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New antidepressant drugs that do not cross the blood–brain barrier
Black plate (83,1)
Medical Hypotheses (2002) 58(1), 83±84 & 2002 Harcourt Publishers Ltd doi: 10.1054/mehy.2001.1462, available online at http://www.idealibrary.com on
1
New antidepressant drugs that do not cross the blood±brain barrier H. Manev, R. Manev Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, USA
Summary Stimulation of neurogenesis in the adult brain (i.e. in the hippocampus) has recently been proposed as a putative mechanism of antidepressant action of drugs. This effect of antidepressants may not be achieved by their primary action on proliferating cells, but may involve the drug-triggered mobilization of trophic factors, such as brainderived neurotrophic factor (BDNF), glia-derived protein S100b, or insulin-like growth factor I (IFG-I). Whereas BDNF and S100b are produced in the brain, IGF-I is primarily released from peripheral tissues. Administered peripherally, IGF-I increases hippocampal neurogenesis in the adult rat. Because synthesis and release of IGF-I appear to be stimulated by serotonergic mechanisms, we propose that antidepressants that affect serotonergic mechanisms might be rendered more effective by mobilizing IGF-I. Moreover, we suggest that new antidepressant drugs could be designed that would not enter into the brain but would stimulate peripheral mediators such as IGF-I. & 2002 Harcourt Publishers Ltd
INTRODUCTION The exact mechanisms of the antidepressant action of drugs are still unclear in spite of significant progress in new drug development. It is becoming increasingly evident that novel therapeutic targets beyond the regulation of monoamine transporters and receptors might be operative (1). Recent research in experimental animals points to the possibility of a previously unsuspected mechanism that increases neurogenesis in the adult brain as a mediator of antidepressant drug action (2,3). Based on these findings, a novel theory of depression has been formulated that proposes a deficiency in adult brain neurogenesis (e.g. in the hippocampus) as a pathobiological basis of depression (4). The biological pathways leading to antidepressant-triggered neurogenesis in the adult brain are not clear and are being actively investigated.
Received 9 April 2001 Accepted 10 July 2001 Correspondence to: Hari Manev MD, PhD, Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, M/C912, Chicago, IL 60612, USA. Phone: 312 413 4558; Fax: 312 413 4569; E-mail: [email protected]
For example, it has been suggested that trophic factors may be mobilized by antidepressants and that they could be a link between the primary drug action and stimulation of adult neurogenesis. Thus, prolonged administration of antidepressants to rats stimulates the expression of hippocampal brain-derived neurotrophic factor (BDNF) (5) or the glia-derived neurotrophic factor S100b (6). On the other hand, administration of trophic factors to adult rats increases neurogenesis; it was found that intraventicular infusion of BDNF was capable of increasing neurogenesis in the adult olfactory bulb (7) whereas a peripheral infusion of insulin-like growth factor I (IGF-I) increased the proliferation and survival of hippocampal neurons in the adult rat (8). DISCUSSION Whereas BDNF and S100b are predominantly produced in the brain, IGF-I is predominantly synthesized in and released from peripheral tissues, for example liver and muscle (9). IGF-I is a 70 amino acid peptide that easily crosses the blood±brain barrier (10,11) and promotes growth and development of the CNS (12). The main positive physiological regulator of circulating levels of IGF-I is growth hormone (GH) (9,13). Other hormones,
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i.e. the indoleamines melatonin and serotonin (5-hydroxytriptamine; 5-HT), appear to be capable of stimulating IGF-I release as well (14). In the CNS, serotonergic mechanisms are important targets for antidepressant drugs. For example, it is believed that the primary site of action of drugs such as fluoxetine (Prozac) is the transporter for serotonin, and that the immediate result of the action of a drug is an increase in the extracellular content of serotonin. However, this primary effect of serotonin reuptake inhibitors alone does not appear to be a satisfactory explanation of their antidepressant activity (15). Although no direct data are available on the effect of serotonin reuptake inhibitors on IGF-I, there is evidence that pharmacological alterations of serotonerigc mechanisms can stimulate IGF-I. For example, stimulation of the 5-HT receptors that increase cAMP was shown to be capable of stimulating the synthesis of IGF-I (16). Thus, we hypothesize that antidepressant drugs, particularly those acting via 5-HT mechanisms and effective in stimulating neurogenesis in the adult brain (2,3), in part are therapeutic due to their action on IGF-I. To test this hypothesis, serum levels of IGF-I would be monitored in patients treated with antidepressants and correlated with a clinical assessment of symptoms. In adult rats, peripheral injections of IGF-I stimulated neurogenesis in the hippocampus (8). Although a human recombinant IGF-I could be administered via injections to human (17), it is unlikely that injections could be used as an antidepressant treatment. On the other hand, since IGF-I is a peptide, it is unlikely to become an orally active CNS drug (local effects of orally administered IGF-I may be achieved in the intestine (18)). Thus, a drug capable of selectively and directly stimulating the synthesis and/or release of IGF-I (or some other factor with similar CNS activity) from peripheral sources could become a prototype for a new antidepressant that does not cross the blood±brain barrier. Because this new type of antidepressant does not enter the brain, the CNS sideeffects of such novel drugs might be significantly reduced. ACKNOWLEDGEMENTS H. Manev received a 2000 NARSAD Independent Investigator Award.
2. Malberg J. E., Eisch A. J., Nestler E. J., Duman R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20: 9104±9110. 3. Manev H., Uz T., Smalheiser N. R., Manev R. Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro. Eur J Pharmacol 2001; 411: 67±70. 4. Jacobs B. L., Praag H., Gage F. H. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000; 5: 262±269. 5. Nibuya M., Morinobu S., Duman R. S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995; 15: 7539±7547. 6. Manev R., Uz T., Manev H. Fluoxetine increases the content of neurotrophic protein S100b in the rat hippocampus. Eur J Pharmacol 2001; 420: R1±R2. 7. Zigova T., Pencea V., Wiegand S., Luskin M. Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol Cell Neurosci 1998; 11: 234±245. 8. Aberg M. A. I., Aberg N. D., Hedbacker H., Oscarsson J., Eriksson P. S. Peripheral infusion of IGF-1 selectively induces neurogenesis in the adult rat hippocampus. J Neurosci 2000; 20: 2896±2903. 9. Le Roith D., Scavo L., Butler A. What is the role of circualting IGF-I? Trends Endocrinol Metab 2001; 12: 48±52. 10. Duffy, K. R., Pardrige W. M., Rosenfeld R. G. Human blood±brain barrier insulin-like growth factor receptor. Metabolism 1998; 37: 136±140. 11. Reinhardt R. R., Bondy C. A. Insulin-like growth factors cross the blood-brain barrier. Endocrinology 1994; 135: 1753±1761. 12. O'Kusky J. R., Ye P., D'Ercole A. J. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci 2000; 20: 8435±8442. 13. Humbel R. E. Insulin-like growth factors I and II. Eur J Biochem 1990; 190: 445±462. 14. Schaeffer H. J., Sirotkin A. V. Melatonin and serotonin regulate the release of insulin-like growth factor-I, oxytocin and progesterone by cultured human granulosa cells. Exp Clin Endocrinol Diabetes 1997; 105: 109±112. 15. Leonard B. E. Pharmacological differences of serotonin reuptake inhibitors and possible clinical relevance. Drugs 1992; 43(Suppl. 2): 3±9. 16. Lambert H. W., Lauder J. M. Serotonin receptor agonists that increase cyclic AMP positively regulate IGF-I in mouse mandibular mesenchymal cells. Dev Neurosci 1999; 21: 105±112. 17. Gianotti L., Ramunni J., Lanfranco F., et al. Recombinant human IGF-I does not modify the ACTH and cortisol responses to hCRH and hexarelin, a peptidyl GH secretagogue, in humans. J Endocrinol Invest 2001; 24: 67±71. 18. Alexander A. N., Carey H. V. Oral IGF-I enhances nutrient and electrolyte absorption in neonatal piglet intestine. Am J Physiol 1999; 277: G619±625.
REFERENCES 1. Reid I. C., Stewart C. A. How antidepressants work: new perspectives on the pathophysiology of depressive disorder. Br J Psychiatry 2001; 178: 299±303.
Medical Hypotheses (2002) 58(1), 83±84
& 2002 Harcourt Publishers Ltd
Medical Hypotheses (2002) 58(1), 83±84 & 2002 Harcourt Publishers Ltd doi: 10.1054/mehy.2001.1462, available online at http://www.idealibrary.com on
1
New antidepressant drugs that do not cross the blood±brain barrier H. Manev, R. Manev Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, USA
Summary Stimulation of neurogenesis in the adult brain (i.e. in the hippocampus) has recently been proposed as a putative mechanism of antidepressant action of drugs. This effect of antidepressants may not be achieved by their primary action on proliferating cells, but may involve the drug-triggered mobilization of trophic factors, such as brainderived neurotrophic factor (BDNF), glia-derived protein S100b, or insulin-like growth factor I (IFG-I). Whereas BDNF and S100b are produced in the brain, IGF-I is primarily released from peripheral tissues. Administered peripherally, IGF-I increases hippocampal neurogenesis in the adult rat. Because synthesis and release of IGF-I appear to be stimulated by serotonergic mechanisms, we propose that antidepressants that affect serotonergic mechanisms might be rendered more effective by mobilizing IGF-I. Moreover, we suggest that new antidepressant drugs could be designed that would not enter into the brain but would stimulate peripheral mediators such as IGF-I. & 2002 Harcourt Publishers Ltd
INTRODUCTION The exact mechanisms of the antidepressant action of drugs are still unclear in spite of significant progress in new drug development. It is becoming increasingly evident that novel therapeutic targets beyond the regulation of monoamine transporters and receptors might be operative (1). Recent research in experimental animals points to the possibility of a previously unsuspected mechanism that increases neurogenesis in the adult brain as a mediator of antidepressant drug action (2,3). Based on these findings, a novel theory of depression has been formulated that proposes a deficiency in adult brain neurogenesis (e.g. in the hippocampus) as a pathobiological basis of depression (4). The biological pathways leading to antidepressant-triggered neurogenesis in the adult brain are not clear and are being actively investigated.
Received 9 April 2001 Accepted 10 July 2001 Correspondence to: Hari Manev MD, PhD, Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, M/C912, Chicago, IL 60612, USA. Phone: 312 413 4558; Fax: 312 413 4569; E-mail: [email protected]
For example, it has been suggested that trophic factors may be mobilized by antidepressants and that they could be a link between the primary drug action and stimulation of adult neurogenesis. Thus, prolonged administration of antidepressants to rats stimulates the expression of hippocampal brain-derived neurotrophic factor (BDNF) (5) or the glia-derived neurotrophic factor S100b (6). On the other hand, administration of trophic factors to adult rats increases neurogenesis; it was found that intraventicular infusion of BDNF was capable of increasing neurogenesis in the adult olfactory bulb (7) whereas a peripheral infusion of insulin-like growth factor I (IGF-I) increased the proliferation and survival of hippocampal neurons in the adult rat (8). DISCUSSION Whereas BDNF and S100b are predominantly produced in the brain, IGF-I is predominantly synthesized in and released from peripheral tissues, for example liver and muscle (9). IGF-I is a 70 amino acid peptide that easily crosses the blood±brain barrier (10,11) and promotes growth and development of the CNS (12). The main positive physiological regulator of circulating levels of IGF-I is growth hormone (GH) (9,13). Other hormones,
83
Black plate (84,1)
84 Manev and Manev
i.e. the indoleamines melatonin and serotonin (5-hydroxytriptamine; 5-HT), appear to be capable of stimulating IGF-I release as well (14). In the CNS, serotonergic mechanisms are important targets for antidepressant drugs. For example, it is believed that the primary site of action of drugs such as fluoxetine (Prozac) is the transporter for serotonin, and that the immediate result of the action of a drug is an increase in the extracellular content of serotonin. However, this primary effect of serotonin reuptake inhibitors alone does not appear to be a satisfactory explanation of their antidepressant activity (15). Although no direct data are available on the effect of serotonin reuptake inhibitors on IGF-I, there is evidence that pharmacological alterations of serotonerigc mechanisms can stimulate IGF-I. For example, stimulation of the 5-HT receptors that increase cAMP was shown to be capable of stimulating the synthesis of IGF-I (16). Thus, we hypothesize that antidepressant drugs, particularly those acting via 5-HT mechanisms and effective in stimulating neurogenesis in the adult brain (2,3), in part are therapeutic due to their action on IGF-I. To test this hypothesis, serum levels of IGF-I would be monitored in patients treated with antidepressants and correlated with a clinical assessment of symptoms. In adult rats, peripheral injections of IGF-I stimulated neurogenesis in the hippocampus (8). Although a human recombinant IGF-I could be administered via injections to human (17), it is unlikely that injections could be used as an antidepressant treatment. On the other hand, since IGF-I is a peptide, it is unlikely to become an orally active CNS drug (local effects of orally administered IGF-I may be achieved in the intestine (18)). Thus, a drug capable of selectively and directly stimulating the synthesis and/or release of IGF-I (or some other factor with similar CNS activity) from peripheral sources could become a prototype for a new antidepressant that does not cross the blood±brain barrier. Because this new type of antidepressant does not enter the brain, the CNS sideeffects of such novel drugs might be significantly reduced. ACKNOWLEDGEMENTS H. Manev received a 2000 NARSAD Independent Investigator Award.
2. Malberg J. E., Eisch A. J., Nestler E. J., Duman R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20: 9104±9110. 3. Manev H., Uz T., Smalheiser N. R., Manev R. Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro. Eur J Pharmacol 2001; 411: 67±70. 4. Jacobs B. L., Praag H., Gage F. H. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000; 5: 262±269. 5. Nibuya M., Morinobu S., Duman R. S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995; 15: 7539±7547. 6. Manev R., Uz T., Manev H. Fluoxetine increases the content of neurotrophic protein S100b in the rat hippocampus. Eur J Pharmacol 2001; 420: R1±R2. 7. Zigova T., Pencea V., Wiegand S., Luskin M. Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol Cell Neurosci 1998; 11: 234±245. 8. Aberg M. A. I., Aberg N. D., Hedbacker H., Oscarsson J., Eriksson P. S. Peripheral infusion of IGF-1 selectively induces neurogenesis in the adult rat hippocampus. J Neurosci 2000; 20: 2896±2903. 9. Le Roith D., Scavo L., Butler A. What is the role of circualting IGF-I? Trends Endocrinol Metab 2001; 12: 48±52. 10. Duffy, K. R., Pardrige W. M., Rosenfeld R. G. Human blood±brain barrier insulin-like growth factor receptor. Metabolism 1998; 37: 136±140. 11. Reinhardt R. R., Bondy C. A. Insulin-like growth factors cross the blood-brain barrier. Endocrinology 1994; 135: 1753±1761. 12. O'Kusky J. R., Ye P., D'Ercole A. J. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci 2000; 20: 8435±8442. 13. Humbel R. E. Insulin-like growth factors I and II. Eur J Biochem 1990; 190: 445±462. 14. Schaeffer H. J., Sirotkin A. V. Melatonin and serotonin regulate the release of insulin-like growth factor-I, oxytocin and progesterone by cultured human granulosa cells. Exp Clin Endocrinol Diabetes 1997; 105: 109±112. 15. Leonard B. E. Pharmacological differences of serotonin reuptake inhibitors and possible clinical relevance. Drugs 1992; 43(Suppl. 2): 3±9. 16. Lambert H. W., Lauder J. M. Serotonin receptor agonists that increase cyclic AMP positively regulate IGF-I in mouse mandibular mesenchymal cells. Dev Neurosci 1999; 21: 105±112. 17. Gianotti L., Ramunni J., Lanfranco F., et al. Recombinant human IGF-I does not modify the ACTH and cortisol responses to hCRH and hexarelin, a peptidyl GH secretagogue, in humans. J Endocrinol Invest 2001; 24: 67±71. 18. Alexander A. N., Carey H. V. Oral IGF-I enhances nutrient and electrolyte absorption in neonatal piglet intestine. Am J Physiol 1999; 277: G619±625.
REFERENCES 1. Reid I. C., Stewart C. A. How antidepressants work: new perspectives on the pathophysiology of depressive disorder. Br J Psychiatry 2001; 178: 299±303.
Medical Hypotheses (2002) 58(1), 83±84
& 2002 Harcourt Publishers Ltd