BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) ROLE IN THE NEUROTROPHIC HYPOTHESIS OF DEPRESSION
Factorul de creştere neuronală (Brain derived neurotrophic factor, BDNF) este o neutrofină implicată în supravieţuirea neuronală, în semnalizarea şi consolidarea sinaptică ce ajută la creşterea şi menţinerea mai multor s i s t e m e n e u ro n a l e , s e r v e ş t e c a m o d u l a t o r a l neurotransmisiei şi participă la mecanismele de plasticitate. Ipoteza neurotrofică a depresiei a fost dezvoltată pe baza observaţiilor unor nivele scăzute ale BDNF la pacienţii cu tulburare depresivă precum şi a studiilor care arată că nivelurile BDNF cresc după anumite tratamente antidepresive. Măsurarea BDNF ar putea reprezenta un marker pentru tulburarea depresivă precum şi pentru eficienţa tratamentelor antidepresive.
Neurotrophins are involved in many functions, f r o m d i ff e r e n t i a t i o n a n d n e u r o n a l s u r v i v a l t o synaptogenesis and activity-dependent forms of synaptic plasticity. Four neurotrophins have been identified so far: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4). Like other proteins, neurotrophins arise from precursors, proneurotrophins, which are proteolytically cleaved to produce mature proteins (1). Neutrophins act by binding to two distinct classes of transmembrane receptors: the p75 neurotrophin receptor (p75NTR) and the Trk family of receptor tyrosine kinases. The p75NTR receptors are non-selective with affinity for all neurotrophins while Trk receptors are highly selective, each receptor binding a different neurotrophin.
Among neurotrophins, BDNF is the most abundant and it has been most extensively studied. It has been associated with several disorders, such as substance-related d i s o r d e r s , e a t i n g d i s o r d e r s , m o o d d i s o r d e r s , schizophrenia, pain modulation and epilepsy (2). BDNF is a dimeric protein, and it is found throughout the brain, with particular abundance in the hippocampus and cerebral cortex. BDNF is found in both human serum and plasma (3, 4, 5). Serum levels of BDNF have been found to be 200- fold higher than plasma levels (5). Human platelets contain a large amount of the BDNF in blood (3, 6). Thus, the difference between serum and plasma levels of BDNF could reflect the amount of BDNF stored in circulating platelets. Alternative sources of blood BDNF have been identified in endothelial cells (7) and lymphocytes (8), but their contribution is believed to be marginal compared with bulk release from platelets. Since BDNF is known to cross the blood–brain barrier by a transport system in both directions, circulating BDNF might originate from neurons and glial cells of the brain (9). Accordingly, plasma BDNF may reflect circulating levels rather than the levels stored in platelets. Karege et al. (10) showed a positive correlation between BDNF serum and cortical levels.
BDNF was related to neuronal survival, synaptic signaling and synaptic consolidation (11). BDNF enhances the growth and maintenance of several neuronal systems, serves as a neurotransmitter modulator, and participates in plasticity mechanisms such as long-term potentiation (12) and learning (13). Several studies have been performed assessing BDNF levels in major depressive disorder (MDD) and showed important correlations between MDD and BDNF levels.
Stress and antidepressant treatment exert opposing actions on the expression of BDNF in limbic brain regions involved in the regulation of mood and cognition. Moreover, the functional significance of altered BDNF expression is highlighted by studies demonstrating that stress and depression can lead to neuronal atrophy and cell loss in key limbic brain regions implicated in depression, including the amygdala, prefrontal cortex, and hippocampus, and that antidepressant treatment can block or reverse these effects.
The mechanisms underlying the actions of antidepressant treatment are still under investigation, but upregulation of BDNF and other neurotrophic factors could contribute to the long-term adaptations that are required for the therapeutic actions of these treatments.The ‘neurotrophic hypothesis’ of depression has been developed based on an array of clinical and preclinical data BDNF mRNA levels are reduced in the brains of suicide victims (with the possible diagnosis of depression) (14,
15) and are also decreased by stress, an important precipitating factor in mood disorders. In the neurotrophin hypothesis of depression, MDD leads to atrophy of specific brain areas, such as amygdala and hippocampus, that is reversed after antidepressant treatment – hence, neuroplasticity should occur in these sites. The bridging l i n k b e t w e e n p h a r m a c o l o g i c a l ( a n d n o n – pharmacological) treatments and neurogenesis is seen by the actions of BDNF, which might be a ‘final common pathway’ for several types of antidepressant (16). The finding that antidepressants increase neurotrophic factor expression in the adult hippocampus provides the background and rationale for studies of adult neurogenesis. This led to the surprising discovery that antidepressant treatment significantly increases neurogenesis in the adult hippocampus (17, 18). The upregulation of neurogenesis is observed with chronic, but not acute, administration of different classes of antidepressants, including selective serotonin re-uptake inhibitors (SSRI), norepinephrine selective reuptake inhibitors (NESRI), monoamine oxidase inhibitors (MAOI), and electroconvulsive therapy (ECT), indicating that neurogenesis is a common target of antidepressant medications.
Karege et al. (19) were the first to demonstrate that BDNF serum levels are lower in MDD patients compared to healthy controls. Shimizu et al. (20) compared serum BDNF levels of drug-naive and treated patients with major depressive disorder and found that the serum BDNF level was lower in the drug-naive group than in the treated group and normal control group. Subsequently, Aydemir et al. (21) showed that BDNF levels increase after antidepressant treatment. Although most of the studies show that BNDF levels increase after antidepressant treatment, the results are mixed.
Brunoni et al (2) showed in a meta-analysis that included 1504 subjects with MDD that BDNF blood levels increase as depression is treated and that BDNF levels are lower in patients with MDD pre-treatment than in controls. He also showed that BDNF levels are higher in MDD post- treatment patients than in healthy controls and that BDNF levels are correlated with depression symptoms change, period of treatment and previous antidepressant use. Selective serotonine and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and electroconvulsive therapy have been found to up-regulate BDNF. Increased BDNF expression in response to antidepressant treatment has been shown with fluoxetine, fluvoxamine, sertraline, desipramine, imipramine, milnacipran (22, 23). Administration of other classes of psychotropic drugs, including opiates, antipsychotics, and psychostimulants, does not increase BDNF expression in the hippocampus, demonstrating the pharmacological specificity of antidepressants (24).
The role of BDNF in depression has been strengthened by family-based association studies showing that the BDNF gene is a major risk locus for depression (25, 26). Identifying biomarkers that could be used to assist in the diagnosis of major depressive disorder has remained a goal of clinicians and scientists for more than a half of a century. The relative simplicity of the testing and the highly consistent findings of reduced serum BDNF levels in individuals with MDD suggest that the measure may prove to be a clinically useful biomarker. However, the apparent lack of diagnostic specificity is likely to be a major drawback limiting the true clinical utility of the measure. Reduced serum and plasma BDNF levels have also recently been reported in several other disorders including; schizophrenia, bipolar disorder, eating disorders, Huntington’s disease, Alzheimer’s disease and autism.
A second potentially interesting application of serum BDNF measures could be as a biomarker of antidepressant efficacy. There is now strong evidence that serum BDNF levels increase following treatment with antidepressant medications. This suggests that the measure may be used to screen for novel antidepressant agents or possibly even predict an individual’s response to an antidepressant treatment at an early time point after treatment.
1.Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat
Rev Neurosci 2005;6(8): 603-614.
2. Brunoni AR, Lopes M, Fregni F. A systematic review and meta- analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 2008;11: 1169-1180.
3. Fujimura H, Altar CA, Chen R et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost 2002;87: 728–734.
4. Radka SF, Holst PA, Fritsche M, Altar CA. Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay. Brain Res 1996;709:
5. Rosenfeld RD, Zeni L, Haniu M et al. Purification and identification of brain-derived neurotrophic factor from human serum. Protein Expr Purif
6. Pliego-Rivero FB, Bayatti N, Giannakoulopoulos X et al. Brain- derived neurotrophic factor in human platelets. Biochem Pharmacol
7. Nakazaki T, Fujimura H, Altar CA et al. Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett
8. Noga O, Hanf G, Schäper C, O’Connor A, Kunkel G. The influence of inhalative corticosteroids on circulating nerve growth factor, brainderived neurotrophic factor and neurotrophin-3 in allergic asthmatics. Clin Exp Allergy 2001;31: 1906 –1912.
9. Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ. Transport of brainderived neurotrophic factor across the blood-brain barrier. Neuropharmacology 1998;37: 1553–1561.
10. Karege F, Bondolfi G, Gervasoni N, Schwald M, Aubry JM, Bertschy G. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry 2005;57: 1068-1072.
11. Allen SJ, Dawbarn D. Clinical relevance of the neurotrophins and their receptors. Clin Sci 2006;110: 175-191.
12. Gärtner A, Staiger V. Neurotrophin secretion from hippocampal neurons evoked by long-term-potentiation-inducing electrical stimulation patterns. Proc Natl Acad Sci USA 2002;99: 6386-6391.
13. Lindsay RM, Wiegand SJ, Altar CA, DiStephano PS. Neurotrophic factors: From molecule to man. Trends Neurosci 1994;17: 182–190.
14. Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001;50: 260 –265.
15. Dwivedi Y, Rao JS, Hooriyah SR et al. Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects. Arch Gen Psychiatry 2003;60: 273–282.
16. Kempermann G, Kronenberg G. Depressed new neurons – adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biological Psychiatry 2003;54: 499–503.
17. Malberg J, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult hippocampus. J Neurosci 2000;20: 9104–9110.
18. Duman R. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med 2004;5: 11–25.
19. Karege F, Perret H, Bondolfi G, Schwald M, Bertschv G, Aubrey JM. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychol Res 2002; 109: 143–148.
21. Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Biol Psychiatry 2005;29: 261–265.
22. Duman RS, Malberg J, Nakagawa S, D’Sa CM. Neuronal plasticity and survival in mood disorders. Biol Psychiatry 2000;48: 732–739.
23. Popoli M, Gennarelli M, Racagni G. Modulation of synaptic plasticity by stress and antidepressants. Bipolar Disord 2002; 4: 166–182.
24. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006;59: 1116-1127.
25. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F Kennedy JL. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: Evidence from a family-based association study. Am J Hum Genet 2002;71: 651– 655.
26. Sklar P, Gabriel SB, McInnis MG et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 2002;7: 579–593.