title: Role of the endogenous nitric oxide inhibitor asymmetric dimethylarginine (ADMA) and brain-derived neurotrophic factor (BDNF) in depression and behavioural changes: clinical and preclinical data in chronic kidney disease.
abstract: BACKGROUND
  Patients with chronic kidney disease (CKD) exhibit a high prevalence of neuropsychiatric alterations, including depression and behavioural changes. CKD is also associated with decreased physical activity not fully explained by co-morbidities. In patients without CKD, the brain-derived neurotropic factor (BDNF) as well as the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) had been suspected to be involved in major depression. The aim of our study was to examine the role of ADMA and BDNF in the behaviour of haemodialysis patients (CKD5D) as well as in a rat model of 5/6 nephrectomy and chronic ADMA infusion alone.
  
  
  METHODS
  Eleven (5F/6M) CKD5D patients underwent Beck Depression Inventory (BDI) testing along with analysis of ADMA and BDNF. Male Sprague-Dawley rats were randomly assigned to four groups: (i) saline infusion; (ii) ADMA (250 µg/kg/day) infusion via osmotic mini pumps; (iii) 5/6 nephrectomy; (iv) untreated controls. After 28 days, the animals underwent behavioural tests measuring anxiety, locomotion and investigative behaviour. Animals were sacrificed, blood samples were drawn and analysed and hippocampal immunohistology for BDNF was performed.
  
  
  RESULTS
  In CKD5D patients, decreased BDNF levels correlated with higher scores of depression (Pearson r = -0.8156, P = 0.002). ADMA infusion led to a significant decrease of BDNF while the decrease of BDNF in 5/6 nephrectomy was not significant. However, an attenuated hippocampal BDNF expression could be detected in 5/6 nephrecomized animals. Decreased spontaneous locomotor activity was shown in ADMA-infused rats [15.9 (13.5-26.1) lines crossed/min] and 5/6 nephrectomy [14.6 (6.1-20.2) lines crossed/min] when compared with controls [32.5 (15.3-42.4) lines crossed/min]. Anxiety-like behaviour tested by hole investigation time was significantly more pronounced in 5/6 nephrectomy [24 (6-44) s] when compared with ADMA infusion [64 (28-93) s] and controls [33 (26-65) s].
  
  
  CONCLUSIONS
  Progressive renal failure in rats is accompanied by a marked increase of ADMA and a decrease in BDNF. 5/6 nephrectomy leads to significantly decreased exploratory behaviour and locomotion. Both behaviours could be reproduced by ADMA infusion alone. Indicators of anxiety were more pronounced in ADMA-infused animals when compared with 5/6 nephrectomized rats. Furthermore, an inverse relationship of BDNF and BDI in 11 CKD5D patients was shown.
authors.affiliation: Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Kielstein
authors.affiliation: Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
authors.forename: Mayuren
authors.initials: M
authors.lastname: Suntharalingam
authors.affiliation: Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
authors.forename: Ronny
authors.initials: R
authors.lastname: Perthel
authors.affiliation: Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
authors.forename: Rong
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany Department of Neurology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Schneider
authors.affiliation: Institute for Clinical Pharmacology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Martens-Lobenhoffer
authors.affiliation: Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Jäger
authors.affiliation: Institute for Clinical Pharmacology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Bode-Böger
authors.affiliation: Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
authors.forename: Jan T
authors.initials: JT
authors.lastname: Kielstein
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003863:Depression / Q000097:blood* / Q000209:etiology / Q000523:psychology; D003865:Major Depressive Disorder / Q000097:blood* / Q000209:etiology / Q000523:psychology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D000066553:Problem Behavior; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000523:psychology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase
keywords: ADMA; BDNF; behaviour; chronic kidney disease; depression