Correlations and Discrepancies between Serum and Brain Tissue Levels of Neurotrophins after Electroconvulsive Treatment in Rats

Abstract

Introduction: The neurotrophin brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are a central part of the molecular concepts on neuroplastic changes associated with stress, anxiety and depression. An increasing number of studies uses serum BDNF levels as a potential indicator for central nervous system alterations.

Methods: To analyze the relationship between brain tissue and serum BDNF and NGF levels, we used electroconvulsive shocks (ECS), an animal model of electroconvulsive therapy, and studied the temporal profile of neurotrophin expression in the hippocampus, prefrontal cortex and serum. 88 male Sprague-Dawley rats received single or serial ECS treatments and were killed between 3 hours and 14 days after the last treatment.

Results: We found a 2.8-fold rise for BDNF (1.3-fold for NGF) in the prefrontal cortex, and a 2.2-fold rise (1.2-fold for NGF) in the hippocampus after 5 ECS sessions. The temporal expression profile and correlation analyses between tissue and serum BDNF indicate that BDNF crosses the blood-brain barrier. No such correlation was found for NGF.

Discussion: The time course of central and peripheral BDNF changes may significantly differ. However, we demonstrate substantial evidence that it can be justified to measure serum BDNF levels with a time delay to monitor brain tissue neurotrophin alterations.

References

• 1 Altar CA. Neurotrophins and depression.  Trends Pharmacol Sci. 1999;  20 59-61
• 2 Altar CA, Whitehead RE, Chen R. et al . Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain.  Biol Psychiatry. 2003;  54 703-709
• 3 Angelucci F, Aloe L, Jimenez-Vasquez P. et al . Electroconvulsive stimuli alter the regional concentrations of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor in adult rat brain.  J ECT. 2002;  18 138-143
• 4 Blandini F, Rinaldi L, Tassorelli C. et al . Peripheral levels of BDNF and NGF in primary headaches.  Cephalalgia. 2006;  26 136-142
• 5 Bocchio-Chiavetto L, Zanardini R, Bortolomasi M. et al . Electroconvulsive therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients.  Eur Neuropsychopharmacol. 2006;  16 620-624
• 6 Burbach GJ, Hellweg R, Haas CA. et al . Induction of brain-derived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice.  J Neurosci. 2004;  24 2421-2430
• 7 Chiaretti A, Antonelli A, Piastra M. et al . Expression of neurotrophic factors in cerebrospinal fluid and plasma of children with viral and bacterial meningoencephalitis.  Acta Paediatr. 2004;  93 1178-1184
• 8 Chourbaji S, Hellweg R, Brandis D. et al . Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior.  Brain Res Mol Brain Res. 2004;  121 28-36
• 9 Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression.  Arch Gen Psychiatry. 1997;  54 597-606
• 10 Fink M, Taylor MA. Electroconvulsive therapy: evidence and challenges.  JAMA. 2007;  298 330-332
• 11 Frankhauser P, Grimmer Y, Bugert P. et al . Characterization of the neuronal dopamine transporter DAT in human blood platelets.  Neurosci Lett. 2006;  399 197-201
• 12 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
• 13 Gervasoni N, Aubry JM, Bondolfi G. et al . Partial normalization of serum brain-derived neurotrophic factor in remitted patients after a major depressive episode.  Neuropsychobiology. 2005;  51 234-238
• 14 Gronli O, Stensland GO, Wynn R. et al . Neurotrophic factors in serum following ECT: A pilot study.  World J Biol Psychiatry. 2007;  1-7
• 15 Groves JO. Is it time to reassess the BDNF hypothesis of depression?.  Mol Psychiatry. 2007;  12 1079-1088
• 16 Hellweg R, Baethge C, Hartung HD. et al . NGF level in the rat sciatic nerve is decreased after long-term consumption of ethanol.  Neuroreport. 1996;  7 777-780
• 17 Hellweg R, Hock C, Hartung HD. An improved and rapid highly sensitive enzyme immunoassay for nerve growth factor.  Technique, J Methods Cell Mol Biol. 1989;  1 43-48
• 18 Hellweg R, von Arnim CA, Buchner M. et al . Neuroprotection and neuronal dysfunction upon repetitive inhibition of oxidative phosphorylation.  Exp Neurol. 2003;  183 346-354
• 19 Hellweg R, von Arnim CA, Buchner M. Neuroprotection and neuronal dysfunction upon repetitive inhibition of oxidative phosphorylation.  Exp Neurol. 2003;  183 346-354
• 20 Hellweg R, Ziegenhorn A, Heuser I. et al . Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment.  Pharmacopsychiatry. 2008;  41 66-71
• 21 Henn FA, Vollmayr B, Sartorius A. Mechanisms of depression: the role of neurogenesis.  Drug Discovery Today: Disease Mechanisms. 2004;  1 407-411
• 22 Holoubek G, Noldner M, Treiber K. et al . Effect of chronic antidepressant treatment on beta-receptor coupled signal transduction cascade. Which effect matters most?.  Pharmacopsychiatry. 2004;  37 ((Suppl 2)) S113-S119
• 23 Jockers-Scherubl MC, Bauer A, Kuhn S. et al . Nerve growth factor in serum is a marker of the stage of alcohol disease.  Neurosci Lett. 2007;  419 78-82
• 24 Jockers-Scherubl MC, Matthies U, Danker-Hopfe H. et al . Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients.  J Psychopharmacol. 2003;  17 439-445
• 25 Karege F, Schwald M, Cisse M. Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets.  Neurosci Lett. 2002;  328 261-264
• 26 Kastin AJ, Pan W, Maness LM. et al . Peptides crossing the blood-brain barrier: some unusual observations.  Brain Res. 1999;  848 96-100
• 27 Khundakar AA, Zetterstrom TS. Biphasic change in BDNF gene expression following antidepressant drug treatment explained by differential transcript regulation.  Brain Res. 2006;  1106 12-20
• 28 Kirschner PB, Jenkins BG, Schulz JB. et al . NGF, BDNF and NT-5, but not NT-3 protect against MPP+ toxicity and oxidative stress in neonatal animals.  Brain Res. 1996;  713 178-185
• 29 Lang UE, Hellweg R, Bajbouj M. et al . Gender-dependent association of a functional NGF polymorphism with anxiety-related personality traits.  Pharmacopsychiatry. 2008;  41 196-199
• 30 Lang UE, Hellweg R, Seifert F. et al . Correlation between serum brain-derived neurotrophic factor level and an in vivo marker of cortical integrity.  Biol Psychiatry. 2007;  62 530-535
• 31 Lang UE, Jockers-Scherubl MC, Hellweg R. State of the art of the neurotrophin hypothesis in psychiatric disorders: implications and limitations.  J Neural Transm. 2004;  111 387-411
• 32 Laske C, Stransky E, Leyhe T. et al . BDNF serum and CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls.  J Psychiatr Res. 2007;  41 387-394
• 33 Levi-Montalcini R, Skaper SD, Dal TR. et al . Nerve growth factor: from neurotrophin to neurokine.  Trends Neurosci. 1996;  19 514-520
• 34 Li B, Suemaru K, Cui R. et al . Repeated electroconvulsive stimuli have long-lasting effects on hippocampal BDNF and decrease immobility time in the rat forced swim test.  Life Sci. 2007;  80 1539-1543
• 35 Lommatzsch M, Zingler D, Schuhbaeck K. et al . The impact of age, weight and gender on BDNF levels in human platelets and plasma.  Neurobiol Aging. 2005;  26 115-123
• 36 Marano CM, Phatak P, Vemulapalli UR. et al . Increased plasma concentration of brain-derived neurotrophic factor with electroconvulsive therapy: a pilot study in patients with major depression.  J Clin Psychiatry. 2007;  68 512-517
• 37 Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety.  Nat Neurosci. 2007;  10 1089-1093
• 38 Nakahashi T, Fujimura H, Altar CA. et al . Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor.  FEBS Lett. 2000;  470 113-117
• 39 Osim E, Mudzingwa S, Musabayane C. et al . The effect of chloroquine on circulating platelet survival in the rat.  J Cardiovasc Pharmacol Ther. 1999;  4 97-102
• 40 Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter.  Clin Chem. 1994;  40 288-295
• 41 Pan W, Banks WA, Fasold MB. et al . Transport of brain-derived neurotrophic factor across the blood-brain barrier.  Neuropharmacology. 1998;  37 1553-1561
• 42 Poduslo JF, Curran GL. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF.  Brain Res Mol Brain Res. 1996;  36 280-286
• 43 Russo-Neustadt A, Beard RC, Cotman CW. Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression.  Neuropsychopharmacology. 1999;  21 679-682
• 44 Sartorius A, Henn FA, Ende G. Proton magnetic resonance spectroscopy as a monitoring tool for electroconvulsive therapy effects on the brain.  Current Psychiatry Reviews. 2006;  2 39-49
• 45 Sartorius A, Mahlstedt MM, Vollmayr B. et al . Elevated spectroscopic glutamate/gamma-amino butyric acid in rats bred for learned helplessness.  Neuroreport. 2007;  18 1469-1473
• 46 Sartorius A, Wolf J, Henn FA. Lithium and ECT − concurrent use still demands attention: three case reports.  World J Biol Psychiatry. 2005;  6 121-124
• 47 Schulte-Herbruggen O, Chourbaji S, Muller H. et al . Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness.  Exp Neurol. 2006;  202 404-409
• 48 Schulte-Herbruggen O, Hellweg R, Chourbaji S. et al . Differential regulation of neurotrophins and serotonergic function in mice with genetically reduced glucocorticoid receptor expression.  Exp Neurol. 2007;  204 307-316
• 49 Shirayama Y, Chen AC, Nakagawa S. et al . Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.  J Neurosci. 2002;  22 3251-3261
• 50 Siuciak JA, Lewis DR, Wiegand SJ. et al . Antidepressant-like effect of brain-derived neurotrophic factor (BDNF).  Pharmacol Biochem Behav. 1997;  56 131-137
• 51 Trajkovska V, Marcussen AB, Vinberg M. et al . Measurements of brain-derived neurotrophic factor: methodological aspects and demographical data.  Brain Res Bull. 2007;  73 143-149
• 52 Ziegenhorn AA, Schulte-Herbruggen O, Danker-Hopfe H. et al . Serum neurotrophins − a study on the time course and influencing factors in a large old age sample.  Neurobiol Aging. 2007;  28 1436-1445

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