- Email: [email protected]
Detrimental actions of neurotrophic agents
Neurobiology of Aging, Vol. 10, p. 583. ~ Pergamon Press plc, 1989. Printed in the U.S.A.
0197-4580/89 $3.00 ~- .00
Detrimental Actions of Neurotrophic Agents F R A N Z HEVI'I
Andrus Gerontology Center and Department of Biological Sciences University of Southern California, Los Angeles, CA 90089
There is little experimental evidence supporting the speculation that neurotrophic agents in general stimulate the pathological process in Alzheimer's disease. Nevertheless, possible detrimental actions of neurotrophic agents represent a concern when considering the pharmacological use of neurotrophic factors.
THE speculative hypothesis by Butcher and Woolf correctly directs awareness to the possibility that pharmacological use of growth factors and trophic agents may be detrimental to neuronal function, contrary to the beneficial role implied by the term "trophic." Such detrimental actions have to be considered and ruled out before clinically using trophic molecules. Neurotrophic agents may, by promoting the function of selective neuronal systems, alter the balance among various systems within neuronal networks. Trophic agents may induce the formation of aberrant synaptic connections which may disrupt normal signal flow. They may induce the expression of abnormal proteins by neuronal and nonneuronal cells and stimulate pathological proliferation of nonneuronal cells. Such actions are concerns when considering the clinical use of nerve growth factor (NGF) in Alzheimer's disease. The notion that NGF will be useful is based on substantial biochemical and anatomical evidence indicating trophic stimulation of forebrain cholinergic neurons and behavioral findings showing that the cholinergic hypertrophy is accompanied by behavioral improvement [reviews: (2,4)]. Based on these findings it seems unlikely that NGF-mediated cholinergic stimulation is functionally detrimental. However, long-term administration may induce aberrant cholinergic sprouting as observed in lesioned rodents (7). Since intraventricular NGF administration to neonatal animals elevates brain levels of amyloid precursor protein mRNA (3), it has to be determined whether application of NGF to the adult brain elevates amyloid precursor protein levels and whether such elevations produce pathological changes typical for Alzheimer's disease. Furthermore, since some nonneuronal cells seem responsive to NGF (2), the possibility of undesired proliferation
has to be considered. While representing a novel therapeutic approach, clinical application of NGF will have to follow general rules applied to the development of drugs. To rule out unacceptable actions of NGF, clinical application will have to be preceded by toxicology studies. Effective and safe dosages will have to be established. Guidelines for the use of NGF in Alzheimer's disease have been formulated by an ad hoc committee of the National Institute of Aging (4). The scenario outlined by Butcher and Woolf represents an interesting speculation based on very limited experimental support. The group of "neurotrophic agents" is defined to include NGF and thyroid hormones, and findings are presented suggesting that chronic triiodothyronine administration results in degeneration of cholinergic neurons in the nucleus basalis of adult rats. While thyroid hormones, similar to NGF, elevate choline acetyltransferase expression in developing cholinergic neurons (1), the actions of thyroid hormones differ in many ways from those of NGF and they are not normally considered to belong to the group of neurotrophic factors. Therefore, actions of thyroid hormones are not necessarily representative for NGF, ciliary neurotrophic factor, brain-derived neurotrophic factor or classical growth factors acting on neurons (e.g., fibroblast growth factor, insulin, and insulin-like growth factors). It also should be pointed out that clinical findings on patients with thyroid dysfunction are opposite to the prediction derived from the hypothesis by Butcher and Woolf. Hypothyroidism in aging is often associated with mental deficiency that may closely mimic senile dementia and this condition can normally be restored by chronic administration of thyroid hormones (5,6).
REFERENCES 1. Hefti, F.; Hartikka, J.; Bolger, M. B. Effect of thyroid hormone analogs on the activity of choline acetyltransferase in cultures of dissociated septal cells. Brain Res. 375:413-416; 1986. 2. Hefti, F.; Hartikka, J.; Knusel, B. Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases. Neurobiol. Aging. 10:515-533; 1989. 3. Mobley, W. C.; Neve, R. L.; Prusiner, S. B.; McKinley, M. P. Nerve growth factor induces gene expression for prion- and Alzheimer's beta-amyloid proteins. Proc. Natl. Acad. Sci. USA 85:9811-9815; 1988. 4. Phelps, C. H.; Gage, F. H.; Growdon, J. H.; Hefti, F.; Harbaugh, R.; Johnston, M. V.; Khachaturian, Z. S.; Mobley, W. C.; Price, D. L.;
Raskind, M.; Simpkins, J.; Thai, L. J.; Woodcock, J. Potential use of nerve growth factor to treat Alzheimer's disease. Neurobiol. Aging 10:205-207; 1989. 5. Rosenthal, M. J.; Sanchez, C. J. Thyroid disease in the elderly-missed diagnosis or overdiagnosis. West. J. Med. 143:643-647; 1985. 6. Swanson, J. W.; Kelly, J. L.; McConahey, W. M. Neurologic aspects of thyroid dysfunction. Mayo Clin. Proc. 56:504-512; 1981. 7. Williams, L. R.; Varon, S.; Peterson, G. M.; Wictorin, K.; Fischer, W.; Bjorklund, A.; Gage, F. H. Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. Proc. Natl. Acad. Sci. USA 83:9231-9235; 1986.
0197-4580/89 $3.00 ~- .00
Detrimental Actions of Neurotrophic Agents F R A N Z HEVI'I
Andrus Gerontology Center and Department of Biological Sciences University of Southern California, Los Angeles, CA 90089
There is little experimental evidence supporting the speculation that neurotrophic agents in general stimulate the pathological process in Alzheimer's disease. Nevertheless, possible detrimental actions of neurotrophic agents represent a concern when considering the pharmacological use of neurotrophic factors.
THE speculative hypothesis by Butcher and Woolf correctly directs awareness to the possibility that pharmacological use of growth factors and trophic agents may be detrimental to neuronal function, contrary to the beneficial role implied by the term "trophic." Such detrimental actions have to be considered and ruled out before clinically using trophic molecules. Neurotrophic agents may, by promoting the function of selective neuronal systems, alter the balance among various systems within neuronal networks. Trophic agents may induce the formation of aberrant synaptic connections which may disrupt normal signal flow. They may induce the expression of abnormal proteins by neuronal and nonneuronal cells and stimulate pathological proliferation of nonneuronal cells. Such actions are concerns when considering the clinical use of nerve growth factor (NGF) in Alzheimer's disease. The notion that NGF will be useful is based on substantial biochemical and anatomical evidence indicating trophic stimulation of forebrain cholinergic neurons and behavioral findings showing that the cholinergic hypertrophy is accompanied by behavioral improvement [reviews: (2,4)]. Based on these findings it seems unlikely that NGF-mediated cholinergic stimulation is functionally detrimental. However, long-term administration may induce aberrant cholinergic sprouting as observed in lesioned rodents (7). Since intraventricular NGF administration to neonatal animals elevates brain levels of amyloid precursor protein mRNA (3), it has to be determined whether application of NGF to the adult brain elevates amyloid precursor protein levels and whether such elevations produce pathological changes typical for Alzheimer's disease. Furthermore, since some nonneuronal cells seem responsive to NGF (2), the possibility of undesired proliferation
has to be considered. While representing a novel therapeutic approach, clinical application of NGF will have to follow general rules applied to the development of drugs. To rule out unacceptable actions of NGF, clinical application will have to be preceded by toxicology studies. Effective and safe dosages will have to be established. Guidelines for the use of NGF in Alzheimer's disease have been formulated by an ad hoc committee of the National Institute of Aging (4). The scenario outlined by Butcher and Woolf represents an interesting speculation based on very limited experimental support. The group of "neurotrophic agents" is defined to include NGF and thyroid hormones, and findings are presented suggesting that chronic triiodothyronine administration results in degeneration of cholinergic neurons in the nucleus basalis of adult rats. While thyroid hormones, similar to NGF, elevate choline acetyltransferase expression in developing cholinergic neurons (1), the actions of thyroid hormones differ in many ways from those of NGF and they are not normally considered to belong to the group of neurotrophic factors. Therefore, actions of thyroid hormones are not necessarily representative for NGF, ciliary neurotrophic factor, brain-derived neurotrophic factor or classical growth factors acting on neurons (e.g., fibroblast growth factor, insulin, and insulin-like growth factors). It also should be pointed out that clinical findings on patients with thyroid dysfunction are opposite to the prediction derived from the hypothesis by Butcher and Woolf. Hypothyroidism in aging is often associated with mental deficiency that may closely mimic senile dementia and this condition can normally be restored by chronic administration of thyroid hormones (5,6).
REFERENCES 1. Hefti, F.; Hartikka, J.; Bolger, M. B. Effect of thyroid hormone analogs on the activity of choline acetyltransferase in cultures of dissociated septal cells. Brain Res. 375:413-416; 1986. 2. Hefti, F.; Hartikka, J.; Knusel, B. Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases. Neurobiol. Aging. 10:515-533; 1989. 3. Mobley, W. C.; Neve, R. L.; Prusiner, S. B.; McKinley, M. P. Nerve growth factor induces gene expression for prion- and Alzheimer's beta-amyloid proteins. Proc. Natl. Acad. Sci. USA 85:9811-9815; 1988. 4. Phelps, C. H.; Gage, F. H.; Growdon, J. H.; Hefti, F.; Harbaugh, R.; Johnston, M. V.; Khachaturian, Z. S.; Mobley, W. C.; Price, D. L.;
Raskind, M.; Simpkins, J.; Thai, L. J.; Woodcock, J. Potential use of nerve growth factor to treat Alzheimer's disease. Neurobiol. Aging 10:205-207; 1989. 5. Rosenthal, M. J.; Sanchez, C. J. Thyroid disease in the elderly-missed diagnosis or overdiagnosis. West. J. Med. 143:643-647; 1985. 6. Swanson, J. W.; Kelly, J. L.; McConahey, W. M. Neurologic aspects of thyroid dysfunction. Mayo Clin. Proc. 56:504-512; 1981. 7. Williams, L. R.; Varon, S.; Peterson, G. M.; Wictorin, K.; Fischer, W.; Bjorklund, A.; Gage, F. H. Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. Proc. Natl. Acad. Sci. USA 83:9231-9235; 1986.