Lab Anim Res.  2011 Sep;27(3):189-195. 10.5625/lar.2011.27.3.189.

Differential effects of treadmill exercise on cyclooxygenase-2 in the rat hippocampus at early and chronic stages of diabetes

Affiliations
  • 1Department of Anatomy and Cell Biology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea. snumouse@snu.ac.kr, ysyoon@snu.ac.kr
  • 2Department of Biomedical Sciences, College of Health Sciences, Marquette University, Milwaukee, WI, USA.
  • 3Department of Oral Anatomy, College of Dentistry, Gangneung-Wonju National University, Gangneung, Korea.
  • 4Division of Analytical Bio-imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, Korea.
  • 5Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Korea.
  • 6Institute of Sports Science, Seoul National University, Seoul, Korea.

Abstract

Cyclooxygenase-2 (COX-2) is believed to be a multifunctional neural modulator that affects synaptic plasticity in the hippocampus. In the present study, we investigated the differential effects of treadmill exercise on COX-2 immunoreactivity in the dentate gyrus in early and chronic diabetic stages in Zucker diabetic fatty (ZDF) rats and lean control (ZLC) rats. To this end, ZLC and ZDF rats at 6 or 23 weeks of age were put on a treadmill with or without running for 1 h/day for 5 consecutive days at 16-22 m/min for 5 weeks or 12-16 m/min for 7 weeks, respectively. Treadmill exercise in prediabetic and chronic diabetic rats significantly reduced blood glucose levels. In particular, exercise in the prediabetic rat blocked the onset of diabetes. COX-2 immunoreactivity was mainly detected in the granule cell layer of the dentate gyrus and stratum pyramidale of the CA3 region in all groups. COX-2 immunoreactivity was significantly increased in these regions of ZLC and ZDF rats after treadmill exercise in the early diabetic stage. However, COX-2 immunoreactivity was not changed in these regions in ZDF rats after treadmill exercise in the chronic stage. These results suggest that treadmill exercise in diabetic animals in the chronic stage has limited ability to cause plasticity in the dentate gyrus.

Keyword

Cyclooxygenase-2; diabetic stages; type 2 diabetes; treadmill exercise; Zucker diabetic rat

MeSH Terms

Animals
Blood Glucose
Cyclooxygenase 2
Dentate Gyrus
Hippocampus
Plastics
Rats
Running
Blood Glucose
Cyclooxygenase 2
Plastics

Figure

  • Figure 1 Change in blood glucose levels in 12-week-old Zucker lean control (ZLC) and Zucker diabetic fatty (ZDF) rats in the sedentary groups (Co12-ZLC and Co12-ZDF), in the 12-week-old rats in the exercised groups (Ex12-ZLC and Ex12-ZDF), in the 30-week-old rats in the sedentary groups (Co30-ZLC and Co30-ZDF), and in the 30-week-old rats in the exercised groups (Ex30-ZLC and Ex30-ZDF rats; n=5 per group; aP<0.05, significantly different from control group; bP<0.05, significantly different from the ZLC group; cP<0.05, significantly different from 12-week-old age group). The bars indicate the SEM.

  • Figure 2 Cyclooxygenase-2 (COX-2) immunoreactivity in the dentate gyrus of Co12-ZLC (A), Co12-ZDF (B), Ex12-ZLC (C), Ex12-ZDF (D), Co30-ZLC (E), Co30-ZDF (F), Ex30-ZLC (G) and Ex30-ZDF (H) rats. COX-2 immunoreactivity is mainly detected in the granule cell layer (GCL, asterisk) of the dentate gyrus. Note that COX-2 immunoreactivity is strong in the exercised group except in the Ex30-ZDF group. PL, polymorphic layer; ML, molecular layer. Scale bar=100 µm.

  • Figure 3 COX-2 immunoreactivity in the hippocampal CA3 region of Co12-ZLC (A), Co12-ZDF (B), Ex12-ZLC (C), Ex12-ZDF (D), Co30-ZLC (E), Co30-ZDF (F), Ex30-ZLC (G) and Ex30-ZDF (H) rats. COX-2 immunoreactivity is observed in the stratum pyramidal (SP, asterisk). Note that COX-2 immunoreactivity is strong in most exercised groups except the Ex30-ZDF group. SO, stratum oriens; SR, stratum radiatum. Scale bar=100 µm.

  • Figure 4 Relative optical densities (ROD) as percentage values of COX-2 in the dentate gyrus (A), and CA3 (B) of Co12-ZLC, Co12-ZDF, Ex12-ZLC, Ex12-ZDF, Co30-ZLC, Co30-ZDF, Ex30-ZLC and Ex30-ZDF rats. Differences among the means were analyzed statistically by two-way analysis of variance followed by Duncan's new multiple range method (n=5 per group; aP<0.05, significantly different from control group; bP<0.05, significantly different from the ZLC group; cP<0.05, significantly different from the 12-week-old group). Bars indicate the SEM.


Cited by  1 articles

Treadmill exercise prevents diabetes-induced increases in lipid peroxidation and decreases in Cu,Zn-superoxide dismutase levels in the hippocampus of Zucker diabetic fatty rats
Jong Whi Kim, Junghyun Chae, Sung Min Nam, Yo Na Kim, Dae Young Yoo, Jung Hoon Choi, Hyo Young Jung, Wook Song, In Koo Hwang, Je Kyung Seong, Yeo Sung Yoon
J Vet Sci. 2015;16(1):11-16.    doi: 10.4142/jvs.2015.16.1.11.


Reference

1. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron. 1993; 11:371–386. PMID: 8352945.
Article
2. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998; 38:97–120. PMID: 9597150.
Article
3. Kaufmann WE, Andreasson KI, Isakson PC, Worley PF. Cyclooxygenases and the central nervous system. Prostaglandins. 1997; 54:601–624. PMID: 9373877.
Article
4. Yamashita A, Kunimatsu T, Yamamoto T, Yoshida K. Hypothermic, but not normothermic, ischemia causes a drastic increase in cyclooxygenase-2 immunoreactive granule cells in rat dentate gyrus after 4 hours of ischemic reperfusion. Arch Histol Cytol. 2007; 70:197–205. PMID: 18079588.
Article
5. Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA. 1996; 93:2317–2321. PMID: 8637870.
Article
6. Bazan NG. COX-2 as a multifunctional neuronal modulator. Nat Med. 2001; 7:414–415. PMID: 11283664.
Article
7. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004; 3:169–178. PMID: 14980532.
Article
8. Hwang IK, Yi SS, Kim YN, Kim IY, Lee IS, Yoon YS, Seong JK. Reduced hippocampal cell differentiation in the subgranular zone of the dentate gyrus in a rat model of type II diabetes. Neurochem Res. 2008; 33:394–400. PMID: 17712629.
Article
9. Hwang IK, Yi SS, Song W, Won MH, Yoon YS, Seong JK. Effects of age and treadmill exercise in chronic diabetic stages on neuroblast differentiation in a rat model of type 2 diabetes. Brain Res. 2010; 1341:63–71. PMID: 20005869.
Article
10. Vora JP, Zimsen SM, Houghton DC, Anderson S. Evolution of metabolic and renal changes in the ZDF/Drt-fa rat model of type II diabetes. J Am Soc Nephrol. 1996; 7:113–117. PMID: 8808117.
Article
11. Etgen GJ, Oldham BA. Profiling of Zucker diabetic fatty rats in their progression to the overt diabetic state. Metabolism. 2000; 49:684–688. PMID: 10831184.
Article
12. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002; 25:295–301. PMID: 12086747.
Article
13. Tillerson JL, Caudle WM, Reveron ME, Miller GW. Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson's disease. Neuroscience. 2003; 119:899–911. PMID: 12809709.
Article
14. Gobbo OL, O'Mara SM. Exercise, but not environmental enrichment, improves learning after kainic acid-induced hippocampal neurodegeneration in association with an increase in brain-derived neurotrophic factor. Behav Brain Res. 2005; 159:21–26. PMID: 15794993.
Article
15. Van Praag H. Exercise and the brain: something to chew on. Trends Neurosci. 2009; 32:283–290. PMID: 19349082.
Article
16. Leem YH, Lee YI, Son HJ, Lee SH. Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23. Biochem Biophys Res Commun. 2011; 406:359–365. PMID: 21329662.
17. Song W, Kwak HB, Lawler JM. Exercise training attenuates age-induced changes in apoptotic signaling in rat skeletal muscle. Antioxid Redox Signal. 2006; 8:517–528. PMID: 16677096.
Article
18. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 2007. Amsterdam: Elsevier Academic Press.
19. Graham SH, Hickey RW. Cyclooxygenases in central nervous system diseases: a special role for cyclooxygenase 2 in neuronal cell death. Arch Neurol. 2003; 60:628–630. PMID: 12707081.
20. Chen C, Magee JC, Bazan NG. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol. 2002; 87:2851–2857. PMID: 12037188.
21. Murray HJ, O'Connor JJ. A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro. Neuropharmacology. 2003; 44:374–380. PMID: 12604095.
Article
22. Chen C, Bazan NG. Endogenous PGE2 regulates membrane excitability and synaptic transmission in hippocampal CA1 pyramidal neurons. J Neurophysiol. 2005; 93:929–941. PMID: 15653788.
23. Sang N, Zhang J, Marcheselli V, Bazan NG, Chen C. Postsynaptically synthesized prostaglandin E2 modulates hippocampal synaptic transmission via a presynaptic PGE2 EP2 receptor. J Neurosci. 2005; 25:9858–9870. PMID: 16251433.
24. Akaneya Y, Tsumoto T. Bidirectional trafficking of prostaglandin E2 receptors involved in long-term potentiation in visual cortex. J Neurosci. 2006; 26:10209–10221. PMID: 17021176.
Article
25. Yang H, Zhang J, Andreasson K, Chen C. COX-2 oxidative metabolism of endocannabinoids augments hippocampal synaptic plasticity. Mol Cell Neurosci. 2008; 37:682–695. PMID: 18295507.
Article
26. Grillo CA, Piroli GG, Wood GE, Reznikov LR, McEwen BS, Reagan LP. Immunocytochemical analysis of synaptic proteins provides new insights into diabetes-mediated plasticity in the rat hippocampus. Neuroscience. 2005; 136:477–486. PMID: 16226381.
Article
27. Artola A. Diabetes-, stress- and ageing-related changes in synaptic plasticity in hippocampus and neocortex - the same metaplastic process? Eur J Pharmacol. 2008; 585:153–162. PMID: 18395200.
Article
28. Reisi P, Babri S, Alaei H, Sharifi MR, Mohaddes G, Lashgari R. Effects of treadmill running on short-term pre-synaptic plasticity at dentate gyrus of streptozotocin-induced diabetic rats. Brain Res. 2008; 1211:30–36. PMID: 18433735.
Article
29. Breder CD, Dewitt D, Kraig RP. Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol. 1995; 355:296–315. PMID: 7608344.
Article
30. Kim SK, Choi JW, Hwang IK, Yoo DY, Yoo KY, Lee CH, Choi JH, Shin HC, Seong JK, Yoon YS, Won MH. Species-difference of cyclooxygenase-2 in the hippocampus of rodents. J Vet Med Sci. 2010; 72:1153–1158. PMID: 20424394.
Article
31. Hwang IK, Yi SS, Yoo KY, Park OK, Yan B, Kim IY, Kim YN, Song W, Moon SM, Won MH, Seong JK, Yoon YS. Effects of treadmill exercise on cyclooxygenase-2 in the hippocampus in type 2 diabetic rats: correlation with the neuroblasts. Brain Res. 2010; 1341:84–92. PMID: 20219444.
Article
32. Zhang X, Dong F, Ren J, Driscoll MJ, Culver B. High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex. Exp Neurol. 2005; 191:318–325. PMID: 15649487.
Article
33. Uchida K, Kumihashi K, Kurosawa S, Kobayashi T, Itoi K, Machida T. Stimulatory effects of prostaglandin E2 on neurogenesis in the dentate gyrus of the adult rat. Zoolog Sci. 2002; 19:1211–1216. PMID: 12499663.
34. Sasaki T, Kitagawa K, Sugiura S, Omura-Matsuoka E, Tanaka S, Yagita Y, Okano H, Matsumoto M, Hori M. Implication of cyclooxygenase-2 on enhanced proliferation of neural progenitor cells in the adult mouse hippocampus after ischemia. J Neurosci Res. 2003; 72:461–471. PMID: 12704808.
Article
35. Goncalves MB, Williams EJ, Yip P, Yáñez-Muñoz RJ, Williams G, Doherty P. The COX-2 inhibitors, meloxicam and nimesulide, suppress neurogenesis in the adult mouse brain. Br J Pharmacol. 2010; 159:1118–1125. PMID: 20136845.
Article
36. Kumihashi K, Uchida K, Miyazaki H, Kobayashi J, Tsushima T, Machida T. Acetylsalicylic acid reduces ischemia-induced proliferation of dentate cells in gerbils. Neuroreport. 2001; 12:915–917. PMID: 11303759.
Article
37. Jung KH, Chu K, Lee ST, Kim J, Sinn DI, Kim JM, Park DK, Lee JJ, Kim SU, Kim M, Lee SK, Roh JK. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol Dis. 2006; 23:237–246. PMID: 16806953.
Article
38. Andreasson KI, Savonenko A, Vidensky S, Goellner JJ, Zhang Y, Shaffer A, Kaufmann WE, Worley PF, Isakson P, Markowska AL. Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. J Neurosci. 2001; 21:8198–8209. PMID: 11588192.
Article
39. Ho L, Purohit D, Haroutunian V, Luterman JD, Willis F, Naslund J, Buxbaum JD, Mohs RC, Aisen PS, Pasinetti GM. Neuronal cyclooxygenase 2 expression in the hippocampal formation as a function of the clinical progression of Alzheimer disease. Arch Neurol. 2001; 58:487–492. PMID: 11255454.
Article
40. Cassano P, Hidalgo A, Burgos V, Adris S, Argibay P. Hippocampal upregulation of the cyclooxygenase-2 gene following neonatal clomipramine treatment (a model of depression). Pharmacogenomics J. 2006; 6:381–387. PMID: 16568149.
Article
41. Choi JS, Kim HY, Chun MH, Chung JW, Lee MY. Differential regulation of cyclooxygenase-2 in the rat hippocampus after cerebral ischemia and ischemic tolerance. Neurosci Lett. 2006; 393:231–236. PMID: 16253424.
Article
42. Lukiw WJ, Cui JG, Musto AE, Musto BC, Bazan NG. Epileptogenesis in diacylglycerol kinase epsilon deficiency up-regulates COX-2 and tyrosine hydroxylase in hippocampus. Biochem Biophys Res Commun. 2005; 338:77–81. PMID: 16137646.
Article
43. Yokota O, Terada S, Ishihara T, Nakashima H, Kugo A, Ujike H, Tsuchiya K, Ikeda K, Saito Y, Murayama S, Ishizu H, Kuroda S. Neuronal expression of cyclooxygenase-2, a proinflammatory protein, in the hippocampus of patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2004; 28:715–721. PMID: 15276698.
Article
44. Yokota O, Terada S, Ishizu H, Ishihara T, Nakashima H, Kugo A, Tsuchiya K, Ikeda K, Hayabara T, Saito Y, Murayama S, Uda K, Checler F, Kuroda S. Increased expression of neuronal cyclooxygenase-2 in the hippocampus in amyotrophic lateral sclerosis both with and without dementia. Acta Neuropathol. 2004; 107:399–405. PMID: 14991384.
Article
45. Tu B, Bazan NG. Hippocampal kindling epileptogenesis upregulates neuronal cyclooxygenase-2 expression in neocortex. Exp Neurol. 2003; 179:167–175. PMID: 12618123.
46. Miettinen S, Fusco FR, Yrjänheikki J, Keinänen R, Hirvonen T, Roivainen R, Närhi M, Hökfelt T, Koistinaho J. Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. Proc Natl Acad Sci USA. 1997; 94:6500–6505. PMID: 9177247.
Full Text Links
  • LAR
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr