The Pattern of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampus of Diabetic Rats

Document Type : Original Article


1 Department of Physiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

2 Biotechnology Research Center & Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

3 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

4 Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran


The aim of this study was to evaluate the effects of regular exercise in preventing diabetes complication in the hippocampus of streptozotocin (STZ)-induced diabetic rat.
Materials and Methods
A total of 48 male wistar rats were divided into four groups (control, control exercise, diabetic and diabetic exercise). Diabetes was induced by injection of single dose of STZ. Exercise was performed for one hr every day, over a period of 8 weeks. The antioxidant enzymes (SOD, GPX, CAT and GR) and oxidant indexes with brain-derived neurotrophic factor (BDNF) protein and its mRNA and apoptosis were measured in hippocampus of rats.
A significant decrease in antioxidant enzymes activities and increased malondialdehyde (MDA) level were observed in diabetic rats (P= 0.004). In response to exercise, antioxidant enzymes activities increased (P= 0.004). In contrast, MDA level decreased in diabetic rats (P= 0.004). Induction of diabetes caused an increase of BDNF protein and its mRNA expression. In response to exercise, BDNF protein and its mRNA expression reduced in hippocampus of diabetic rats.
Diabetes induced oxidative stress and increased BDNF gene expression. Exercise ameliorated oxidative stress and decreased BDNF gene expression.


1.Carsten RE, Whalen LR, Ishii DN. Impairment of spinal cord conduction velocity in diabetic rats. Diabetes 1989; 38:730-736.
2.Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med 1999; 16:93-112.
3.Moorhouse CP, Halliwell B, Grootveld M, Gutteridge JM. Cobalt (II) ion as a promoter of hydroxyl radical and possible 'crypto-hydroxyl' radical formation under physiological conditions. Differential effects of hydroxyl radical scavengers. Biochim Biophys Acta 1985; 843:261-268.
4.Barde YA. What, if anything, is a neurotrophic factor? Trends Neurosci 1988; 11:343-346.
5.Berchtold NC, Chinn G, Chou M, Kesslak JP, Cotman CW. Exercise primes a molecular memory for brain- derived neurotrophic factor protein induction in the rat hippocampus. Neuroscience 2005; 133:853-581.
6.Phillips HS, Hams JM, Laramee GR, Rosenthal A,Winslow JW. Widespread expression of BDNF but not NT-3 by target areas of basal forebrain cholinergic neurons. Science 1990; 12:290-294.
7.Hanaoka Y, Ohi T, Furukawa S, Furukawa Y, Hayashi K, Matsukura S. The therapeutic effects of 4- methylcatechol, a stimulator of endogenous nerve growth factor synthesis, on experimental diabetic neuropathy in rats. J Neurol Sci 1994; 122:28-32.
8.Fleischer A, Ghadiri A, Dessauge F, Duhamel M, Rebollo MP, Alvarez-Franco F, et al. Modulating apoptosis as a target for effective therapy. Mol Immunol 2006; 43:1065-1079.
9.Radak Z, Chung HY, Goto S. Systemic adaptation to oxidative challenge induced by regular exercise. Free Radic Biol Med 2008; 44:153-159.
10.Mattson MP. Energy intake, meal frequency, and health: a neurobiological perspective. Annu Rev Nutr 2005; 25:237-260.
11.Mattson MP, Maudsley S, Martin B. A neural signaling triumvirate that influences ageing and age-related disease: insulin/IGF-1, BDNF and serotonin. Ageing Res Rev 2004; 3:445-464.
12.Nadai M, Yoshizumi H, Kuzuya T, Hasegawa T, Johno I, Kitazawa S. Effect of diabetes on disposition and renal handling of cefazolin in rats. Drug Metab Dispos 1990; 18:565-570.
13.Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193:265-275.
14.Draper HH, Hadley M. Malondialdeyde determination as an index of lipid peroxidation. Methods Enzymol 1990; 186:421-431.
15.Griffith OW. Determination of glutathione and glutathione disulfide using glutathione reductase and 2- vinylpyridine. Anal Biochem 1980; 106:207-212.
16.Aebi H. Catalase in vitro. Methods Enzymol 1984; 105:121-126.
17.Carlberg I, Mannervik B. Glutathione reductase. Methods Enzymol 1985; 113:484-490.
18.Sano T, Umeda F, Hashimoto T, Nawata H, Utsumi H. Oxidative stress measurement by in vivo electron spins resonance spectroscopy in rats with streptozotocin-induced diabetes. Diabetologia 1988; 41:1355-1360.
19.Ceriello A. Oxidative stress and glycemic regulation. Metabolism 2000; 49:27-29.
20.Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: A new perspective on an old paradigm. Diabetes 1999; 48:1-9.
21.Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991; 40:405-412.
22.Klepac N, Rudes Z, Klepac R. Effects of melatonin on plasma oxidative stress in rats with streptozotocin induced diabetes. Biomed Pharmacother 2006; 60:32-35.
23.Han BH, Holtzman DM. BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci 2000; 20:5775-5781.
24.Nitta A, Ohmiya M, Jin-nouchi T, Sometani A, Asami T, Kinukawa H, et al. Endogenous neurotrophin-3 is retrogradely transported in the rat sciatic nerve. Neuroscience 1999; 88:679-685.
25.Apfel SC. Neurotrophic factors in peripheral neuropathies: therapeutic implications. Brain Pathol 1999; 9:393-413. 
26.Busciglio J, Yankner BA. Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro. Nature 1995; 21-28.
27.Park LC, Calingasan NY, Uchida K, Zhang H, Gibson GE. Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell death in culture. J Neurochem 2000; 74:114-124.
28.Facchinetti F, Dawson VL, Dawson TM. Free radicals as mediators of neuronal injury. Cellular Mol Neurobiol 1998; 18:667- 682.
29.Wang H, Yuan G, Prabhakar NR, Boswell M, Katz DM. Secretion of brain-derived neurotrophic factor from PC12 cells in response to oxidative stress requires autocrine dopamine signaling. J Neurochem 2006; 96:694-705.
30.Lindholm D, Dechant G, Heisenberg P, Thoenen H. Brain-derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity. Eur J Neurosci 1993; 5:1455-1464.
31.Beck T, Lindholm D, Castren E, Wree A. Brain derived neurotrophic factor protects against ischemic cell damage in rat hippocampus. J Cereb Blood Flow Metab 1994; 14:689-692.
32.Sendtner M, Holtmann B, Kolbeck R, Thoenen H, Barde YA. Brain-derived neurotrophic factor prevens the death of motoneurons in newborn rats after nerve section. Nature 1992; 360:757-759.
33.Radak Z, Sasvari M, Nyakas C, Kaneko T, Tahara S, Nakamoto H, et al. Single bout of exercise eliminates the immobilization-induced oxidative stress rat brain. Neurochem Int 2001; 39:33-38.
34.Somani SM, Husain K. Exercise training alters kinetics of antioxidant enzymes in rat tissues. Biochem Mol Biol Int 1996; 38:587-595.
38.Devi SA, Kiran TR. Regional responses in antioxidant system to exercise training and dietary vitamin E in aging rat brain. Neurobiol Aging 2004; 25:501-508.
35.Radak Z, Asano K, Inoue M, Kizaki T, Ohishi S, Suzuki K, et al. Acute bout of exercise does not alter the antioxidant enzyme status and lipid peroxidation in rat hippocampus and cerebellum. Pathophysiology 1995; 2:243-245.
36.Ozkaya YG, Agar A, Yargicoglu P, Hacioglu G, Bilmen-Sarikcioglu S, Ozen I, et al. The effect of exercise on brain antioxidant status of diabetic rats. Diabetes Metab 2002; 28:377-384.
37.Tong L, Shen H, Perreau VM, Balazs R, Cotman CW. Effects of exercise on gene-expression profile in the rat hippocampus. Neurobiol Dis 2001; 8:1046-1056.
38.Almli CR, Levy TJ, Han BH, Shah AR, Gidday JM, Holtzman DM. BDNF protects against spatial memory deficits following neonatal hypoxia-ischemia. Exp Neurol 2000; 166:99-114.
39.Henry K, Kenneth K, Ramee L, Saundrene W, Seema T, Ramiro D, et al. Hempstead. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 2005; 25:5455-5463.