title: Low blood and vitreal BDNF, LXA4 and altered Th1/Th2 cytokine balance are potential risk factors for diabetic retinopathy.
abstract: OBJECTIVE
  The study was conducted to observe the serum and vitreous levels of LXA4, BDNF and Th1/Th2 cytokines in type 2 diabetes mellitus (DM) and changes associated with diabetic retinopathy (DR). Further, the in vitro study was performed to analyze the exposure of BDNF and LXA4 on LPS-induced pro-inflammatory state in ARPE 19 cells.
  
  
  METHODS
  Totally 114 individuals were recruited in a prospective case control study. Of these, 27 were type 2 DM cases with no complications, 30 cases were type 2 DM with non proliferative diabetic retinopathy (NPDR), 30 were type 2 DM with proliferative diabetic retinopathy (PDR), and 27 were healthy control. ELISA was done to estimate the serum and vitreous levels of BDNF, VEGF and PEDF. FACS cytometric Bead Array system was used to analyze the serum cytokines.
  
  
  RESULTS
  The serum BDNF and LXA4 levels were significantly reduced in both NPDR and PDR cases compared to control (p=0.005, 0.01; p=0.033, 0.015). Serum IL-6 was significantly increased in the PDR group (p=0.04). BDNF showed a significant negative correlation with VEGF levels (r=-0.522, p<0.01) and positive correlation with IL-10 (r=0.67, p<0.05) in serum. A significant odds ratio for the serum BDNF (OR: 3.20, p=0.025) as well as serum IL-6 (OR: 1.244, p=0.042) indicated them as potential risk factors for progression of type 2 DM to DR. A significant decrease in both the LXA4 (p=0.013) and BDNF (p=0.0008) with increase in cytokines IL-6 and IL-10 levels were observed in the vitreous of PDR cases ((p=0.04, 0.01). In vitro studies showed that both LXA4 (10 nmol/L) and BDNF (500 pg) decreased the IL-6 levels (p=0.036, 0.0002), in LPS induced pro-inflammatory condition in ARPE 19 cells, thereby their anti-inflammatory effect.
  
  
  CONCLUSIONS
  This study reports that low serum BDNF and higher IL-6 levels are potential risk factors for DR in type 2 DM. This study supports the role of BDNF in modulating the pro- and anti-inflammatory cytokines, and low level of BDNF is associated with development of diabetic retinopathy.
authors.affiliation: R. S. Mehta Jain Department of Biochemistry and Cell Biology, Vision Research Foundation, Chennai, 600 006, India.
authors.forename: Kuppan
authors.initials: K
authors.lastname: Kaviarasan
authors.affiliation: R. S. Mehta Jain Department of Biochemistry and Cell Biology, Vision Research Foundation, Chennai, 600 006, India.
authors.forename: Mohanlal
authors.initials: M
authors.lastname: Jithu
authors.affiliation: Shri Bhagwan Mahavir Vitreo Retinal Services, Medical Research Foundation, Chennai, 600 006, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Arif Mulla
authors.affiliation: Shri Bhagwan Mahavir Vitreo Retinal Services, Medical Research Foundation, Chennai, 600 006, India.
authors.forename: Tarun
authors.initials: T
authors.lastname: Sharma
authors.affiliation: R. S. Mehta Jain Department of Biochemistry and Cell Biology, Vision Research Foundation, Chennai, 600 006, India.
authors.forename: Shanmuganathan
authors.initials: S
authors.lastname: Sivasankar
authors.affiliation: Department of Medicine, GVP Hospital and BioScience Research Centre, Visakhapatnam, 530 048, India; UND Life Sciences, 2020 S 360th St, #K-202, Federal Way, WA 98003, USA.
authors.forename: Undurti Narasimha
authors.initials: UN
authors.lastname: Das
authors.affiliation: R. S. Mehta Jain Department of Biochemistry and Cell Biology, Vision Research Foundation, Chennai, 600 006, India. Electronic address: angayar07@gmail.com.
authors.forename: Narayanasamy
authors.initials: N
authors.lastname: Angayarkanni
mesh_terms: D000328:Adult; D000368:Aged; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood*; D016022:Case-Control Studies; D002460:Cell Line; D016207:Cytokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003930:Diabetic Retinopathy / Q000097:blood* / Q000453:epidemiology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D044045:Lipoxins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012160:Retina / Q000166:cytology; D012307:Risk Factors; D058408:Th1-Th2 Balance; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D008070:Lipopolysaccharides; D044045:Lipoxins; D042461:Vascular Endothelial Growth Factor A; C040527:lipoxin A4
keywords: BDNF; Cytokines; Diabetic retinopathy; LXA(4); Type 2 diabetes