. After axotomy, sensitivity to target-derived factor (e.g., NGF) may play a major role in survival and regeneration (19), but additional moieties with trophic activity may also act under the specific requirements of regrowth (28,321. While the levels of, or access to, target-derived neurotrophic factors may be controlling at some stages of development, their effects are continually a portion of the neuron's total trophic environment. As our understanding of the identity, actions, and interactions of neurotrophic factors proceeds, we may come to learn that the trophic response is a symphonic one. It has become apparent that neuronal afferent communication is a complex blend of neurotransmitter, -modulator, and -regulator action (6,30). The overlapping and interactive nonneuronal effects of peptide growth factors have become apparent (31). With an equally sophisticated understanding of neurotropbic activities, we can hope to someday understand and intervene in the processes which control neuronal maintenance and survival. ACKNOWLEDGEMENTS l thank Jim McManaman, Ron Oppenheim, and Stan Appel for much helpful discussion and comment.
REFERENCES 1. Anderson, K. J.; Dam, D.; Lee, S.; Cotman, C. W. Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo. Nature 332:360-361; 1988. 2. Appel, S. H.; Bostwick, J. R.; Haverkamp, L. J.; McManaman, J. L. Multiple trophic factors influence neuronal cholinergic activity. In: Biggio, G., ed. Symposia in neumscience, vol. 7. Neuronal plasticity and trophic factors. Padova, Italy: Liviana Press; 1988:1-8. 3. Arnold, A. P.; Gorski, R. A. Gonadal steroid induction of structural sex differences in the central nervous system. Annu. Rev. Neurosci. 7:413--442; 1984. 4. Bandtlow, C. E.; Hedmann, R.; Schwabb, M. E.; Thoenen, H. Cellular localization of nerve growth factor synthesis by in situ hybridization. EMBO J. 6:891-899; 1987. 5. Barde, Y. A. What, if anything, is a neurotrophic factor? Trends Neurosci. 11:343-346; 1988. 6. Barker, J. L.; Smith, T. G., Jr. Three modes of communication in the nervous system. Adv. Exp. Med. Biol. 116:3-25; 1979. 7. Bixby, J. L.; Lilien, J.; Reichardt, L. F. Identification of the major proteins that promote neuronal process outgrowth on Schwann cells in vitro. J. Cell Biol. 107:353-361; 1988. 8. Brenneman, D. E.; Neale, E. A.; Foster, G. A.; d'Autremont, S. W.; Westbrook, G. L. Nonneuronal cells mediate neurotrophic action of vasoactive intestinal peptide. J. Cell Biol. 104:1603-1610; 1987. 9. Campenot, R. B. Development of sympathetic neurons in compartmentalized cultures. II. Local control of neurite survival by nerve growth factor. Dev. Biol. 93:13-21; 1982. 10. Connold, A. L.; Evers, J. V.; Vrbova, G. Effect of low calcium and protease inhibitors on synapse elimination during postnatal development in the rat soleus. Dev. Brain Res. 28:99-107; 1986. 11. Friedman, W. J.; Dreyfus, C. F.; McEwen, B.; Black, I. B. Presynaptic transmitters and depolarizing influences regulate development of the substantia nigra in culture. J. Neurosci. 8:3616-3623; 1988. 12. Goedert, M.; Otten, U.; Thoenen, H. Biochemical effects of antibodies against nerve growth factor on developing and differentiated sympathetic ganglia. Brain Res. 148:264-268; 1978. 13. Goldberg, J. I.; Kater, S. B. Expression and function of the neurotransmitter serotonin during development of the Helisoma nervous
system. Dev. Biol. 131:483-495; 1989. 14. Gospodarowicz, D.; Neufeld, G.; Schweigerer, L. Fibroblast growth factor: Structural and biological properties. J. Cell. Physiol. Suppl. 5:15-26; 1987. 15. Gundersen, R. W.; Barrett, J. N. Neuronal chemotaxis: Chick dorsal-root axons turn toward high concentrations of nerve growth factor. Science 206:1079-1080; 1979. 16. Hamburger, V.; Brunso-Bechtold, J. K.; Yip, J. W. Neuronaldeath in the spinal ganglia of the chick embryo and its reduction by nerve growth factor. J. Neurosci. 1:60-71; 1981. 17. Hefti, F.; Montero, C. N.; Mash, D. C. Nerve growth factor rescues septal cholinergic neurons and promotes reinnervation of the hippocampus in rats with partial fimbrial transections. In: Reier, P. J.; Bunge, R. D.; Seil, F. J., eds. Current issues in neural regeneration research. New York: Alan R. Liss Inc.; 1988:105-115. 18. Ishii, D. N. Relationship of insulin-like growth factor I/ gene expression in muscle to synaptogenesis. Proc. Natl. Acad. Sci. USA 86:2898-2902; 1989. 19. Johnson, E. M., Jr.; Rich, K. M.; Yip, H. K. The role of NGF in sensory neurons in vivo. Trends Neurosci. 9:33-37; 1986. 20. Landmesser, L.; Dahm. L. M.; Schultz, K.; Rutishauser, U. Distinct roles for adhesion molecules during innervation of embryonic chick muscle. Dev. Biol. 130:645-670; 1988. 21. McManaman, J. L.; Crawford, F.; Clark, R.; Richker, J.: Fuller, F. Multiple neurotrophic factors from skeletal muscle: Demonstration of effects of bFGF and comparisons with the 22-k dalton CAT development factor, J. Neurochem., m press: 1989. 22. Monard, D. Cell-derived proteases and protease inhibitors as regulators of neurite outgrowth. Trends Neurosci. l 1:541-544; 1988. 23. Okado, N.; Oppenheim, R. W. Cell death of motoneurons in the chick embryo spinal cord. IX. The loss of motoneurons following removal of afferent inputs. J. Neurosci. 4:1639-1652; 1984. 24. Oppenheim, R. W. The neurotrophic theory and naturally occurring motoneuron death. Trends Neurosci.. in press: 1989. 25. Recio-Pinto, E.; Rechler, M. M.; Ishii. D. N. Effects of insulin. insulin-like growth factor-I/, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J. Neurosci. 6:1211-1219; 1986.
Neurobiologyof Aging. Vol. 10, pp. 539-540. e Pergamon Press plc, 1989. Printed in the U.S.A. 26. Richardson, P. M.; Riopelle, R. J. Uptake of nerve growth factor along peripheral and spinal axons of primary sensory neurons. J. Neurosci. 4:1683-1689; 1984. 27. Schmalbruch, H. Motonueron death after sciatic nerve section in newborn rats. J. Comp. Neurol. 224:252-258; 1984. 28. Sjoberg, J.; Kanje, M. Insulin-like growth factor (IGF-1) as a stimulator of regeneration in the freeze-injured rat sciatic nerve. Brain Res. 485:102-108; 1989. 29. Smith, R. G.; McManaman, J. L.; Appel, S. H. Trophic effects of skeletal muscle extracts on ventral spinal cord neurons in vitro: Separation of a protein with morphologic activity from proteins with cholinergic activity. J. Cell Biol. 101:1608-1621; 1985.
0197-4580/89 $3.00 + .00
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Towards Trophic Factor Pharmacology? A. C L A U D I O C U E L L O
Department of Pharmacology and Therapeutics, Mclntyre Medical Sciences Building, 3655 Drummond Street, McGill University, Montreal, PQ, Canada H3G 1 Y6
Recent developments in neurobiology have lent support to the idea that neural degeneration can be prevented, if not reverted, by the judicious application of substances which specifically affect the trophism of neurones in the adult. A great many of these substances have been proposed and some fully identified chemically. In addition to well characterized neurotrophic factors, other molecules can bring about equally dramatic effects in experimental animals. These investigations are leading us to a new field in neuropharmacology, that of "trophic factor pharmacology." Clinical expectations are high and the anticipation felt in the laboratory equally so.
THE timely review of Franz Hefti on "Functions of neurotrophic factors in the adult and aging brain and their possible uses in the treatment of neurodegenerative diseases" has assembled a remarkable amount of information on the neurobiology of substances capable of "stimulating mechanisms necessary for survival, neurite growth, and functions related to transmitter production and release." More importantly, Franz Hefti has managed to stimulate excitement in a field which has its foundations in biochemistry, and cell and molecular biology and which is now moving towards pharmacological clinical applications aimed at the prevention of neuronal cell degeneration and death. Hefti's review emphasizes the compelling evidence for the role of trophic factors, in particular NGF, on neuronal cell survival in the adult. From this base, the case is presented for potential therapeutic applications of neurotrophic factors in human neurodegenerative disease. Although the idea is not new (1,4) clinical evidence for the involvement of trophic factors in diseases of the nervous system is not yet available. Nevertheless, there is a great deal of interest in the possible therapeutic scenario where putative trophic substances may be applied. Much of this interest is being generated by dramatic observations in the laboratory. Thus, nourished by the excitement of the laboratory, and the great hope of potential therapeutic possibilities, "trophic factor pharmacolog y , " a new branch in neuropharmacology, has been conceived. It is difficult to anticipate the extent of the practical benefits medicine and society at large will obtain from this intensive and exciting research exercise, but I would venture to say positive developments should be expected. Even if no " m i r a c l e " drugs are developed from the effort, it is highly likely that these investigations will provide us with a clearer understanding of the underlying
mechanisms of brain repair, involution and aging well beyond our most optimistic expectations. Subsequently, clues may be uncovered for therapeutic intervention to prevent or limit the decline in brain functions as a consequence of disease, trauma or aging. The current status of basic research on neuronal cell survival, for which Hefti himself has been a pioneer, is comprehensively covered in this review. In addition to providing sufficient arguments for the serious consideration of potential therapeutic applications, it indicates present ambiguities and possible directions for future research. Ambiguities in the field are caused by a lack of consensus in defining what constitutes a neurotrophic factor in the adult. The lack of guiding principles can be explained by the fact that investigations into the effects of these factors are presently being carried out in mature animals while, historically, the intellectual input in this area had its basis in the field of developmental neurobiology. Hefti provides a fairly open definition of what constitutes a neurotrophic factor. This is probably wise since our understanding of the biological scope of these substances is still extremely limited. Some neurotrophic factors might be strictly target derived, while others might be produced and secreted in a more diffuse manner. Others could be restricted or may act preferentially on transmitter or pathway specific systems, e.g., NGF actions on subsets of CNS cholinergic neurones. Still others may be almost universal trophic agents acting on many different cell types, i.e., neurones, glia, etc. Finally, it is very clear we know little about the circumstances in which these factors alone, or in combination, might affect the injured, diseased or aged nervous system. The review excludes as neurotrophic factors substances which can directly or indirectly elicit some or all of the effects such as