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Denizci E, Altun G, Kaplan S. Morphological evidence for the potential protective effects of curcumin and Garcinia kola against diabetes in the rat hippocampus. Brain Res 2024; 1839:149020. [PMID: 38788929 DOI: 10.1016/j.brainres.2024.149020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 05/26/2024]
Abstract
This research investigated the effects of sciatic nerve transection and diabetes on the hippocampus, and the protective effects of Garcinia kola and curcumin. Thirty-five adults male Wistar albino rats were divided into five groups: a control group (Cont), a transected group (Sham group), a transected + diabetes mellitus group (DM), a transected + diabetes mellitus + Garcinia kola group (DM + GK), and a transected + DM + curcumin group (DM + Cur), each containing seven animals. The experimental diabetes model was created with the intraperitoneal injection of a single dose of streptozotocin. No procedure was applied to the Cont group, while sciatic nerve transection was performed on the other groups. Garcinia kola was administered to the rats in DM + GK, and curcumin to those in DM + Cur. Cardiac perfusion was performed at the end of the experimental period. Brain tissues were dissected for stereological, histopathological, and immunohistochemical evaluations. The volume ratios of hippocampal layers to the entire hippocampus volume were compared between the groups. Anti-S100, anti-caspase 3, and anti-SOX 2 antibodies were used for immunohistochemical analysis. No statistically significant difference was observed in the volume ratios of the four hippocampal layers. However, the volume ratio of the stratum lucidum was higher in the Sham, DM, and DM + Cur groups compared to the Cont group. While curcumin exhibited a protective effect on hippocampal tissue following diabetes induction, Garcinia kola had only a weak protective effect. Increased cell density and nuclear deterioration due to diabetes and nerve transection can be partially ameliorated by treatment with Garcinia kola and curcumin.
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Affiliation(s)
- Eda Denizci
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey
| | - Gamze Altun
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey
| | - Süleyman Kaplan
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey; Nelson Mandela African Institution of Science and Technology, Arusha, Tanzania.
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Feng L, Gao L. The role of neurovascular coupling dysfunction in cognitive decline of diabetes patients. Front Neurosci 2024; 18:1375908. [PMID: 38576869 PMCID: PMC10991808 DOI: 10.3389/fnins.2024.1375908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 03/05/2024] [Indexed: 04/06/2024] Open
Abstract
Neurovascular coupling (NVC) is an important mechanism to ensure adequate blood supply to active neurons in the brain. NVC damage can lead to chronic impairment of neuronal function. Diabetes is characterized by high blood sugar and is considered an important risk factor for cognitive impairment. In this review, we provide fMRI evidence of NVC damage in diabetic patients with cognitive decline. Combined with the exploration of the major mechanisms and signaling pathways of NVC, we discuss the effects of chronic hyperglycemia on the cellular structure of NVC signaling, including key receptors, ion channels, and intercellular connections. Studying these diabetes-related changes in cell structure will help us understand the underlying causes behind diabetes-induced NVC damage and early cognitive decline, ultimately helping to identify the most effective drug targets for treatment.
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Affiliation(s)
| | - Ling Gao
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China
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Fernandes V, Sood A, Preeti K, Khatri DK, Singh SB. Neuroepigenetic alterations in the prefrontal cortex of type 2 diabetic mice through DNA hypermethylation. Mol Biol Rep 2022; 49:12017-12028. [DOI: 10.1007/s11033-022-08018-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 10/07/2022] [Indexed: 11/28/2022]
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Nam SM, Yoo DY, Kwon HJ, Kim JW, Jung HY, Kim DW, Seong JK, Hwang IK, Yoon YS. Effects of long-term exposure to aluminum in the hippocampus in the type 2 diabetes model rats. Toxicol Res (Camb) 2019; 8:206-215. [PMID: 30931101 PMCID: PMC6404161 DOI: 10.1039/c8tx00192h] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 11/21/2018] [Indexed: 11/21/2022] Open
Abstract
We investigated the long-term effects of aluminum (Al) exposure in the hippocampus in Zucker diabetic fatty (ZDF) rats and Zucker lean control (ZLC) rats. Six-week-old ZLC and ZDF rats were randomly divided into Al- and non-Al-groups. They were sacrificed 27 weeks after Al exposure (2000 ppm) through drinking water. Al exposure did not affect physiological parameters such as the body weight and blood glucose levels, but the prolonged diabetic condition had significant effects on the body weight and blood glucose levels. To determine the effects of diabetes and Al exposure on the neural plasticity and inflammatory response in the hippocampus, we examined the levels of doublecortin (DCX), N-methyl-d-aspartate receptors (NMDAR1, NMDAR2A, and NMDAR2B), and ionized calcium-binding adapter molecule 1 (Iba-1) in the hippocampus. DCX immunohistochemical staining revealed that Al exposure significantly reduced neuronal differentiation in both ZLC and ZDF rats. In particular, ZDF rats showed significantly decreased DCX immunoreactive neuroblasts compared with ZLC rats after aluminum exposure. In contrast, the expression of postsynaptic NMDARs was altered only in ZDF-Al rats; the protein expression level of NMDAR1 was reduced, but that of NMDAR2B increased in the hippocampus. Iba-1-immunoreactive microglia with morphological changes, including increased cytoplasm and retracted processes, were detected in the long-term diabetic condition and in the case of the co-existence of diabetes and Al exposure. Al exposure aggravated the diabetes-induced reduction of neuroblast differentiation and NMDAR signaling and facilitated the morphological changes associated with inflammatory activation in microglia in the hippocampus. However, further studies are still needed to confirm these findings.
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Affiliation(s)
- Sung Min Nam
- Department of Anatomy and Cell Biology , College of Veterinary Medicine , and Research Institute for Veterinary Science , Seoul National University , Seoul 08826 , South Korea . ; ; Tel: +82 2 8801264
- Department of Anatomy , College of Veterinary Medicine , Konkuk University , Seoul 05030 , Republic of Korea
| | - Dae Young Yoo
- Department of Anatomy and Cell Biology , College of Veterinary Medicine , and Research Institute for Veterinary Science , Seoul National University , Seoul 08826 , South Korea . ; ; Tel: +82 2 8801264
| | - Hyun Jung Kwon
- Department of Biochemistry and Molecular Biology , Research Institute of Oral Sciences , College of Dentistry , Gangneung-Wonju National University , Gangneung 25457 , South Korea
| | - Jong Whi Kim
- Department of Anatomy and Cell Biology , College of Veterinary Medicine , and Research Institute for Veterinary Science , Seoul National University , Seoul 08826 , South Korea . ; ; Tel: +82 2 8801264
| | - Hyo Young Jung
- Department of Anatomy and Cell Biology , College of Veterinary Medicine , and Research Institute for Veterinary Science , Seoul National University , Seoul 08826 , South Korea . ; ; Tel: +82 2 8801264
| | - Dae Won Kim
- Department of Biochemistry and Molecular Biology , Research Institute of Oral Sciences , College of Dentistry , Gangneung-Wonju National University , Gangneung 25457 , South Korea
| | - Je Kyung Seong
- Department of Anatomy and Cell Biology , College of Veterinary Medicine , and Research Institute for Veterinary Science , Seoul National University , Seoul 08826 , South Korea . ; ; Tel: +82 2 8801264
- KMPC (Korea Mouse Phenotyping Center) , Seoul National University , Seoul 08826 , South Korea
| | - In Koo Hwang
- Department of Anatomy and Cell Biology , College of Veterinary Medicine , and Research Institute for Veterinary Science , Seoul National University , Seoul 08826 , South Korea . ; ; Tel: +82 2 8801264
- KMPC (Korea Mouse Phenotyping Center) , Seoul National University , Seoul 08826 , South Korea
| | - Yeo Sung Yoon
- Department of Anatomy and Cell Biology , College of Veterinary Medicine , and Research Institute for Veterinary Science , Seoul National University , Seoul 08826 , South Korea . ; ; Tel: +82 2 8801264
- KMPC (Korea Mouse Phenotyping Center) , Seoul National University , Seoul 08826 , South Korea
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Nam SM, Kwon HJ, Kim W, Kim JW, Hahn KR, Jung HY, Kim DW, Yoo DY, Seong JK, Hwang IK, Yoon YS. Changes of myelin basic protein in the hippocampus of an animal model of type 2 diabetes. Lab Anim Res 2018; 34:176-184. [PMID: 30671103 PMCID: PMC6333608 DOI: 10.5625/lar.2018.34.4.176] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/01/2018] [Accepted: 10/05/2018] [Indexed: 12/31/2022] Open
Abstract
In this study, we observed chronological changes in the immunoreactivity and expression level of myelin basic protein (MBP), one of the most abundant proteins in the central nervous system, in the hippocampus of Zucker diabetic fatty (ZDF) rats and their control littermates (Zucker lean control; ZLC). In the ZLC group, body weight steadily increased with age; the body weight of the ZDF group, however, peaked at 30 weeks of age, and subsequently decreased. Based on the changes of body weight, animals were divided into the following six groups: early (12-week), middle (30-week), and chronic (52-week) diabetic groups and their controls. MBP immunoreactivity was found in the alveus, strata pyramidale, and lacunosum-moleculare of the CA1 region, strata pyramidale and radiatum of the CA3 region, and subgranular zone, polymorphic layer, and molecular layer of the dentate gyrus. MBP immunoreactivity was lowest in the hippocampus of 12-week-old rats in the ZLC group, and highest in 12-week-old rats in the ZDF group. Diabetes increased MBP levels in the 12-week-old group, while MBP immunoreactivity decreased in the 30-week-old group. In the 52-week-old ZLC and ZDF groups, MBP immunoreactivity was detected in the hippocampus, similar to the 30-week-old ZDF group. Western blot results corroborated with immunohistochemical results. These results suggested that changes in the immunoreactivity and expression of MBP in the hippocampus might be a compensatory response to aging, while the sustained levels of MBP in diabetic animals could be attributed to a loss of compensatory responses in oligodendrocytes.
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Affiliation(s)
- Sung Min Nam
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
- Department of Anatomy, College of Veterinary Medicine, Konkuk University, Seoul, Korea
| | - Hyun Jung Kwon
- Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, Korea
| | - Woosuk Kim
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
| | - Jong Whi Kim
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
| | - Kyu Ri Hahn
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
| | - Hyo Young Jung
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
| | - Dae Won Kim
- Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, Korea
| | - Dae Young Yoo
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
- Department of Anatomy, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Je Kyung Seong
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
- KMPC (Korea Mouse Phenotyping Center), Seoul National University, Seoul, Korea
| | - In Koo Hwang
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
| | - Yeo Sung Yoon
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
- KMPC (Korea Mouse Phenotyping Center), Seoul National University, Seoul, Korea
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Diabetes-Induced Dysfunction of Mitochondria and Stem Cells in Skeletal Muscle and the Nervous System. Int J Mol Sci 2017; 18:ijms18102147. [PMID: 29036909 PMCID: PMC5666829 DOI: 10.3390/ijms18102147] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 10/11/2017] [Indexed: 12/21/2022] Open
Abstract
Diabetes mellitus is one of the most common metabolic diseases spread all over the world, which results in hyperglycemia caused by the breakdown of insulin secretion or insulin action or both. Diabetes has been reported to disrupt the functions and dynamics of mitochondria, which play a fundamental role in regulating metabolic pathways and are crucial to maintain appropriate energy balance. Similar to mitochondria, the functions and the abilities of stem cells are attenuated under diabetic condition in several tissues. In recent years, several studies have suggested that the regulation of mitochondria functions and dynamics is critical for the precise differentiation of stem cells. Importantly, physical exercise is very useful for preventing the diabetic alteration by improving the functions of both mitochondria and stem cells. In the present review, we provide an overview of the diabetic alterations of mitochondria and stem cells and the preventive effects of physical exercise on diabetes, focused on skeletal muscle and the nervous system. We propose physical exercise as a countermeasure for the dysfunction of mitochondria and stem cells in several target tissues under diabetes complication and to improve the physiological function of patients with diabetes, resulting in their quality of life being maintained.
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Hyperglycemia induced the Alzheimer's proteins and promoted loss of synaptic proteins in advanced-age female Goto-Kakizaki (GK) rats. Neurosci Lett 2017; 655:41-45. [PMID: 28652187 DOI: 10.1016/j.neulet.2017.06.041] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Revised: 06/08/2017] [Accepted: 06/23/2017] [Indexed: 11/21/2022]
Abstract
Although both type 2 diabetes mellitus (T2DM) and aging are related with Alzheimer's disease (AD), the effects of aging on the Alzheimer's proteins and the synaptic markers in T2DM have not been investigated. This study, we hypothesized that T2DM rats with advanced-age, aggravates the reduction of synaptic proteins and an increase in the Alzheimer's protein markers. Goto-Kakizaki rats (GK) were used as a T2DM group and wild-type rats (WT) were used as a control group. Rats in each group were categorized by age into young-adult (7 months) and advanced-age rats (12.5 months). Blood was collected in all rats to determine plasma glucose and insulin levels. The brains were used for determining the level of Alzheimer's and synaptic proteins. Our data demonstrated that GK rats had a decreased body weight and increased blood glucose levels, compared to their age-matched WT. p-Tau was increased in both advanced-age WT and GK, compared to their young-adult rats. Moreover, amyloid-beta (Aβ) level was higher in advanced-age GK than their age-matched WT. The synaptic proteins were decreased in advanced-age GK, compared to young-adult GK rats. However, no difference in the level of Alzheimer's proteins and synaptic proteins in the brains of young-adult GK compared to age-matched WT was found. Our data suggested that aging contributes to the pathogenesis of AD and the reduction of synaptic proteins to greater extent in a diabetic than in a healthy condition.
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Son JS, Kim HJ, Son Y, Lee H, Chae SA, Seong JK, Song W. Effects of exercise-induced apelin levels on skeletal muscle and their capillarization in type 2 diabetic rats. Muscle Nerve 2017; 56:1155-1163. [PMID: 28164323 DOI: 10.1002/mus.25596] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 01/24/2017] [Accepted: 01/28/2017] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Exercise-induced apelin as a myokine is believed to play a role in the improvement of type 2 diabetes mellitus (T2DM) and capillarization. In this study, we evaluated the association between exercise-induced apelin and muscle capillarization. METHODS Zucker rats underwent a treadmill exercise program. Body composition, muscle strength, muscle size, muscle capillarization, and insulin resistance (homeostatic model assessment [HOMA-IR]) were measured. Apelin levels of skeletal muscle and plasma were then analyzed. RESULTS Exercise improved body composition (P < 0.05), HOMA-IR (P < 0.05), and grip strength (P < 0.001). In the soleus, the fiber size of T2DM was decreased (P < 0.001), but it increased in fiber size and capillarization after exercise (P < 0.001) occurred. We identified an increase in plasma apelin (P < 0.05) and a decrease in soleus apelin (P < 0.01), as well as an association between soleus apelin and angiogenesis (P < 0.01). DISCUSSION A role for exercise-induced apelin in improving metabolism indicates the possibility of a new drug target for the treatment of metabolic diseases and repairing skeletal muscle damage. Muscle Nerve 56: 1155-1163, 2017.
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Affiliation(s)
- Jun Seok Son
- Health and Exercise Science Laboratory, Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.,Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea
| | - Hee-Jae Kim
- Health and Exercise Science Laboratory, Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.,Physical Activity & Performance Institute, Konkuk University, Seoul, Republic of Korea
| | - Yeri Son
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Development Biology and Genomics, BK21 Program for Veterinary Science, Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea
| | - Hojun Lee
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Development Biology and Genomics, BK21 Program for Veterinary Science, Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea
| | - Song Ah Chae
- Health and Exercise Science Laboratory, Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Je Kyung Seong
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Development Biology and Genomics, BK21 Program for Veterinary Science, Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea
| | - Wook Song
- Health and Exercise Science Laboratory, Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.,Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea.,Institute on Aging, Seoul National University, Seoul, Republic of Korea
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YOO DY, YIM HS, JUNG HY, NAM SM, KIM JW, CHOI JH, SEONG JK, YOON YS, KIM DW, HWANG IK. Chronic type 2 diabetes reduces the integrity of the blood-brain barrier by reducing tight junction proteins in the hippocampus. J Vet Med Sci 2016; 78:957-62. [PMID: 26876499 PMCID: PMC4937155 DOI: 10.1292/jvms.15-0589] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 02/04/2016] [Indexed: 12/11/2022] Open
Abstract
In the present study, we investigated the effects of type 2 diabetes-induced hyperglycemia on the integrity of the blood-brain barrier and tight junction markers in the rat hippocampus. Forty-week-old diabetic (Zucker diabetic fatty, ZDF) rats and littermate control (Zucker lean control, ZLC) rats were used in this study. We evaluated the integrity of the blood-brain barrier by measuring sodium fluorescein extravasation and blood vessel ultrastructure. In addition, tight junction markers, such as zona occludens-1, occludin and claudin-5, were quantified by western blot analysis. ZDF rats showed significantly increased sodium fluorescein leakage in the hippocampus. Tight junction markers, such as occludin and claudin-5, were significantly decreased in the hippocampi of ZDF rats compared to those of ZLC rats. In addition, ZDF rats showed ultrastructural changes with phagocytic findings in the blood vessels. These results suggest that chronic untreated diabetes impairs the permeability of the hippocampal blood-brain barrier by down-regulating occludin and claudin-5, indicating that chronic untreated diabetes may cause hippocampus-dependent dysfunction.
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Affiliation(s)
- Dae Young YOO
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and
Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea
| | - Hee Sun YIM
- Department of Biochemistry and Molecular Biology, Research Institute of Oral
Sciences, College of Dentistry, Kangneung-Wonju National University, Gangneung 25457; South Korea
| | - Hyo Young JUNG
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and
Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea
| | - Sung Min NAM
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and
Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea
| | - Jong Whi KIM
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and
Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea
| | - Jung Hoon CHOI
- Department of Anatomy, College of Veterinary Medicine, Kangwon National
University, Chuncheon 24341, South Korea
| | - Je Kyung SEONG
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and
Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea
- KMPC (Korea Mouse Phenotyping Center), Seoul National University, Seoul 08826,
South Korea
| | - Yeo Sung YOON
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and
Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea
- KMPC (Korea Mouse Phenotyping Center), Seoul National University, Seoul 08826,
South Korea
| | - Dae Won KIM
- Department of Biochemistry and Molecular Biology, Research Institute of Oral
Sciences, College of Dentistry, Kangneung-Wonju National University, Gangneung 25457; South Korea
| | - In Koo HWANG
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and
Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea
- KMPC (Korea Mouse Phenotyping Center), Seoul National University, Seoul 08826,
South Korea
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Prabhakar V, Gupta D, Kanade P, Radhakrishnan M. Diabetes-associated depression: the serotonergic system as a novel multifunctional target. Indian J Pharmacol 2015; 47:4-10. [PMID: 25821303 PMCID: PMC4375817 DOI: 10.4103/0253-7613.150305] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Revised: 11/16/2013] [Accepted: 12/05/2014] [Indexed: 12/26/2022] Open
Abstract
Diabetes associated depression is a largely understudied field which nonetheless carries a significant disease burden. The very low therapeutic efficacy of the existing conventional drugs with poor outcome may be, in part, due to uncertainty of the mechanism involved that clearly explains the existing comorbidity. The main purpose of this review was to address the sophisticated mechanisms of this comorbidity with a view of developing potential novel targets with higher efficacy and specificity. Data were collected from database searches including PubMed, references from relevant English language research/review articles and other official publications. Articles from 1990 to 2013 were included, and a broad search term criteria were followed for data mining so that relevant information was not missed out. Some of the search terms used included; diabetes-induced depression, diabetes and serotonin, hypothalamic-pituitary-adrenal (HPA) axis and diabetes and glucocorticoids in diabetes. Neuropathologically, depletion of brain monoaminergic activity specifically the serotonin (5-hydroxytryptamine [5-HT]) system, due to chronically persisting diabetic state may lead to the mood and behavioral complications that further add on worsening the quality life years. The 5-HT system through multifunctional tasks regulates neurogenesis and plasticity and by complex receptor mechanism controls the emotional and behavioral activity. Persisting hyperglycemia leads to impaired neurogenesis, decreased synaptic plasticity, undesired neuro-anatomical alterations, neurochemical deficits, and reduced neurotransmitter activity. The neurotrophic factors and secondary messenger functions affected at molecular and genetic levels indicate the impact of diabetes-mediated dysregulation on neuronal circuits. HPA activity, glycogen synthase kinase 3, and insulin signaling controls were also found to be hampered, interlinked to 5-HT system following diabetic progression.
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Affiliation(s)
- Visakh Prabhakar
- Department of Pharmacy and, Birla Institute of Technology and Science, Pilani, Rajasthan, India
| | - Deepali Gupta
- Department of Pharmacy and, Birla Institute of Technology and Science, Pilani, Rajasthan, India
| | - Prateek Kanade
- Department of Pharmacy and, Birla Institute of Technology and Science, Pilani, Rajasthan, India
| | - Mahesh Radhakrishnan
- Department of Pharmacy and, Birla Institute of Technology and Science, Pilani, Rajasthan, India
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Diabetes and stem cell function. BIOMED RESEARCH INTERNATIONAL 2015; 2015:592915. [PMID: 26075247 PMCID: PMC4449886 DOI: 10.1155/2015/592915] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 12/01/2014] [Indexed: 12/30/2022]
Abstract
Diabetes mellitus is one of the most common serious metabolic diseases that results in hyperglycemia due to defects of insulin secretion or insulin action or both. The present review focuses on the alterations to the diabetic neuronal tissues and skeletal muscle, including stem cells in both tissues, and the preventive effects of physical activity on diabetes. Diabetes is associated with various nervous disorders, such as cognitive deficits, depression, and Alzheimer's disease, and that may be caused by neural stem cell dysfunction. Additionally, diabetes induces skeletal muscle atrophy, the impairment of energy metabolism, and muscle weakness. Similar to neural stem cells, the proliferation and differentiation are attenuated in skeletal muscle stem cells, termed satellite cells. However, physical activity is very useful for preventing the diabetic alteration to the neuronal tissues and skeletal muscle. Physical activity improves neurogenic capacity of neural stem cells and the proliferative and differentiative abilities of satellite cells. The present review proposes physical activity as a useful measure for the patients in diabetes to improve the physiological functions and to maintain their quality of life. It further discusses the use of stem cell-based approaches in the context of diabetes treatment.
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12
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Yi SS. Effects of exercise on brain functions in diabetic animal models. World J Diabetes 2015; 6:583-597. [PMID: 25987956 PMCID: PMC4434079 DOI: 10.4239/wjd.v6.i4.583] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 01/16/2015] [Accepted: 02/09/2015] [Indexed: 02/05/2023] Open
Abstract
Human life span has dramatically increased over several decades, and the quality of life has been considered to be equally important. However, diabetes mellitus (DM) characterized by problems related to insulin secretion and recognition has become a serious health problem in recent years that threatens human health by causing decline in brain functions and finally leading to neurodegenerative diseases. Exercise is recognized as an effective therapy for DM without medication administration. Exercise studies using experimental animals are a suitable option to overcome this drawback, and animal studies have improved continuously according to the needs of the experimenters. Since brain health is the most significant factor in human life, it is very important to assess brain functions according to the different exercise conditions using experimental animal models. Generally, there are two types of DM; insulin-dependent type 1 DM and an insulin-independent type 2 DM (T2DM); however, the author will mostly discuss brain functions in T2DM animal models in this review. Additionally, many physiopathologic alterations are caused in the brain by DM such as increased adiposity, inflammation, hormonal dysregulation, uncontrolled hyperphagia, insulin and leptin resistance, and dysregulation of neurotransmitters and declined neurogenesis in the hippocampus and we describe how exercise corrects these alterations in animal models. The results of changes in the brain environment differ according to voluntary, involuntary running exercises and resistance exercise, and gender in the animal studies. These factors have been mentioned in this review, and this review will be a good reference for studying how exercise can be used with therapy for treating DM.
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Yoo DY, Chae J, Jung HY, Yim HS, Kim JW, Nam SM, Kim DW, Choi JH, Seong JK, Yoon YS, Hwang IK. Treadmill exercise is associated with reduction of reactive microgliosis and pro-inflammatory cytokine levels in the hippocampus of type 2 diabetic rats. Neurol Res 2015; 37:732-8. [PMID: 25797150 DOI: 10.1179/1743132815y.0000000015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
OBJECTIVES In the present study, we investigated the effects of treadmill exercise on microglial activation and the subsequent release of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1-beta in the hippocampus in a rat model of type 2 diabetes. METHODS At 30 weeks of age, diabetic (Zucker diabetic fatty, ZDF) rats and their littermate control (Zucker lean control, ZLC) rats were either placed on a stationary treadmill or made to run for 1 hour/day at 12-16 m/minute on five consecutive days, for 10 weeks. Once the rats reached 40 weeks, they were perfused and their hippocampus collected for immunohistochemistry or hippocampus collected fresh for the Western blotting or enzyme-linked immunosorbent assay (ELISA). RESULTS The whole blood glucose levels in exercised ZDF rats were significantly higher than in the sedentary or exercised ZLC rats, but were significantly lower than in the sedentary ZDF rats. In the sedentary ZLC and exercised ZLC rats, ionised calcium-binding adapter molecule 1 (Iba-1) immunoreactive microglia showed normal morphology which had small cytoplasm with ramified processes. In the sedentary ZDF rats, some Iba-1 immunoreactive microglia showed abnormal morphology which had hypertrophied cytoplasm with retracted processes. However, exercised ZDF rats had small cytoplasm with highly ramified processes. Levels of TNF-alpha, IL-6 and IL-1beta in the hippocampal homogenates were significantly increased in sedentary ZDF rats compared to sedentary ZLC rats, respectively. However, TNF-alpha, IL-6 and IL-1beta levels in the exercised ZDF rats were significantly decreased compared with those of sedentary ZDF rats, respectively. DISCUSSION These results suggest that exercise in type 2 diabetic rats reduces microglial activation and the subsequent increase of pro-inflammatory cytokine levels in the hippocampus.
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Chung JY, Yoo DY, Im W, Choi JH, Yi SS, Youn HY, Hwang IK, Seong JK, Yoon YS. Electroacupuncture at the Zusanli and Baihui acupoints ameliorates type-2 diabetes-induced reductions in proliferating cells and differentiated neuroblasts in the hippocampal dentate gyrus with increasing brain-derived neurotrophic factor levels. J Vet Med Sci 2014; 77:167-73. [PMID: 25342636 PMCID: PMC4363018 DOI: 10.1292/jvms.14-0400] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
In the current study, we investigated whether electroacupuncture (EA) can inhibit pathological reductions in neurogenesis. Zucker diabetic fatty (ZDF) rats at 7 weeks of age were anesthetized with zoletil, and sham-acupuncture or EA at the Zusanli (ST36) and Baihui (GV20) acupoints was administered once a day for 5 weeks. In the ZDF group that received sham-EA (ZDF-Sham group), the blood glucose level was significantly increased together with age as compared to the control littermates [Zucker lean control (ZLC) rat]. In contrast, proliferating cells and differentiated neuroblasts were significantly decreased in the ZDF-Sham group compared to the ZLC group. Although EA treatment decreased blood glucose levels, this was not statistically significant when compared to blood glucose levels changes in the ZDF-Sham group. However, proliferating cells and differentiated neuroblasts were significantly increased with EA in ZDF rats as compared to those in the ZDF-Sham group.
Brain-derived neurotrophic factor (BDNF) levels were significantly decreased in hippocampal homogenates of ZDF-Sham group compared to those in the ZLC group. The EA treatment significantly increased the BDNF levels compared to those in the ZDF-Sham group, and BDNF levels in this group were similar to those in the ZLC group. These results suggest that EA at ST36 and GV20 can ameliorate the reductions in proliferating cells and differentiated neuroblasts in the dentate gyrus induced by type-2 diabetes without significantly reducing blood glucose levels with increasing BDNF levels.
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Affiliation(s)
- Jin Young Chung
- Department of Veterinary Internal Medicine and Geriatrics, College of Veterinary Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea
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Kim JW, Chae J, Nam SM, Kim YN, Yoo DY, Choi JH, Jung HY, Song W, Hwang IK, Seong JK, Yoon YS. 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. J Vet Sci 2014; 16:11-6. [PMID: 25293488 PMCID: PMC4367140 DOI: 10.4142/jvs.2015.16.1.11] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 10/07/2014] [Indexed: 11/20/2022] Open
Abstract
In the present study, we investigated the effects of treadmill exercise on lipid peroxidation and Cu,Zn-superoxide dismutase (SOD1) levels in the hippocampus of Zucker diabetic fatty (ZDF) rats and lean control rats (ZLC) during the onset of diabetes. At 7 weeks of age, ZLC and ZDF rats were either placed on a stationary treadmill or made to run for 1 h/day for 5 consecutive days at 16~22 m/min for 5 weeks. At 12 weeks of age, the ZDF rats had significantly higher blood glucose levels and body weight than the ZLC rats. In addition, malondialdehyde (MDA) levels in the hippocampus of the ZDF rats were significantly higher than those of the ZLC rats whereas SOD1 levels in the hippocampus of the ZDF rats were moderately decreased. Notably, treadmill exercise prevented the increase of blood glucose levels in ZDF rats. In addition, treadmill exercise significantly ameliorated changes in MDA and SOD1 levels in the hippocampus although SOD activity was not altered. These findings suggest that diabetes increases lipid peroxidation and decreases SOD1 levels, and treadmill exercise can mitigate diabetes-induced oxidative damage in the hippocampus.
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Affiliation(s)
- Jong Whi Kim
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea
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Nam SM, Kim YN, Yoo DY, Yi SS, Choi JH, Hwang IK, Seong JK, Yoon YS. Hypothyroidism affects astrocyte and microglial morphology in type 2 diabetes. Neural Regen Res 2014; 8:2458-67. [PMID: 25206556 PMCID: PMC4146114 DOI: 10.3969/j.issn.1673-5374.2013.26.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 07/25/2013] [Indexed: 12/03/2022] Open
Abstract
In the present study, we investigated the effects of hypothyroidism on the morphology of astrocytes and microglia in the hippocampus of Zucker diabetic fatty rats and Zucker lean control rats. To induce hypothyroidism, Zucker lean control and Zucker diabetic fatty rats at 7 weeks of age orally received the vehicle or methimazole, an anti-thyroid drug, treatment for 5 weeks and were sacrificed at 12 weeks of age in all groups for blood chemistry and immunohistochemical staining. In the methimazole-treated Zucker lean control and Zucker diabetic fatty rats, the serum circulating thyronine (T3) and thyroxine (T4) levels were significantly decreased compared to levels observed in the vehicle-treated Zucker lean control or Zucker diabetic fatty rats. This reduction was more prominent in the methimazole-treated Zucker diabetic fatty group. Glial fibrillary acidic protein immunoreactive astrocytes and ionized calcium-binding adapter molecule 1 (Iba-1)-immunoreactive microglia in the Zucker lean control and Zucker diabetic fatty group were diffusely detected in the hippocampal CA1 region and dentate gyrus. There were no significant differences in the glial fibrillary acidic protein and Iba-1 immunoreactivity in the CA1 region and dentate gyrus between Zucker lean control and Zucker diabetic fatty groups. However, in the methimazole-treated Zucker lean control and Zucker diabetic fatty groups, the processes of glial fibrillary acidic protein tive astrocytes and Iba-1 immunoreactive microglia, were significantly decreased in both the CA1 region and dentate gyrus compared to that in the vehicle-treated Zucker lean control and Zucker diabetic fatty groups. These results suggest that diabetes has no effect on the morphology of astrocytes and microglia and that hypothyroidism during the onset of diabetes prominently reduces the processes of astrocytes and microglia.
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Affiliation(s)
- Sung Min Nam
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea
| | - Yo Na Kim
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea
| | - Dae Young Yoo
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea
| | - Sun Shin Yi
- Department of Biomedical Laboratory Science, College of Biomedical Sciences, Soonchunhyang University, Asan 336-745, South Korea
| | - Jung Hoon Choi
- Department of Anatomy, College of Veterinary Medicine, Kangwon National University, Chuncheon 200-701, South Korea
| | - In Koo Hwang
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea
| | - Je Kyung Seong
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea
| | - Yeo Sung Yoon
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea
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Hwang IK, Choi JH, Nam SM, Park OK, Yoo DY, Kim W, Yi SS, Won MH, Seong JK, Yoon YS. Activation of microglia and induction of pro-inflammatory cytokines in the hippocampus of type 2 diabetic rats. Neurol Res 2014; 36:824-32. [PMID: 24571083 DOI: 10.1179/1743132814y.0000000330] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The majority of immune cells in the brain are comprised of microglia, which undergo morphological changes when activated to remove damaged neurons and infectious agents from the brain tissue. In this study, we investigated the effects of type 2 diabetes on microglial activation and the subsequent secretion of pro-inflammatory cytokines, such as interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta), in the hippocampus using Zucker diabetic fatty (ZDF) rats and Zucker lean control (ZLC) rats at various diabetic stages. METHODS Zucker lean control and Zucker diabetic fatty rats were sacrificed at 12 (early diabetic stage), 20, or 30 weeks of age (chronic diabetic stage), and the hippocampus was obtained via transcardiac perfusion or dissection for immunohistochemistry and western blot analysis, respectively. RESULTS Zucker diabetic fatty rats demonstrated significantly higher glucose levels at 12 and 30 weeks of age compared to ZLC rats. Microglia immunoreactive to ionized calcium-binding adapter molecule 1 (Iba-1) had hypertrophied cytoplasm with retracted processes at 30 weeks of age. In contrast, Iba-1-immunoreactive microglia displayed similar morphology in ZDF and ZLC rats at 12 and 20 weeks of age. Similarly, IFN-gamma and IL-1beta protein levels were significantly increased in ZDF rats compared to ZLC rats at 30 weeks of age, but not at 12 and 20 weeks of age. Interleukin-1beta immunoreactivity in the ZDF rats predominantly increased in the dentate gyrus and CA1 region of the hippocampus compared to that of ZLC rats at 30 weeks of age. In addition, IL-1beta immunoreactive structures in ZDF rats at 30 weeks of age were detected near the astrocytes and microglia. CONCLUSION These results suggest that chronic diabetes activates microglia and significantly increases pro-inflammatory cytokine levels in the hippocampus.
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Kim HJ, Park JY, Oh SL, Kim YA, So B, Seong JK, Song W. Effect of treadmill exercise on interleukin-15 expression and glucose tolerance in zucker diabetic Fatty rats. Diabetes Metab J 2013; 37:358-64. [PMID: 24199165 PMCID: PMC3816137 DOI: 10.4093/dmj.2013.37.5.358] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 04/30/2013] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Interleukin-15 (IL-15), a well-known myokine, is highly expressed in skeletal muscle and is involved in muscle-fat crosstalk. Recently, a role of skeletal muscle-derived IL-15 in the improvement of glucose homeostasis and insulin sensitivity has been proposed. However, little is known regarding the influence of endurance training on IL-15 expression in type 2 diabetic skeletal muscles. We investigated the effect of endurance exercise training on glucose tolerance and IL-15 expression in skeletal muscles using type 2 diabetic animal models. METHODS MALE ZUCKER DIABETIC FATTY (ZDF) AND ZDF LEAN CONTROL (ZLC) RATS WERE RANDOMLY DIVIDED INTO THREE GROUPS: sedentary ZLC, sedentary ZDF (ZDF-Con), and exercised ZDF (ZDF-Ex). The ZDF-Ex rats were forced to run a motor-driven treadmill for 60 minutes once a day 5 times per week for 12 weeks. Intraperitoneal glucose tolerance test (IPGTT) was performed after 12 weeks. Expression of IL-15 was measured using ELISA in extracted soleus (SOL) and gastrocnemius medial muscles. RESULTS After 12 weeks of treadmill training, reduction of body weight was observed in ZDF-Ex compared to ZDF-Con rats. Glucose tolerance using IPGTT in diabetic rats was significantly improved in ZDF-Ex rats. Furthermore, the expression of IL-15 was significantly increased (P<0.01) only in the SOL of ZDF-Ex rats compared to ZDF-Con. Additionally, IL-15 expression in SOL muscles was negatively correlated with change of body weight (R=-0.424, P=0.04). CONCLUSION The present study results suggest that 12 weeks of progressive endurance training significantly improved glucose tolerance with concomitant increase of IL-15 expression in SOL muscles of type 2 diabetic rats.
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Affiliation(s)
- Hee-Jae Kim
- Health and Exercise Science Laboratory, The Institute of Sports Science, Seoul National University, Seoul, Korea
| | - Jae Young Park
- Department of Sport, Kyungil University College of Arts and Sports, Gyeongsan, Korea
| | - Seung Lyul Oh
- Health and Exercise Science Laboratory, The Institute of Sports Science, Seoul National University, Seoul, Korea
| | - Yong-An Kim
- Health and Exercise Science Laboratory, The Institute of Sports Science, Seoul National University, Seoul, Korea
| | - Byunghun So
- Health and Exercise Science Laboratory, The Institute of Sports Science, Seoul National University, Seoul, Korea
| | - Je Kyung Seong
- Department of Anatomy and Cell Biology, Research Institute for Veterinary Science, Seoul National University College of Veterinary Medicine, Seoul, Korea
| | - Wook Song
- Health and Exercise Science Laboratory, The Institute of Sports Science, Seoul National University, Seoul, Korea
- Institute on Aging, Seoul National University College of Medicine, Seoul, Korea
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Renno WM, Al-Banaw AG, George P, Abu-Ghefreh AA, Akhtar S, Benter IF. Angiotensin-(1-7) via the mas receptor alleviates the diabetes-induced decrease in GFAP and GAP-43 immunoreactivity with concomitant reduction in the COX-2 in hippocampal formation: an immunohistochemical study. Cell Mol Neurobiol 2012; 32:1323-36. [PMID: 22711212 PMCID: PMC11498388 DOI: 10.1007/s10571-012-9858-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Accepted: 06/05/2012] [Indexed: 12/23/2022]
Abstract
We have previously shown that chronic treatment with angiotensin-(1-7) [Ang-(1-7)] can prevent diabetes-induced cardiovascular dysfunction. However, effect of Ang-(1-7) treatment on diabetes-induced alterations in the CNS is unknown. The aim of this study was to test the hypothesis that treatment with Ang-(1-7) can produce protection against diabetes-induced CNS changes. We examined the effect of Ang-(1-7) on the number of cyclooxygenase-2 (COX-2) immunoreactive neurons and the glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes and assessed the changes in the neuronal growth-associated protein-43 (GAP-43) of the hippocampal formation in streptozotocin-induced diabetes in rats. Animals were sacrificed 30 days after induction of diabetes and/or treatment with Ang-(1-7). Ang-(1-7) treatment significantly prevented diabetes-induced decrease in the number of GFAP immunoreactive astrocytes and GAP-43 positive neurons in all hippocampal regions. Co-administration of A779, a selective Ang-(1-7) receptor antagonist, inhibited Ang-(1-7)-mediated protective effects indicating that Ang-(1-7) produces its effects through activation of receptor Mas. Further, Ang-(1-7) treatment through activation of Mas significantly prevented diabetes-induced increase in the number of the COX-2 immunolabeled neurons in all sub-regions of the hippocampus examined. These results show that Ang-(1-7) has a protective role against diabetes-induced changes in the CNS.
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Affiliation(s)
- Waleed M Renno
- Department of Anatomy, Faculty of Medicine, Kuwait University, P. O. Box 24923, Safat, 13110, Kuwait.
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Hypothyroid states mitigate the diabetes-induced reduction of calbindin D-28k, calretinin, and parvalbumin immunoreactivity in type 2 diabetic rats. Neurochem Res 2011; 37:253-60. [PMID: 22037839 DOI: 10.1007/s11064-011-0602-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 08/29/2011] [Accepted: 09/09/2011] [Indexed: 10/15/2022]
Abstract
In this study, we investigated the differences in calbindin D-28k (CB), calretinin, (CR) and parvalbumin (PV) immunoreactivity in the hippocampus of Zucker diabetic fatty (ZDF) rats and Zucker lean control (ZLC) rats. In addition, we observed the effects of hypothyroidism on the levels of immunoreactivity of these proteins in ZDF rats. For this study, 7-week-old ZDF rats were used, and methimazole treatment was continued for 5 weeks to induce hypothyroidism. The animals were sacrificed at 12 weeks of age. ZDF rats showed increased blood glucose levels compared to those in ZLC rats. Methimazole intervention significantly reduced total and free T3 levels, and it ameliorated the increase of blood glucose levels in ZDF rats. In ZLC rats, CB, CR, and PV immunoreactivity was detected in regions of the hippocampus proper. In vehicle-treated ZDF rats, CB, CR, and PV immunoreactivity was significantly decreased in the hippocampus. However, in the methimazole-treated rats, CB, CR, and PV immunoreactivity was significantly increased compared to that in the vehicle-treated rats. These results suggest that hypothyroidism ameliorated the diabetes-induced reduction of CB, CR, and PV immunoreactivity in the hippocampus.
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Differential effects of treadmill exercise on cyclooxygenase-2 in the rat hippocampus at early and chronic stages of diabetes. Lab Anim Res 2011; 27:189-95. [PMID: 21998607 PMCID: PMC3188725 DOI: 10.5625/lar.2011.27.3.189] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2011] [Revised: 08/06/2011] [Accepted: 08/17/2011] [Indexed: 11/21/2022] Open
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.
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Yoo DY, Shin BN, Kim IH, Kim W, Kim DW, Yoo KY, Choi JH, Lee CH, Yoon YS, Choi SY, Won MH, Hwang IK. Effects of Cu,Zn-superoxide dismutase on cell proliferation and neuroblast differentiation in the mouse dentate gyrus. Neurochem Res 2011; 37:261-7. [PMID: 21927927 DOI: 10.1007/s11064-011-0605-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Revised: 09/08/2011] [Accepted: 09/10/2011] [Indexed: 12/28/2022]
Abstract
Oxidative stress is one of the most important factors in reducing adult hippocampal neurogenesis in the adult brain. In this study, we observed the effects of Cu,Zn-superoxide dismutase (SOD1) on lipid peroxidation, cell proliferation, and neuroblast differentiation in the mouse dentate gyrus using malondialdehyde (MDA), Ki67, and doublecortin (DCX), respectively. We constructed an expression vector, PEP-1, fused PEP-1 with SOD1, and generated PEP-1-SOD1 fusion protein. We administered PEP-1 and 100 or 500 μg PEP-1-SOD1 intraperitoneally once a day for 3 weeks and sacrificed at 30 min after the last administrations. PEP-1 administration did not change the MDA levels compared to those in the vehicle-treated group, while PEP-1-SOD1 treatment significantly reduced MDA levels compared to the vehicle-treated group. In the PEP-1-treated group, the number of Ki67-positive nuclei was similar to that in the vehicle-treated group. In the 100 μg PEP-1-SOD1-treated group, the number of Ki67-positive nuclei was slightly decreased; however, in the 500 μg PEP-1-SOD1-treated group, Ki67-positive nuclei were decreased to 78.5% of the vehicle-treated group. The number of DCX-positive neuroblasts in the PEP-1-treated group was similar to that in the vehicle-treated group. However, the arborization of DCX-positive neuroblasts was significantly decreased in both the 100 and 500 μg PEP-1-SOD1-treated groups compared to that in the vehicle-treated group. The number of DCX-positive neuroblasts with tertiary dendrites was markedly decreased in the 500 μg PEP-1-SOD1-treated group. These results suggest that a SOD1 supplement to healthy mice may not be necessary to modulate cell proliferation and neuroblast differentiation in the dentate gyrus.
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Affiliation(s)
- Dae Young Yoo
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, 151-742, South Korea
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Effects of Adrenalectomy and Replacement Therapy of Corticosterone on Cell Proliferation and Neuroblast Differentiation in the Rat Dentate Gyrus. Neurochem Res 2011; 36:1767-75. [DOI: 10.1007/s11064-011-0492-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2011] [Indexed: 12/20/2022]
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Nam SM, Hwang IK, Yi SS, Yoo KY, Park OK, Yan B, Song W, Won MH, Yoon YS, Seong JK. Differential effects of treadmill exercise on calretinin immunoreactivity in type 2 diabetic rats in early and chronic diabetic stages. J Vet Med Sci 2011; 73:1037-42. [PMID: 21519158 DOI: 10.1292/jvms.11-0043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In this study, we investigated the effects of treadmill exercise on calretinin (CR), a marker of early postmitotic neurons, immunoreactivity in the dentate gyrus (DG) of Zucker diabetic fatty (ZDF) rats, before or after diabetes onset, and Zucker lean control (ZLC) rats. For this study, 6-week-old ZLC and prediabetic ZDF rats, and 22-week-old ZLC and ZDF rats were exercised on the treadmill. Sedentary ZLC and ZDF rats of the same age were used as exercise experiment controls. The exercised prediabetic ZDF rats did not show diabetes onset, while the sedentary prediabetic ZDF rats showed significantly increased blood glucose levels. The exercised diabetic ZDF rats exhibited a decrease in their blood glucose levels compared to the sedentary diabetic ZDF rats, but the levels were still above 20 mmol/l. ZLC rats of both ages were in the normoglycemic range. CR immunoreactivity was detected throughout the DG, including the subgranular zone and the polymorphic layer. Diabetic rats exhibited a significant decrease in the number of CR-immunoreactive cells and fibers in the DG. Exercise in the prediabetic ZDF rats significantly increased the number of CR-immunoreactive cells and fibers in the subgranular zone of the DG. In the ZLC and ZDF rats of chronic diabetic phase, exercise increased CR-immunoreactive neurons in the hilar region. These results suggest that diabetes significantly reduces the number of postmitotic CR-immunoreactive neurons and the intensity of immunoreactivity and that exercise increases these CR-related parameters in a diabetic stage-dependent manner.
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Affiliation(s)
- Sung Min Nam
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea
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Differential effects of treadmill exercise in early and chronic diabetic stages on parvalbumin immunoreactivity in the hippocampus of a rat model of type 2 diabetes. Neurochem Res 2011; 36:1526-32. [PMID: 21516442 DOI: 10.1007/s11064-011-0480-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2011] [Indexed: 12/23/2022]
Abstract
In the present study, we investigated the effects of treadmill exercise in early and chronic diabetic stages on parvalbumin (PV) immunoreactivity in the subgranular zone of the dentate gyrus of Zucker diabetic fatty (ZDF) and its lean control rats (ZLC). To investigate the effects, ZLC and ZDF rats at 6 or 23 weeks of age were put on a treadmill with or without running for 1 h/day/5 consecutive days at 16-22 m/min for 5 weeks or 12-16 m/min for 7 weeks, respectively. Physical exercise in pre-diabetic rats prevented onset of diabetes, while exercise in rats at chronic diabetic stage significantly reduced blood glucose levels. In addition, physical exercise in the pre-diabetic rats significantly increased PV immunoreactive fibers in the strata oriens and radiatum of the CA1-3 region and in the polymorphic and molecular layers of the dentate gyrus compared to that in sedentary controls. However, in rats at chronic stages, PV immunoreactivity was slightly increased in the CA1-3 region as well as in the dentate gyrus compared to that in the sedentary controls. These results suggest that physical exercise has differential effects on blood glucose levels and PV immunoreactivity according to diabetic stages. Early exercise improves diabetic phenotype and PV immunoreactive fibers in the rat hippocampus.
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Effect of treadmill exercise on blood glucose, serum corticosterone levels and glucocorticoid receptor immunoreactivity in the hippocampus in chronic diabetic rats. Neurochem Res 2010; 36:281-7. [PMID: 21076867 DOI: 10.1007/s11064-010-0315-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2010] [Indexed: 10/18/2022]
Abstract
Abnormal excess of glucocorticoid is one of feature characteristics in type 2 diabetes. In the present study, we investigated the effect of treadmill exercise at chronic diabetic stages on glucocorticoid receptor (GR) immunoreactivity in the hippocampal CA1 region and dentate gyrus, which are very vulnerable to diabetes. For this study, we used Zucker diabetic fatty (ZDF) rats and Zucker lean control (ZLC) rats. Twenty-three-week-old ZLC and ZDF rats were put on the treadmill with or without running for 7 weeks and sacrificed at 30 weeks of age. Treadmill exercise significantly decreased diabetes-induced blood glucose and serum corticosteroid levels although they did not drop to control levels. In sedentary ZLC rats, GR immunoreactivity was detected in pyramidal cells of the CA1 region as well as in granule cells of the dentate gyrus. In the sedentary ZDF rats, GR immunoreactivity was significantly increased in these regions. However, treadmill exercise significantly decreased GR immunoreactivity in these regions. These results indicate that treadmill exercise in chronic diabetic rats significantly decreased GR immunoreactivity in the hippocampal CA1 region and dentate gyrus, although blood glucose and serum corticosteroid levels did not fully recover to normal state.
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Yi SS, Hwang IK, Choi JW, Won MH, Seong JK, Yoon YS. Effects of hypothyroidism on cell proliferation and neuroblasts in the hippocampal dentate gyrus in a rat model of type 2 diabetes. Anat Cell Biol 2010; 43:185-93. [PMID: 21212858 PMCID: PMC3015036 DOI: 10.5115/acb.2010.43.3.185] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Revised: 09/01/2010] [Accepted: 09/02/2010] [Indexed: 11/27/2022] Open
Abstract
We observed how the hypothyroid state affects diabetic states and modifies cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus (DG). For this, 0.03% methimazole, an anti-thyroid drug, was administered to 7-week-old, pre-diabetic Zucker diabetic fatty (ZDF) rats by drinking water for 5 weeks, and the animals were sacrificed at 12 weeks of age. At this age, corticosterone levels were significantly increased in the ZDF rats compared to those in the control (Zucker lean control, ZLC) rats. Methimazole (methi) treatment in the ZDF rats (ZDF-methi rats) significantly decreased corticosterone levels and diabetes-induced hypertrophy of adrenal glands. In the DG, Ki67 (a marker for cell proliferation)- and doublecortin (DCX, a marker for neuronal progenitors)-immunoreactive cells were much lower in the ZDF rats than those in the ZLC rats. However, in ZDF-methi rats, numbers of Ki67- and DCX-immunoreactive cells were similar to those in the ZLC rats. These suggest that methi significantly reduces diabetes-induced hypertrophy of the adrenal gland and alleviates the diabetes-induced reduction of cell proliferation and neuronal progenitors in the DG.
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Affiliation(s)
- Sun Shin Yi
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea
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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. [DOI: 10.1016/j.brainres.2010.02.057] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2009] [Revised: 02/07/2010] [Accepted: 02/19/2010] [Indexed: 11/20/2022]
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Hwang IK, Kim IY, Joo EJ, Shin JH, Choi JW, Won MH, Yoon YS, Seong JK. Metformin Normalizes Type 2 Diabetes-Induced Decrease in Cell Proliferation and Neuroblast Differentiation in the Rat Dentate Gyrus. Neurochem Res 2010; 35:645-50. [DOI: 10.1007/s11064-009-0115-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2009] [Indexed: 11/27/2022]
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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 2009; 1341:63-71. [PMID: 20005869 DOI: 10.1016/j.brainres.2009.12.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2009] [Revised: 11/26/2009] [Accepted: 12/03/2009] [Indexed: 01/21/2023]
Abstract
In the present study, we investigated the effects of type 2 diabetes and treadmill exercise in chronic diabetic stages on neuroblast differentiation using doublecortin (DCX) in the subgranular zone of the dentate gyrus (SZDG) in Zucker diabetic fatty (ZDF) rats. Four-, 12-, 20- and 30-week-old Zucker lean control (ZLC) and ZDF rats were used to elucidate age-dependent changes of DCX-immunoreactive neuroblasts. DCX-immunoreactive neuroblasts were significantly decreased with age in the SZDG. This reduction was prominent in the age-matched ZDF rats compared to that in the ZLC rats. To investigate the effects of treadmill exercise, ZLC and ZDF rats at 23 weeks of age were put on the treadmill with or without running for 1 h/day/5 consecutive days at 12-16 m/min for 7 weeks. Treadmill exercise significantly increased the tertiary dendrites of DCX-immunoreactive neuroblasts in both ZLC and ZDF rats. In addition, exercise significantly increased the number of DCX-immunoreactive neuroblasts in the ZLC rats, but not in the ZDF rats. These results suggest that diabetes significantly decreases neuroblast differentiation and treadmill exercise in chronic diabetic animals has limitation to increase neuroblast differentiation although it increases neural plasticity.
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Affiliation(s)
- In Koo Hwang
- Department of Anatomy and Cell Biology, College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University, Seoul 151-742, South Korea
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Hwang IK, Kim IY, Kim YN, Yi SS, Lee YH, Ju EJ, Lee IS, Park IS, Won MH, Yoon YS, Seong JK. Effects of methimazole on the onset of type 2 diabetes in leptin receptor-deficient rats. J Vet Med Sci 2009; 71:275-80. [PMID: 19346693 DOI: 10.1292/jvms.71.275] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We investigated the effects of methimazole, an anti-thyroid drug, on the onset of type 2 diabetes in Zucker diabetic fatty (ZDF) rats. For this, 0.03% methimazole was administered to 7-week-old, pre-diabetic ZDF rats in drinking water for 5 weeks and the animals were sacrificed at 12 weeks of age. Methimazole treatment to ZDF rats significantly reduced blood glucose levels, food intake, body weight, and serum T3 levels. Hepatocytes in ZDF-methi rats were more densely stained with eosin than those in ZDF rats because of low fat accumulation in ZDF-methi hepatocytes. The pancreatic islet in ZDF-methi rats was normal compared to that in ZDF rats. Glucagon, not insulin, immunoreactivity in ZDF-methi rats was significantly higher than that in ZDF-methi rats. These suggest that methimazole treatment may delay the onset of type 2 diabetes in leptin receptor-deficient rats and also suggests that thyroid hormones may be necessary for the onset of diabetes.
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Affiliation(s)
- In Koo Hwang
- Department of Anatomy and Cell Biology, College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University, Seoul, South Korea
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Effects of treadmill exercise on cell proliferation and differentiation in the subgranular zone of the dentate gyrus in a rat model of type II diabetes. Neurochem Res 2008; 34:1039-46. [PMID: 18982449 DOI: 10.1007/s11064-008-9870-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2008] [Indexed: 12/23/2022]
Abstract
In the present study, we investigated the effects of a treadmill exercise on serum glucose levels and Ki67 and doublecortin (DCX) immunoreactivity, which is a marker of cell proliferation expressed during cell cycles except G0 and early G1 and a marker of progenitors differentiating into neurons, respectively, in the subgranular zone of the dentate gyrus (SZDG) using a type II diabetic model. At 6 weeks of age, Zucker lean control (ZLC) and Zucker diabetic fatty (ZDF) rats were put on a treadmill with or without running for 1 h/day/5 consecutive days at 22 m/min for 5 weeks. Body weight was significantly increased in the control (without running)-ZDF rats compared to that in the other groups. In the control groups blood glucose levels were increased by 392.7 mg/dl in the control-ZDF rats and by 143.3 mg/dl in the control-ZLC rats. However, in the exercise groups, blood glucose levels were similar between the exercise-ZLC and ZDF rats: The blood glucose levels were 110.0 and 118.2 mg/dl, respectively. Ki67 positive nuclei were detected in the SZDG in control and exercise groups. The number of Ki67 positive nuclei was significantly high in exercise groups compared to that in the control groups. In addition, Ki67 positive cells were abundant in ZLC groups compared to those in ZDF groups. DCX-immunoreactive structures in the control-ZDF rats were lower than that in the control-ZLC rats. In the exercise groups, DCX-immunoreactive structures (somata and processes with tertiary dendrites) and DCX protein levels were markedly increased in both the exercise-ZLC and ZDF rats compared to that in the control groups. These results suggest that a treadmill exercise reduces blood glucose levels in ZDF rats and increases cell proliferation and differentiation in the SZDG in ZLC and ZDF rats compared to those in control groups.
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Yi SS, Hwang IK, Chun MS, Kim YN, Kim IY, Lee IS, Seong JK, Yoon YS. Glucocorticoid receptor changes associate with age in the paraventricular nucleus of type II diabetic rat model. Neurochem Res 2008; 34:851-8. [PMID: 18758953 DOI: 10.1007/s11064-008-9836-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2008] [Accepted: 08/12/2008] [Indexed: 12/25/2022]
Abstract
Diabetes is a metabolic disorder that is associated with the dysregulation of a number of systems within the body. In the present study, we investigated glucocorticoid receptor (GR) immunoreactivity and its protein levels in the paraventricular nuclei of 4-, 12-, 20- and 30-week-old Zucker diabetic fatty (fa/fa, ZDF) and in Zucker lean control (fa/+ or +/+, ZLC) rats, because the progressive induction of diabetes is detectable in this model after 7 weeks of age and chronic diabetic conditions are maintained after 12 weeks of age. GR immunoreactivity was detected in parvocellular paraventricular nuclei and this and GR protein levels were exponentially increased according to the ages. In particular, GR immunoreactivities and protein levels were markedly more increased in 30-week-old ZDF rats than in age-matched ZLC group and in younger ZDF group. The present study suggests that GR immunoreactivity and its protein level is associated with a degenerative phenotype in the hypothalamus of from 12-weeks old in the ZDF rat type II diabetes model.
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Affiliation(s)
- Sun Shin Yi
- Department of Anatomy and Cell Biology, College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University, Seoul, South Korea
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Enhanced expressions of arginine vasopressin (Avp) in the hypothalamic paraventricular and supraoptic nuclei of type 2 diabetic rats. Neurochem Res 2007; 33:833-41. [PMID: 17940875 DOI: 10.1007/s11064-007-9519-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Accepted: 09/25/2007] [Indexed: 01/16/2023]
Abstract
Arginine vasopressin (AVP) is known to a neuropeptide that plays important roles in water conservation, sodium homeostasis, and in the regulation of serum osmolality. Several studies have reported that the elevated AVP level is related with diabetes mellitus as an acute or chronic stressor using type 1 diabetes mellitus animal models. However, it is unclear as to how the immunoreactivity and protein level of AVP in the brain is regulated in animal models of type 2 diabetes mellitus. In the present study, Zucker diabetic fatty (ZDF) rats were employed as a type 2 diabetes mellitus model and were compared with Zucker lean control (ZLC) rats with respect to AVP protein expression. Furthermore, in order to verify the regulation of AVP expression before and after the onset of diabetes mellitus, pre-diabetic rats (4 week-old) and obese-diabetic rats (12 week-old) were used. Blood glucose levels and water consumption were also measured and the results showed significantly high in 12 week-old ZDF than any other groups. AVP expression levels in the paraventricular nucleus and supraoptic nucleus were found to be significantly higher in 12 week-old ZDF rats than in 12 week-old ZLC rats and than in 4 week-old rats by immunostaining and western blotting. Enhanced expression of AVP in these animals may be associated with type 2 diabetes mellitus.
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