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Kim CY, Ko K, Choi SH, Jo M, Kim J, Yoon S, Yi IJ, Morán-Valero MI, Kwon MY, Sohn J, Yi SS. Effects of Saffron Extract (Affron ®) with 100 mg/kg and 200 mg/kg on Hypothalamic-Pituitary-Adrenal Axis and Stress Resilience in Chronic Mild Stress-Induced Depression in Wistar Rats. Nutrients 2023; 15:4855. [PMID: 38068714 PMCID: PMC10707924 DOI: 10.3390/nu15234855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/06/2023] [Accepted: 11/17/2023] [Indexed: 12/18/2023] Open
Abstract
Stress-related symptoms are a global concern, impacting millions of individuals, yet effective and safe treatments remain scarce. Although multiple studies have highlighted the stress- alleviating properties of saffron extract, the underlying mechanisms remain unclear. This study employs the unpredictable chronic mild stress (CMS) animal model to investigate the impact of a standardized saffron extract, Affron® (AFN), on hypothalamic-pituitary-adrenal (HPA) axis regulation and neuroplasticity in Wistar rats following repeated oral administration. The research evaluates AFN's effects on various stress-related parameters, including hypothalamic gene expression, stress hormone levels, and the sucrose preference test. In animals subjected to continuous unpredictable CMS, repetitive administration of AFN at doses of 100 mg/kg and 200 mg/kg effectively normalized HPA axis dysregulation and enhanced neuroplasticity. Increased concentrations of AFN demonstrated greater efficacy. Following AFN oral administration, adrenocorticotropic and corticosterone hormone levels exhibited significant or nearly significant reductions in comparison to subjects exposed to stress only. These changes align with the alleviation of stress and the normalization of the HPA axis. These findings elucidate AFN's role in stress mitigation, affirm its health benefits, validate its potential as a treatment for stress-related symptoms, confirm its physiological effectiveness, and emphasize its therapeutic promise.
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Affiliation(s)
- Chae-Young Kim
- BK21 Four Program, Department of Medical Science, Soonchunhyang University, Asan 31538, Republic of Korea;
| | - Kayoung Ko
- Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan 31538, Republic of Korea; (K.K.); (S.-H.C.); (M.J.)
| | - Seo-Hee Choi
- Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan 31538, Republic of Korea; (K.K.); (S.-H.C.); (M.J.)
| | - Miri Jo
- Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan 31538, Republic of Korea; (K.K.); (S.-H.C.); (M.J.)
| | - Jinhye Kim
- Central Lab., iCONNECTOME Co., Ltd., Cheonan 31168, Republic of Korea; (J.K.); (S.Y.)
| | - Sunmi Yoon
- Central Lab., iCONNECTOME Co., Ltd., Cheonan 31168, Republic of Korea; (J.K.); (S.Y.)
| | - Isaac Jinwon Yi
- Department of Cognitive Science, University of California, San Diego, CA 92093, USA;
| | | | - Min-Young Kwon
- Hyundai Bioland Co., Ltd., Ansan 15407, Republic of Korea; (M.-Y.K.); (J.S.)
| | - Johann Sohn
- Hyundai Bioland Co., Ltd., Ansan 15407, Republic of Korea; (M.-Y.K.); (J.S.)
| | - Sun-Shin Yi
- BK21 Four Program, Department of Medical Science, Soonchunhyang University, Asan 31538, Republic of Korea;
- Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan 31538, Republic of Korea; (K.K.); (S.-H.C.); (M.J.)
- Central Lab., iCONNECTOME Co., Ltd., Cheonan 31168, Republic of Korea; (J.K.); (S.Y.)
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Gaspar JM, Baptista FI, Macedo MP, Ambrósio AF. Inside the Diabetic Brain: Role of Different Players Involved in Cognitive Decline. ACS Chem Neurosci 2016; 7:131-42. [PMID: 26667832 DOI: 10.1021/acschemneuro.5b00240] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus is the most common metabolic disease, and its prevalence is increasing. A growing body of evidence, both in animal models and epidemiological studies, has demonstrated that metabolic diseases like obesity, insulin resistance, and diabetes are associated with alterations in the central nervous system (CNS), being linked with development of cognitive and memory impairments and presenting a higher risk for dementia and Alzheimer's disease. The rising prevalence of diabetes together with its increasing earlier onset suggests that diabetes-related cognitive dysfunction will increase in the near future, causing substantial socioeconomic impact. Decreased insulin secretion or action, dysregulation of glucose homeostasis, impairment in the hypothalamic-pituitary-adrenal axis, obesity, hyperleptinemia, and inflammation may act independently or synergistically to disrupt neuronal homeostasis and cause diabetes-associated cognitive decline. However, the crosstalk between those factors and the mechanisms underlying the diabetes-related CNS complications is still elusive. During the past few years, different strategies (neuroprotective and antioxidant drugs) have emerged as promising therapies for this complication, which still remains to be preventable or treatable. This Review summarizes fundamental past and ongoing research on diabetes-associated cognitive decline, highlighting potential contributors, mechanistic mediators, and new pharmacological approaches to prevent and/or delay this complication.
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Affiliation(s)
- Joana M. Gaspar
- CEDOC,
Chronic Diseases Research Centre, NOVA Medical School/Faculdade de
Ciências Médicas, Universidade Nova de Lisboa, Edifício
CEDOC - IIRua Câmara Pestana no. 6, 6A e 6B, 1150-082 Lisboa, Portugal
- Institute
for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Portuguese Diabetes Association (APDP), R. do Salitre 118-120, 1250-203 Lisboa, Portugal
| | - Filipa I. Baptista
- Institute
for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CNC.IBILI
Consortium, University of Coimbra, 3004-517 Coimbra, Portugal
| | - M. Paula Macedo
- CEDOC,
Chronic Diseases Research Centre, NOVA Medical School/Faculdade de
Ciências Médicas, Universidade Nova de Lisboa, Edifício
CEDOC - IIRua Câmara Pestana no. 6, 6A e 6B, 1150-082 Lisboa, Portugal
- Portuguese Diabetes Association (APDP), R. do Salitre 118-120, 1250-203 Lisboa, Portugal
| | - António F. Ambrósio
- Institute
for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CNC.IBILI
Consortium, University of Coimbra, 3004-517 Coimbra, Portugal
- AIBILI, 3000-548 Coimbra, Portugal
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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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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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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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Shin JH, Seong JK, Yi SS. Sequential alterations of glucocorticoid receptors in the hippocampus of STZ-treated type 1 diabetic rats. J Vet Sci 2013; 15:19-26. [PMID: 23820217 PMCID: PMC3973762 DOI: 10.4142/jvs.2014.15.1.19] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 04/11/2013] [Indexed: 12/28/2022] Open
Abstract
Type 1 diabetes is a common metabolic disorder accompanied by increased blood glucose levels along with glucocorticoid and cognitive deficits. The disease is also thought to be associated with environmental changes in brain and constantly induces oxidative stress in patients. Therefore, glucocorticoid-mediated negative feedback mechanisms involving the glucocorticoid receptor (GR) binding site are very important to understand the development of this disease. Many researchers have used streptozotocin (STZ)-treated diabetic animals to study changes in GR expression in the brain. However, few scientists have evaluated the hyperglycemic period following STZ exposure. In the present study, we found GR expression in the hippocampus varied based on the period after STZ administration for up to 4 weeks. We performed immunohistochemistry and Western blotting to validate the sequential alterations of GR expression in the hippocampus of STZ-treated type 1 diabetic rats. GR protein expression increased significantly until week 3 but decreased at week 4 following STZ administration. GR expression after 70 mg/kg STZ administration was highest at 3 weeks post-treatment and decreased thereafter. Although STZ-induced increase in GR expression in diabetic animals has been described, our data indicate that researchers should consider the sequential GR expression changes during the hyperglycemic period following STZ exposure.
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Affiliation(s)
- Jae Hoon Shin
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea
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Yi SS. Time-dependent changes of calbindin D-28K and parvalbumin immunoreactivity in the hippocampus of rats with streptozotocin-induced type 1 diabetes. J Vet Sci 2013; 14:373-80. [PMID: 23628656 PMCID: PMC3885729 DOI: 10.4142/jvs.2013.14.4.373] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Accepted: 10/23/2012] [Indexed: 01/30/2023] Open
Abstract
The hippocampus is affected by various stimuli that include hyperglycemia, depression, and ischemia. Calcium-binding proteins (CaBPs) have protective roles in the response to such stimuli. However, little is known about the expression of CaBPs under diabetic conditions. This study was conducted to examine alterations in the physiological parameters with type 1 diabetes induced with streptozotocin (STZ) as well as time-dependent changes in the expression of two CaBPs changes of were being evaluated. Rats treated with STZ (70 mg/kg) had high blood glucose levels (>21.4 mmol/L) along with increased food intake and water consumption volumes compared to the sham controls. In contrast, body weight of the animals treated with STZ was significantly reduced compared to the sham group. CB-specific immunoreactivity was generally increased in the hippocampal CA1 region and granule cell layer of the dentate gyrus (DG) 2 weeks after STZ treatment, but decreased thereafter in these regions. In contrast, the number of PV-immunoreactive neurons and fibers was unchanged in the hippocampus and DG 2 weeks after STZ treatment. However, this number subsequently decreased over time. These results suggest that CB and PV expression is lowest 3 weeks after STZ administration, and these deficits lead to disturbances in calcium homeostasis.
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Affiliation(s)
- Sun Shin Yi
- Department of Biomedical Laboratory Science, College of Biomedical Sciences, Soonchunhyang University, Asan 336-745, Korea.
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Park JK, Lee SJ, Oh CS. Treadmill exercise exerts ameliorating effect on isolation-induced depression via neuronal activation. J Exerc Rehabil 2013; 9:234-42. [PMID: 24278866 PMCID: PMC3836509 DOI: 10.12965/jer.130005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 03/09/2013] [Accepted: 04/10/2013] [Indexed: 12/03/2022] Open
Abstract
Maternal isolation has been used as a valid animal model of early life stress, and it induces depression to offspring. Exercise ameliorates the incidence and severity of stress-related mood disorders, such as depression and anxiety. Here in this study, we investigated the effects of treadmill exercise on brain neuronal excitation in the rat pups with maternal isolation-induced depression. Forced swimming test and immunohistochemistry for glucocorticoid receptor and c-Fos in the hippocampal dentate gyrus and hypothalamic paraventricular nucleus were conducted. Maternal isolation lasted for 6 hours per day and was continued from postnatal day 1 to postnatal day 30. The rat pups in the exercise group were forced to run on a treadmill for 30 min once a day for 10 consecutive days, starting from the postnatal day 21 until the postnatal day 30. In the present results, treadmill exercise alleviated depressive state in the maternal separated rat pups, as potently as fluoxetine treatment. Treadmill exercise also restored the expressions of glucocorticoid receptor and c-Fos in the hippocampal dentate gyrus and hypothalamic paraventricular nucleus of the maternal separated rat pups near to the control level, as fluoxetine treatment. The present study suggests the possibility that treadmill exercise can be used as the therapeutic strategy for the childhood depression induced by disturbed mother-child relationship.
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Affiliation(s)
- Joon-Ki Park
- Division of Exercise and Health Science, Incheon National University, Incheon, Korea
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Roubos EW, Dahmen M, Kozicz T, Xu L. Leptin and the hypothalamo-pituitary-adrenal stress axis. Gen Comp Endocrinol 2012; 177:28-36. [PMID: 22293575 DOI: 10.1016/j.ygcen.2012.01.009] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Revised: 01/10/2012] [Accepted: 01/12/2012] [Indexed: 12/20/2022]
Abstract
Leptin is a 16-kDa protein mainly produced and secreted by white adipose tissue and informing various brain centers via leptin receptor long and short forms about the amount of fat stored in the body. In this way leptin exerts a plethora of regulatory functions especially related to energy intake and metabolism, one of which is controlling the activity of the hypothalamo-pituitary-adrenal (HPA) stress axis. First, this review deals with the basic properties of leptin's structure and signaling at the organ, cell and molecule level, from lower vertebrates to humans but with emphasis on rodents because these have been investigated in most detail. Then, attention is given to the various interactions of adipose leptin with the HPA-axis, at the levels of the hypothalamus (especially the paraventricular nucleus), the anterior lobe of the pituitary gland (action on corticotropes) and the adrenal gland, where it releases corticosteroids needed for adequate stress adaptation. Also, possible local production and autocrine and paracrine actions of leptin at the hypothalamic and pituitary levels of the HPA-axis are being considered. Finally, a schematic model is presented showing the ways peripherally and centrally produced leptin may modulate, via the HPA-axis, stress adaptation in conjunction with the control of energy homeostasis.
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Affiliation(s)
- Eric W Roubos
- Department of Cellular Animal Physiology, Faculty of Science, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, PO Box 9010, 6500 GL Nijmegen, The Netherlands.
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Yi SS, Hwang IK, Kim DW, Shin JH, Nam SM, Choi JH, Lee CH, Won MH, Seong JK, Yoon YS. The chronological characteristics of SOD1 activity and inflammatory response in the hippocampi of STZ-induced type 1 diabetic rats. Neurochem Res 2010; 36:117-28. [PMID: 20924670 DOI: 10.1007/s11064-010-0280-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2010] [Indexed: 12/29/2022]
Abstract
Because it appears that oxidative stress and inflammation are implicated with disease pathogenesis in the diabetic brain, many researchers have used streptozotocin (STZ)-induced diabetic animals to study superoxide production and the effects of superoxide scavengers like Cu,Zn-superoxide dismutase (SOD1). However, many studies have been conducted without considering temporal changes after STZ injection. Interestingly, though SOD activities were not significantly different among the groups, SOD1 and 4-hydroxy-2-nonenal (4-HNE) immunoreactivities were significantly enhanced at 3 weeks after an STZ injection (STZ3w) versus only marginal levels in sham controls, whereas microglial activity was remarkably reduced in injected rats at this time. However, SOD1 immunoreactivity and microglial activities were only at the sham level at STZ4w. The present study provides important information concerning cell damage by ROS generated by STZ. Microglial response was found to be inactivated at STZ3w and neuronal cells (NeuN) showed a non-significant tendency to be reduced in number at STZ4w except in the dentate gyrus. We speculated that the above oxidative stress-related events should be accomplished at STZ3w in the brains of STZ-induced diabetes animal models. Therefore, the aim of the present study was to investigate chronological changes in SOD1 immunoreactivity associated with lipid peroxidation and inflammatory responses in the hippocampi of STZ-induced type I diabetic rats.
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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 151-742, South Korea
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Yi SS, Hwang IK, Shin JH, Choi JH, Lee CH, Kim IY, Kim YN, Won MH, Park IS, Seong JK, Yoon YS. Regulatory mechanism of hypothalamo-pituitary-adrenal (HPA) axis and neuronal changes after adrenalectomy in type 2 diabetes. J Chem Neuroanat 2010; 40:130-9. [PMID: 20472052 DOI: 10.1016/j.jchemneu.2010.05.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2010] [Revised: 05/05/2010] [Accepted: 05/07/2010] [Indexed: 12/24/2022]
Abstract
Diabetes, especially type 2, is closely associated with hypothalamo-pituitary-adrenal (HPA) axis regulation. Short-term effects of adrenalectomy (ADX) in type 2 diabetes are well characterized; however, there have been few reports on the long-term effects of ADX in genetically engineered type 2 diabetes and the neuroendocrine system. We performed bilateral ADX in Zucker Lean Control rats (ZLC; ADX-ZLC), Zucker Diabetic Fatty rats (ZDF; ADX-ZDF), and sham control rats to evaluate how the HPA axis would be regulated in long-term corticosterone deficient type 2 diabetic animals. We evaluated arginine vasopressin (AVP), glucocorticoid receptor (GR), and corticotropin-releasing hormone (CRH) expression with immunohistochemistry (IHC), immunofluorescence, real-time PCR, and Western blot analysis in each treatment group 7 weeks post ADX to assess HPA axis regulatory patterns in connection with type 2 diabetes. Additionally, mRNA expression of AVP and CRH receptors (V1aR, V1bR, CRHR1, and CRHR2) was also measured and adrenocorticotropin hormone (ACTH) immunoreactivity was surveyed by IHC to add to data regarding the regulatory mechanism. AVP and CRH protein expression levels increased after ADX in the hypothalamus of diabetic rats based on IHC results; however, we found that the subtypes of each receptor may be regulated differently in ADX groups compared to sham groups. Immunoreactivity of ACTH in the pituitary gland was enhanced in ADX groups and GR expression levels in the hypothalamic paraventricular nuclei (PVN) remained high, as determined by IHC as well as Western blot analysis. Without the negative feedback system of corticosterone, CRH is highly enhanced and may primarily combine with CRHR1 to stimulate negative feedback through ACTH in the pituitary gland in type 2 diabetic rats with long-term ADX. Although the negative feedback signal was not transmitted appropriately following long-term ADX with type 2 diabetes, a high GR protein level was maintained as in type 2 diabetes. The long-termed lack of corticosterone in the blood stream is a very important factor for normal regulation of the HPA axis even in diabetic animals. From the data, we can conclude that the stimulated HPA axis regulation in the developing type 2 diabetic animals following long-term adrenalectomy has remained elevated rather than diminished. Therefore, the current study may provide useful information to better understand patients suffering from both type 2 diabetes and Addison's disease.
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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 151-742, South Korea
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