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Abolhasani F, Pourshojaei Y, Mohammadi F, Esmaeilpour K, Asadipour A, Ilaghi M, Shabani M. Exploring the potential of a novel phenoxyethyl piperidine derivative with cholinesterase inhibitory properties as a treatment for dementia: Insights from STZ animal model of dementia. Neurosci Lett 2023; 810:137332. [PMID: 37302565 DOI: 10.1016/j.neulet.2023.137332] [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: 04/10/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/13/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease, often characterized by progressive deficits in memory and cognitive functions. Cholinesterase inhibitors have been introduced as promising agents to enhance cognition and memory in both human patients and animal models of AD. In the current study, we assessed the effects of a synthetic phenoxyethyl piperidine derivative, compound 7c, as a novel dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), on learning and memory, as well as serum and hippocampal AChE levels in an animal model of AD. The model of dementia was induced by intracerebroventricular injection of streptozotocin (STZ, 2 mg/kg) to male Wistar rats. STZ-treated rats received compound 7c (3, 30, and 300 µg/kg) for five consecutive days. Passive avoidance (PA) learning and memory, as well as spatial learning and memory using Morris water maze, were evaluated. The level of AChE was measured in the serum and the left and right hippocampus. Findings demonstrated that compound 7c (300 µg/kg) was able to reverse STZ-induced impairments in PA memory, while also reduced the increased AChE level in the left hippocampus. Taken together, compound 7c appeared to act as a central AChE inhibitor, and its role in alleviating cognitive deficits in the AD animal model suggests that it may have therapeutic potential in AD dementia. Further research is required to assess the effectiveness of compound 7c in more reliable models of AD in light of these preliminary findings.
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Affiliation(s)
- Fatemeh Abolhasani
- Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Yaghoub Pourshojaei
- Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran; Extremophile and Productive Microorganisms Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Khadijeh Esmaeilpour
- Department of Physics and Astronomy, University of Waterloo, Waterloo, Ontario, Canada; Institute of Neuropharmacology, Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Asadipour
- Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Mehran Ilaghi
- Institute of Neuropharmacology, Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mohammad Shabani
- Institute of Neuropharmacology, Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.
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2
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Cohen N, Faleschini S, Rifas-Shiman SL, Bouchard L, Doyon M, Simard O, Arguin M, Fink G, Alman AC, Kirby R, Chen H, Wilson R, Fryer K, Perron P, Oken E, Hivert MF. Associations of maternal glucose markers in pregnancy with cord blood glucocorticoids and child hair cortisol levels. J Dev Orig Health Dis 2023; 14:88-95. [PMID: 35801348 PMCID: PMC9825683 DOI: 10.1017/s2040174422000381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Exposure to maternal hyperglycemia in utero has been associated with adverse metabolic outcomes in offspring. However, few studies have investigated the relationship between maternal hyperglycemia and offspring cortisol levels. We assessed associations of gestational diabetes mellitus (GDM) with cortisol biomarkers in two longitudinal prebirth cohorts: Project Viva included 928 mother-child pairs and Gen3G included 313 mother-child pairs. In Project Viva, GDM was diagnosed in N = 48 (5.2%) women using a two-step procedure (50 g glucose challenge test, if abnormal followed by 100 g oral glucose tolerance test [OGTT]), and in N = 29 (9.3%) women participating in Gen3G using one-step 75 g OGTT. In Project Viva, we measured cord blood glucocorticoids and child hair cortisol levels during mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In Gen3G, we measured hair cortisol at 5.4 (0.3) years. We used multivariable linear regression to examine associations of GDM with offspring cortisol, adjusting for child age and sex, maternal prepregnancy body mass index, education, and socioeconomic status. We additionally adjusted for child race/ethnicity in the cord blood analyses. In both Project Viva and Gen3G, we observed null associations of GDM and maternal glucose markers in pregnancy with cortisol biomarkers in cord blood at birth (β = 16.6 nmol/L, 95% CI -60.7, 94.0 in Project Viva) and in hair samples during childhood (β = -0.56 pg/mg, 95% CI -1.16, 0.04 in Project Viva; β = 0.09 pg/mg, 95% CI -0.38, 0.57 in Gen3G). Our findings do not support the hypothesis that maternal hyperglycemia is related to hypothalamic-pituitary-adrenal axis activity.
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Affiliation(s)
- Nathan Cohen
- College of Public Health, University of South Florida, Tampa, FL, USA
| | - Sabrina Faleschini
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Sheryl L. Rifas-Shiman
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Luigi Bouchard
- Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada
- Clinical Department of Laboratory medicine, Centre intégré universitaire de santé et de services sociaux (CIUSSS) du Saguenay–Lac-St-Jean – Hôpital Universitaire de Chicoutimi, Saguenay, Quebec, Canada
| | - Myriam Doyon
- Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Olivier Simard
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada
| | - Melina Arguin
- Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Guy Fink
- Department of Medical Biology, University Health and Social Service Center of the Estrie, Fleurimont, Quebec, Canada
| | - Amy C. Alman
- College of Public Health, University of South Florida, Tampa, FL, USA
| | - Russell Kirby
- College of Public Health, University of South Florida, Tampa, FL, USA
| | - Henian Chen
- College of Public Health, University of South Florida, Tampa, FL, USA
| | - Ronee Wilson
- College of Public Health, University of South Florida, Tampa, FL, USA
| | - Kimberly Fryer
- Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Patrice Perron
- Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
- Department of Medicine, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada
| | - Emily Oken
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Marie-France Hivert
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
- Massachusetts General Hospital, Diabetes Unit, Boston, MA, USA
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3
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Ameliorative Effects of Bifidobacterium animalis subsp. lactis J-12 on Hyperglycemia in Pregnancy and Pregnancy Outcomes in a High-Fat-Diet/Streptozotocin-Induced Rat Model. Nutrients 2022; 15:nu15010170. [PMID: 36615827 PMCID: PMC9824282 DOI: 10.3390/nu15010170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/20/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022] Open
Abstract
Bifidobacterium, a common probiotic, is widely used in the food industry. Hyperglycemia in pregnancy has become a common disease that impairs the health of the mother and can lead to adverse pregnancy outcomes, such as preeclampsia, macrosomia, fetal hyperinsulinemia, and perinatal death. Currently, Bifidobacterium has been shown to have the potential to mitigate glycolipid derangements. Therefore, the use of Bifidobacterium-based probiotics to interfere with hyperglycemia in pregnancy may be a promising therapeutic option. We aimed to determine the potential effects of Bifidobacterium animalis subsp. lactis J-12 (J-12) in high-fat diet (HFD)/streptozotocin (STZ)-induced rats with hyperglycemia in pregnancy (HIP) and respective fetuses. We observed that J-12 or insulin alone failed to significantly improve the fasting blood glucose (FBG) level and oral glucose tolerance; however, combining J-12 and insulin significantly reduced the FBG level during late pregnancy. Moreover, J-12 significantly decreased triglycerides and total cholesterol, relieved insulin and leptin resistance, activated adiponectin, and restored the morphology of the maternal pancreas and hepatic tissue of HIP-induced rats. Notably, J-12 ingestion ameliorated fetal physiological parameters and skeletal abnormalities. HIP-induced cardiac, renal, and hepatic damage in fetuses was significantly alleviated in the J-12-alone intake group, and it downregulated hippocampal mRNA expression of insulin receptor (InsR) and insulin-like growth factor-1 receptor (IGF-1R) and upregulated AKT mRNA on postnatal day 0, indicating that J-12 improved fetal neurological health. Furthermore, placental tissue damage in rats with HIP appeared to be in remission in the J-12 group. Upon exploring specific placental microbiota, we observed that J-12 affected the abundance of nine genera, positively correlating with FBG and leptin in rats and hippocampal mRNA levels of InsR and IGF-1R mRNA in the fetus, while negatively correlating with adiponectin in rats and hippocampal levels of AKT in the fetus. These results suggest that J-12 may affect the development of the fetal central nervous system by mediating placental microbiota via the regulation of maternal-related indicators. J-12 is a promising strategy for improving HIP and pregnancy outcomes.
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Järvinen I, Launes J, Lipsanen J, Virta M, Vanninen R, Lehto E, Schiavone N, Tuulio-Henriksson A, Hokkanen L. No Clinically Relevant Memory Effects in Perinatal Hyperglycemia and Hypoglycemia: A 40-Year Follow-Up of a Small Cohort. Front Public Health 2022; 10:858210. [PMID: 35844845 PMCID: PMC9283869 DOI: 10.3389/fpubh.2022.858210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 06/09/2022] [Indexed: 11/13/2022] Open
Abstract
Maternal diabetes mellitus in pregnancy is associated with impairments in memory functions of the offspring in childhood and adolescence but has not been studied in adulthood. The association of perinatal hypoglycemia with memory has not been studied in adulthood either. The combined sequelae of these two risk factors have not been directly compared. We studied general cognitive ability and memory functions in a prospective follow-up of a cohort born in 1971 to 1974. The sample included participants exposed to prenatal hyperglycemia (n = 24), perinatal hypoglycemia (n = 19), or both (n = 7). It also included controls with no early risks (n = 82). We assessed the participants' Intelligence quotient (IQ), working memory, and immediate and delayed recall of both verbal and visual material at the age of 40. We did not find significant differences in IQ or the memory tests between the groups. We did identify an interaction (p = 0.03) of the early risk with the type of digit span task: compared to the controls, the participants exposed to perinatal hypoglycemia had a larger difference between the forward digit span, a measure of attention, and the backward digit span, a measure of working memory processing (p = 0.022). The interaction remained significant when birth weight was controlled for (p = 0.026). Thus, in this small cohort, prenatal hyperglycemia, perinatal hypoglycemia, and their combination appeared relatively benign disorders. The association of these conditions with neurocognitive impairments in adulthood remains unconfirmed. The significance of the working memory difference needs to be verified with a larger sample.
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Affiliation(s)
- Ilkka Järvinen
- Faculty of Medicine, Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
| | - Jyrki Launes
- Faculty of Medicine, Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
| | - Jari Lipsanen
- Faculty of Medicine, Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
| | - Maarit Virta
- Faculty of Medicine, Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
| | - Ritva Vanninen
- University of Eastern Finland, Institute of Clinical Medicine, Radiology, Kuopio, Finland
- Department of Clinical Radiology, Diagnostic Imaging Center, Kuopio University Hospital, Kuopio, Finland
| | - Eliisa Lehto
- Faculty of Medicine, Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
| | - Nella Schiavone
- Faculty of Medicine, Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
| | | | - Laura Hokkanen
- Faculty of Medicine, Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
- *Correspondence: Laura Hokkanen
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5
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Abstract
This article summarizes the available evidence reporting the relationship between perinatal dysglycemia and long-term neurodevelopment. We review the physiology of perinatal glucose metabolism and discuss the controversies surrounding definitions of perinatal dysglycemia. We briefly review the epidemiology of hypoglycemia and hyperglycemia in fetal, preterm, and term infants. We discuss potential pathophysiologic mechanisms contributing to dysglycemia and its effect on neurodevelopment. We highlight current strategies to prevent and treat dysglycemia in the context of neurodevelopmental outcomes. Finally, we discuss areas of future research and the potential role of continuous glucose monitoring.
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Affiliation(s)
- Megan E Paulsen
- Department of Pediatrics, University of Minnesota Medical School, Academic Office Building, 2450 Riverside Avenue S AO-401, Minneapolis, MN 55454, USA; Masonic Institute for the Developing Brain, 2025 East River Parkway, Minneapolis, MN 55414.
| | - Raghavendra B Rao
- Department of Pediatrics, University of Minnesota Medical School, Academic Office Building, 2450 Riverside Avenue S AO-401, Minneapolis, MN 55454, USA; Masonic Institute for the Developing Brain, 2025 East River Parkway, Minneapolis, MN 55414
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Luo SS, Zou KX, Zhu H, Cheng Y, Yan YS, Sheng JZ, Huang HF, Ding GL. Integrated Multi-Omics Analysis Reveals the Effect of Maternal Gestational Diabetes on Fetal Mouse Hippocampi. Front Cell Dev Biol 2022; 10:748862. [PMID: 35237591 PMCID: PMC8883435 DOI: 10.3389/fcell.2022.748862] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 01/19/2022] [Indexed: 11/25/2022] Open
Abstract
Growing evidence suggests that adverse intrauterine environments could affect the long-term health of offspring. Recent evidence indicates that gestational diabetes mellitus (GDM) is associated with neurocognitive changes in offspring. However, the mechanism remains unclear. Using a GDM mouse model, we collected hippocampi, the structure critical to cognitive processes, for electron microscopy, methylome and transcriptome analyses. Reduced representation bisulfite sequencing (RRBS) and RNA-seq in the GDM fetal hippocampi showed altered methylated modification and differentially expressed genes enriched in common pathways involved in neural synapse organization and signal transmission. We further collected fetal mice brains for metabolome analysis and found that in GDM fetal brains, the metabolites displayed significant changes, in addition to directly inducing cognitive dysfunction, some of which are important to methylation status such as betaine, fumaric acid, L-methionine, succinic acid, 5-methyltetrahydrofolic acid, and S-adenosylmethionine (SAM). These results suggest that GDM affects metabolites in fetal mice brains and further affects hippocampal DNA methylation and gene regulation involved in cognition, which is a potential mechanism for the adverse neurocognitive effects of GDM in offspring.
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Affiliation(s)
- Si-Si Luo
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Ke-Xin Zou
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Hong Zhu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Yi Cheng
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Yi-Shang Yan
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Jian-Zhong Sheng
- The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - He-Feng Huang
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.,Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China.,The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Guo-Lian Ding
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China
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Peyvandi Karizbodagh M, Sadr-Nabavi A, Hami J, Mohammadipour A, Khoshdel-Sarkarizi H, Kheradmand H, Fallahnezhad S, Mahmoudi M, Haghir H. Developmental regulation and lateralization of N-methyl-d-aspartate (NMDA) receptors in the rat hippocampus. Neuropeptides 2021; 89:102183. [PMID: 34333368 DOI: 10.1016/j.npep.2021.102183] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 07/25/2021] [Accepted: 07/25/2021] [Indexed: 12/01/2022]
Abstract
N-methyl-d-aspartate receptors (NMDARs) are expressed abundantly in the brain and play a crucial role in the regulation of central nervous system (CNS) development, learning, and memory. During early neuronal development, NMDARs modulate neurogenesis, neuronal differentiation and migration, and synaptogenesis. The present study aimed to examine the developmental expression of NMDARs subunits, NR1 and NR2B, in the developing hippocampus of neonatal rats during the first two postnatal weeks. Fifty-four male offspring were randomly divided into three age groups, postnatal days (P) 0, 7, and 14. Real-time-PCR, western blotting, and immunohistochemistry (IHC) analyses were employed to examine and compare the hippocampal expression of the NMDA receptor subunits. The highest mRNA expression of NR1 and NR2B subunits was observed at P7, regardless of its laterality. The mRNA expression of both subunits in the right hippocampus was significantly higher than that of the left one at P0 and P7. Similarly, the highest protein level expression of NR1 and NR2B subunits was also observed at P7 in both sides hippocampi. Although the protein expression of NR1 was significantly higher on the right side in all studied days, the NR2B was significantly higher in the right hippocampus only at P7. The analysis of optical density (OD) has shown a marked increase in the distribution pattern of the NR1 and NR2B subunits at P7 in all hippocampal subregions. In conclusion, there is a marked right-left asymmetry in the expression of NR1 and NR2B subunits in the developing rat hippocampus, which might be considered as a probable mechanism for the lateral differences in the structure and function of the hippocampus in rats.
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Affiliation(s)
- Mostafa Peyvandi Karizbodagh
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ariane Sadr-Nabavi
- Medical Genetic Research Center (MGRC), School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Hami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran; Institute of Anatomy and Cell Biology, Universitäsmedizin Greifswald, 17487 Greifswald, Germany
| | - Abbas Mohammadipour
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hoda Khoshdel-Sarkarizi
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Kheradmand
- Hazrat Rasoul Hospital, Department of Neurosurgery, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Somaye Fallahnezhad
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Research Center, School of Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Haghir
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetic Research Center (MGRC), School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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8
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Intrauterine hyperglycemia impairs memory across two generations. Transl Psychiatry 2021; 11:434. [PMID: 34417446 PMCID: PMC8379206 DOI: 10.1038/s41398-021-01565-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/27/2021] [Accepted: 08/10/2021] [Indexed: 12/22/2022] Open
Abstract
Studies on humans and animals suggest associations between gestational diabetes mellitus (GDM) with increased susceptibility to develop neurological disorders in offspring. However, the molecular mechanisms underpinning the intergenerational effects remain unclear. Using a mouse model of diabetes during pregnancy, we found that intrauterine hyperglycemia exposure resulted in memory impairment in both the first filial (F1) males and the second filial (F2) males from the F1 male offspring. Transcriptome profiling of F1 and F2 hippocampi revealed that differentially expressed genes (DEGs) were enriched in neurodevelopment and synaptic plasticity. The reduced representation bisulfite sequencing (RRBS) of sperm in F1 adult males showed that the intrauterine hyperglycemia exposure caused altered methylated modification of F1 sperm, which is a potential epigenetic mechanism for the intergenerational neurocognitive effects of GDM.
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Sardar R, Hami J, Soleimani M, Joghataei MT, Shirazi R, Golab F, Namjoo Z, Zandieh Z. Maternal diabetes-induced alterations in the expression of brain-derived neurotrophic factor in the developing rat hippocampus. J Chem Neuroanat 2021; 114:101946. [PMID: 33745942 DOI: 10.1016/j.jchemneu.2021.101946] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/19/2021] [Accepted: 03/04/2021] [Indexed: 01/06/2023]
Abstract
Maternal diabetes during pregnancy affects the development of hippocampus in the offspring. Brain-derived neurotrophic factor (BDNF) has received increasing attention for its role in regulating the survival and differentiation of neuronal cells in developing and adult brain. In the current study, we evaluated the effects of maternal diabetes and insulin treatment on expression and distribution pattern of BDNF in the hippocampus of neonatal rats at the first two postnatal weeks. We found no differences in hippocampal expression of BDNF between diabetics with normal control or insulin treated neonatal rats at postnatal day (P0) (P > 0.05 each). Nevertheless, there was a marked BDNF downregulation in both sides' hippocampi of male/female diabetic group in two-week-old offspring (P ≤ 0.05 each). Furthermore, the numerical density of BDNF+ cells was significantly reduced in the right/left dentate gyrus (DG) of male and female newborns born to diabetic animals at all studied postnatal days (P ≤ 0.05 each). In addition, a lower number of reactive cells have shown in the all hippocampal subareas in the diabetic pups at P14 (P ≤ 0.05 each). Our results have demonstrated that the insulin-treatment improves some of the negative impacts of diabetes on the expression of hippocampal BDNF in the newborns. We conclude that diabetes in pregnancy bilaterally disrupts the expression of BDNF in the hippocampus of the both male and female newborns at early postnatal days. In addition, good glycemic control by insulin in the most cases is sufficient to prevent the alterations in expression of BDNF protein in developing hippocampus.
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Affiliation(s)
- Reza Sardar
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Javad Hami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran; Institute for Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Mansoureh Soleimani
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Mohammad-Taghi Joghataei
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Shirazi
- Department of Anatomy, School of Medical Sciences, Medicine & Health, UNSW Sydney, Sydney, Australia
| | - Fereshteh Golab
- Cellular and Molecular Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Namjoo
- Department of Anatomical Science, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Zahra Zandieh
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran; Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran University of Medical Science, Tehran, Iran.
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10
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A Neonatal Mild Defect in Brain Insulin Signaling Predisposes a Subclinical Model of Sporadic Alzheimer's to Develop the Disease. J Mol Neurosci 2021; 71:1473-1484. [PMID: 33492616 DOI: 10.1007/s12031-021-01797-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/11/2021] [Indexed: 10/22/2022]
Abstract
Brain insulin system dysfunction has been proposed as a key player in the pathogenesis of sporadic Alzheimer's disease (sAD). Given this fact, an adult rat model for sAD has been developed by intracerebroventricular injection of a subdiabetogenic streptozotocin dosage (icv-STZ). A low dose of icv-STZ in adult rats leads to a subclinical model of Alzheimer's disease. According to the brain developmental origin for sAD occurrence, the present study evaluated the effect of neonatal injection of icv-STZ on the development and progression of Alzheimer's disease later in the adult animals treated with a low dose of icv-STZ. Although no alteration was observed in the rats receiving an adult low dose of icv-STZ, these animals displayed cognitive deficits if they were also treated neonatally with icv-STZ. These impairments were associated with altered gene expression of insulin receptor, tau and choline acetyltransferase, along with increased astrocyte and dark neuron densities in the hippocampus. This study highlights neonatal brain insulin system dysfunction in the programming of brain insulin signaling sensitivity and provides more evidence for the developmental origin of sAD.
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11
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Abbasi F, Baradaran R, Khoshdel-Sarkarizi H, Kargozar S, Hami J, Mohammadipour A, Kheradmand H, Haghir H. Distribution pattern of nicotinic acetylcholine receptors in developing cerebellum of rat neonates born of diabetic mothers. J Chem Neuroanat 2020; 108:101819. [PMID: 32522497 DOI: 10.1016/j.jchemneu.2020.101819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 05/25/2020] [Accepted: 05/28/2020] [Indexed: 11/15/2022]
Affiliation(s)
- Faeze Abbasi
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran
| | - Raheleh Baradaran
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran
| | - Hoda Khoshdel-Sarkarizi
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran
| | - Saeid Kargozar
- Tissue Engineering Research Group (TERG), Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Hami
- Department of Anatomical Sciences, School of Medicine, BirjandUniversity of Medical Sciences, Birjand, Iran
| | - Abbas Mohammadipour
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran
| | - Hamed Kheradmand
- Hazrat Rasoul Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Haghir
- Department of Anatomy and cell Biology, School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran; Medical Genetic Research Center (MGRC), School of Medicine, MashhadUniversity of Medical Sciences, Mashhad, Iran.
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12
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Głombik K, Trojan E, Kurek A, Budziszewska B, Basta-Kaim A. Inflammatory Consequences of Maternal Diabetes on the Offspring Brain: a Hippocampal Organotypic Culture Study. Neurotox Res 2019; 36:357-375. [PMID: 31197747 PMCID: PMC6616224 DOI: 10.1007/s12640-019-00070-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 05/10/2019] [Accepted: 05/28/2019] [Indexed: 01/09/2023]
Abstract
Gestational diabetes is a disorder associated with abnormal chronic inflammation that poses a risk to the developing fetus. We investigated the effects of experimentally induced diabetes (streptozotocin model) in Wistar female rats on the inflammatory status of the hippocampi of their offspring. Additionally, the impact of antidiabetic drugs (metformin and glyburide) on inflammatory processes was evaluated. Organotypic hippocampal cultures (OHCs) were prepared from the brains of the 7-day-old rat offspring of control and diabetic mother rats. On the 7th day in vitro, the cultures were pretreated with metformin (3 μM) or glyburide (1 μM) and then stimulated for 24 h with lipopolysaccharide (LPS, 1 μg/ml). The OHCs obtained from the offspring of diabetic mothers were characterized by the increased mortality of cells and an enhanced susceptibility to damage caused by LPS. Although we showed that LPS stimulated the secretion of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in the control and diabetic cultures, the levels of IL-1β and IL-6 in the OHC medium obtained from the offspring of diabetic mothers were more pronounced. In the diabetic cultures, enhanced levels of TLR-4 and the overactivation of the NLRP3 inflammasome were demonstrated. Metformin and glyburide pretreatment normalized the LPS-induced IL-1β secretion in the control and diabetic cultures. Furthermore, glyburide diminished both: LPS-induced IL-6 and TNF-α secretion in the control and diabetic cultures and increased NF-κB p65 subunit phosphorylation. Glyburide also diminished the levels of the NLRP3 subunit and caspase-1, but only in the diabetic cultures. The results showed that maternal diabetes affected inflammatory processes in the offspring brain and increased hippocampal sensitivity to the LPS-induced inflammatory response. The use of antidiabetic agents, especially glyburide, had a beneficial impact on the changes caused by maternal diabetes.
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Affiliation(s)
- Katarzyna Głombik
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343, Kraków, Poland.
| | - Ewa Trojan
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343, Kraków, Poland
| | - Anna Kurek
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343, Kraków, Poland
| | - Bogusława Budziszewska
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343, Kraków, Poland
| | - Agnieszka Basta-Kaim
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343, Kraków, Poland
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13
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Late Cognitive Consequences of Gestational Diabetes to the Offspring, in a New Mouse Model. Mol Neurobiol 2019; 56:7754-7764. [PMID: 31115777 DOI: 10.1007/s12035-019-1624-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 04/24/2019] [Indexed: 12/17/2022]
Abstract
Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during gestation, which affects approximately 10% of pregnant women. Although previously considered a transient condition with few long-term consequences, growing evidence suggest that GD may be linked to permanent metabolic and neurologic changes in the offspring. Currently available GD models fail to recapitulate the full spectrum of this disease, thus providing limited information about the true burden of this condition. Here, we describe a new mouse model of GD, based on the administration of an insulin receptor antagonist (S961, 30 nmol/kg s.c. daily) during pregnancy. Pregnant mice developed increased fasting glycemia and glucose intolerance in the absence of maternal obesity, with a return to normoglycemia shortly after parturition. Moreover, we showed that the adult offspring of GD dams presented pronounced metabolic and cognitive dysfunction when exposed to short-term high-fat diet (HFD). Our data demonstrate that S961 administration to pregnant mice comprises a valuable approach to study the complex pathophysiology of GD, as well as strategies focused on prevention and treatment of both the mother and the offspring. Our findings suggest that the offspring of GD mothers are more susceptible to metabolic and cognitive impairments when exposed to high-fat diet later in life, thus indicating that approaches to prevent and treat these late effects should be pursued.
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14
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Sadeghi A, Esfandiary E, Hami J, Khanahmad H, Hejazi Z, Mardani M, Razavi S. The effects of maternal diabetes and insulin treatment on neurogenesis in the developing hippocampus of male rats. J Chem Neuroanat 2018; 91:27-34. [DOI: 10.1016/j.jchemneu.2018.03.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/17/2018] [Accepted: 03/21/2018] [Indexed: 12/19/2022]
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15
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De Sousa RAL. Gestational diabetes is associated to the development of brain insulin resistance in the offspring. Int J Diabetes Dev Ctries 2018. [DOI: 10.1007/s13410-018-0618-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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16
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Márquez-Valadez B, Valle-Bautista R, García-López G, Díaz NF, Molina-Hernández A. Maternal Diabetes and Fetal Programming Toward Neurological Diseases: Beyond Neural Tube Defects. Front Endocrinol (Lausanne) 2018; 9:664. [PMID: 30483218 PMCID: PMC6243582 DOI: 10.3389/fendo.2018.00664] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/25/2018] [Indexed: 12/20/2022] Open
Abstract
The purpose of this review was to search for experimental or clinical evidence on the effect of hyperglycemia in fetal programming to neurological diseases, excluding evident neural tube defects. The lack of timely diagnosis and the inadequate control of diabetes during pregnancy have been related with postnatal obesity, low intellectual and verbal coefficients, language and motor deficits, attention deficit with hyperactivity, problems in psychosocial development, and an increased predisposition to autism and schizophrenia. It has been proposed that several childhood or adulthood diseases have their origin during fetal development through a phenomenon called fetal programming. However, not all the relationships between the outcomes mentioned above and diabetes during gestation are clear, well-studied, or have been related to fetal programming. To understand this relationship, it is imperative to understand how developmental processes take place in health, in order to understand how the functional cytoarchitecture of the central nervous system takes place; to identify changes prompted by hyperglycemia, and to correlate them with the above postnatal impaired functions. Although changes in the establishment of patterns during central nervous system fetal development are related to a wide variety of neurological pathologies, the mechanism by which several maternal conditions promote fetal alterations that contribute to impaired neural development with postnatal consequences are not clear. Animal models have been extremely useful in studying the effect of maternal pathologies on embryo and fetal development, since obtaining central nervous system tissue in humans with normal appearance during fetal development is an important limitation. This review explores the state of the art on this topic, to help establish the way forward in the study of fetal programming under hyperglycemia and its impact on neurological and psychiatric disorders.
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Affiliation(s)
- Berenice Márquez-Valadez
- Department of Physiology and Cell Development, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City, Mexico
- Department of Physiology, Biophysics and Neurosciences, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - Rocío Valle-Bautista
- Department of Physiology and Cell Development, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City, Mexico
- Department of Physiology, Biophysics and Neurosciences, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - Guadalupe García-López
- Department of Physiology and Cell Development, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City, Mexico
| | - Néstor Fabián Díaz
- Department of Physiology and Cell Development, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City, Mexico
| | - Anayansi Molina-Hernández
- Department of Physiology and Cell Development, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City, Mexico
- *Correspondence: Anayansi Molina-Hernández
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17
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A transient insulin system dysfunction in newborn rat brain followed by neonatal intracerebroventricular administration of streptozotocin could be accompanied by a labile cognitive impairment. Neurosci Res 2017; 132:17-25. [PMID: 29055675 DOI: 10.1016/j.neures.2017.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 09/16/2017] [Accepted: 10/06/2017] [Indexed: 01/22/2023]
Abstract
The early postnatal period is a critical period of hippocampus development, which is highly dependent on insulin receptor (IR) signaling and very important in cognitive function. The present study was conducted in order to present a model of neonatal transient brain insulin system dysfunction through finding an appropriate dose of injection of streptozotocin (STZ) during the neonatal period. Sixty male Wistar rat pups were divided into 4 groups of 15 and received intracerebroventricular saline or STZ (icv-STZ) (15, 20 and 25μg/kg) on postnatal day 7. Gene expression of IR and target genes for IR signaling (choline acetyltransferase (ChAT) and Tau) were measured at the ages of 2 and 7 weeks. Behavioral tests were performed at the ages of 3 and 6 weeks to assess short- and long-term cognitive function. 20μg/kg dose of icv-STZ was estimated as the optimal dose causing transient alteration in gene expression of IR, ChAT and Tau. Additionally, cognitive function of the animals restored to normal level at the age of 6 weeks. Therefore, 20μg/kg dose of icv-STZ is proposed as a new approach to generating transient brain insulin system dysfunction associated with transient cognitive impairments at a critical postnatal period of brain development.
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18
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Sousa RALDE, Torres YS, Figueiredo CP, Passos GF, Clarke JR. Consequences of gestational diabetes to the brain and behavior of the offspring. AN ACAD BRAS CIENC 2017; 90:2279-2291. [PMID: 28813108 DOI: 10.1590/0001-3765201720170264] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 05/30/2017] [Indexed: 01/11/2023] Open
Abstract
Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during the second/third trimesters of pregnancy in previously normoglycemic women. It is currently estimated that 10% of all pregnancies in the United States show this condition. For many years, the transient nature of GD has led researchers and physicians to assume that long-term consequences were absent. However, GD diagnosis leads to a six-fold increase in the risk of developing type 2 diabetes (T2D) in women and incidence of obesity and T2D is also higher among their infants. Recent and concerning evidences point to detrimental effects of GD on the behavior and cognition of the offspring, which often persist until adolescence or adulthood. Considering that the perinatal period is critical for determination of adult behavior, it is expected that the intra-uterine exposure to hyperglycemia, hyperinsulinemia and pro-inflammatory mediators, hallmark features of GD, might affect brain development. Here, we review early clinical and experimental evidence linking GD to consequences on the behavior of the offspring, focusing on memory and mood disorders. We also discuss initial evidence suggesting that downregulation of insulin signaling cascades are seen in the brains of GD offspring and could contribute to the consequences on their behavior.
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Affiliation(s)
- Ricardo A L DE Sousa
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Yasmin S Torres
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Claudia P Figueiredo
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Giselle F Passos
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Julia R Clarke
- School of Pharmacy, Carlos Chagas Filho Street, 373, Building A, Underground, Room 024, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil
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19
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Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring. Mol Neurodegener 2017; 12:57. [PMID: 28768549 PMCID: PMC5541692 DOI: 10.1186/s13024-017-0198-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 07/24/2017] [Indexed: 12/11/2022] Open
Abstract
Background Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Among these, chronic central complications in DMO remain poorly understood, and in extreme cases, diabetes can essentially function as a gestational brain insult. Nevertheless, therapeutic alternatives for DMO are limited. Methods Therefore, we have analyzed the central long-term complications in the offspring from CD1 diabetic mothers treated with streptozotozin, as well as the possible reversion of these alterations by insulin administration to neonates. Brain atrophy, neuronal morphology, tau phosphorylation, proliferation and neurogenesis were assessed in the short term (P7) and in the early adulthood (10 weeks) and cognitive function was also analyzed in the long-term. Results Central complications in DMO were still detected in the adulthood, including cortical and hippocampal thinning due to synaptic loss and neuronal simplification, increased tau hyperphosphorylation, and diminished cell proliferation and neurogenesis. Additionally, maternal diabetes increased the long-term susceptibility to spontaneous central bleeding, inflammation and cognition impairment in the offspring. On the other hand, intracerebroventricular insulin administration to neonates significantly reduced observed alterations. Moreover, non-invasive intranasal insulin reversed central atrophy and tau hyperphosphorylation, and rescued central proliferation and neurogenesis. Vascular damage, inflammation and cognitive alterations were also comparable to their counterparts born to nondiabetic mice, supporting the utility of this pathway to access the central nervous system. Conclusions Our data underlie the long-term effects of central complications in DMO. Moreover, observed improvement after insulin treatment opens the door to therapeutic alternatives for children who are exposed to poorly controlled gestational diabetes, and who may benefit from more individualized treatments.
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Haghir H, Hami J, Lotfi N, Peyvandi M, Ghasemi S, Hosseini M. Expression of apoptosis-regulatory genes in the hippocampus of rat neonates born to mothers with diabetes. Metab Brain Dis 2017; 32:617-628. [PMID: 28078553 DOI: 10.1007/s11011-017-9950-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 01/03/2017] [Indexed: 01/01/2023]
Abstract
Diabetes during pregnancy impairs the development of the central nervous system (CNS) and causes cognitive and behavioral abnormalities in offspring. However, the exact mechanism by which the maternal diabetes affects the development of the brain remains to be elucidated. The aim of the present study was to investigate the effects of maternal diabetes in pregnancy on the expression of Bcl-2 and Bax genes and the numerical density of degenerating dark neurons (DNs) in the hippocampus of offspring at the first postnatal two weeks. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was sacrificed at P0, P7, and P14. Our findings demonstrated a significant down-regulation in the hippocampal expression of Bcl-2 in the diabetic group newborns (P < 0.05). In contrast, the mRNA expression of Bax was markedly up-regulated in the offspring born to diabetic dams at all of studied time-points (P < 0.05). Moreover, we found a striking increase in the numerical density of DNs in the various subfields of hippocampus of diabetic group pups (P < 0.05). The results of the present study revealed that maternal hyperglycemia during gestational period may result in disturbances in the expression of Bcl-2 and Bax genes as two important genes in neuronal apoptosis regulation and induces the production of DNs in the developing hippocampus of neonatal rats. These disturbances may be a reason for the cognitive, structural, and behavioral anomalies observed in offspring born to diabetic mothers. Furthermore, the control of maternal glycaemia by insulin administration in most cases normalized these negative impacts.
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Affiliation(s)
- Hossein Haghir
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetic Research Center (MGRC), School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Hami
- Department of Anatomical Sciences, School of Medicine, Birjand University of Medical Sciences, Ghaffari St., Birjand, Iran.
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
| | - Nassim Lotfi
- Department of Anatomical Sciences, School of Medicine, Birjand University of Medical Sciences, Ghaffari St., Birjand, Iran
| | - Mostafa Peyvandi
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Simagol Ghasemi
- Microanatomy Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Hosseini
- Department of Public Health, Deputy of Research and Technology, Research Centre of Experimental Medicine, Birjand University of Medical Sciences, Birjand, Iran
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21
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Hlavica M, Delparente A, Good A, Good N, Plattner PS, Seyedsadr MS, Schwab ME, Figlewicz DP, Ineichen BV. Intrathecal insulin-like growth factor 1 but not insulin enhances myelin repair in young and aged rats. Neurosci Lett 2017; 648:41-46. [PMID: 28363754 DOI: 10.1016/j.neulet.2017.03.047] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 03/16/2017] [Accepted: 03/28/2017] [Indexed: 12/29/2022]
Abstract
One main pathological hallmark of multiple sclerosis (MS) is demyelination. Novel therapies which enhance myelin repair are urgently needed. Insulin and insulin-like growth factor 1 (IGF-1) have strong functional relationships. Here, we addressed the potential capacity of IGF-1 and insulin to enhance remyelination in an animal demyelination model in vivo. We found that chronic intrathecal infusion of IGF-1 enhanced remyelination after lysolecithin-induced demyelination in the spinal cord of young and aged rats. Aged rats showed a weaker innate remyelination capacity and are therefore a good model for progressive MS which is defined by chronic demyelination. In contrast to IGF-1, Insulin had no effect on remyelination in either age group. Our findings highlight the potential use of IGF-1 as remyelinating therapy for MS, particularly the progressive stage in which chronic demyelination is the hallmark.
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Affiliation(s)
- Martin Hlavica
- Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, ETH Zurich, 8057 Zurich, Switzerland; Cantonal Hospital St.Gallen, Department of Neurosurgery, Switzerland
| | - Aro Delparente
- Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, ETH Zurich, 8057 Zurich, Switzerland
| | - Andrin Good
- Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, ETH Zurich, 8057 Zurich, Switzerland
| | - Nicolas Good
- Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, ETH Zurich, 8057 Zurich, Switzerland
| | - Patricia S Plattner
- Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, ETH Zurich, 8057 Zurich, Switzerland
| | - Maryam S Seyedsadr
- Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, ETH Zurich, 8057 Zurich, Switzerland
| | - Martin E Schwab
- Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, ETH Zurich, 8057 Zurich, Switzerland
| | - Dianne P Figlewicz
- VA Puget Sound Health Care System, University of Washington, Seattle, WA, USA
| | - Benjamin V Ineichen
- Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, ETH Zurich, 8057 Zurich, Switzerland; University Hospital Zurich, Department of Neurology, 8091 Zurich, Switzerland.
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Kruse MS, Suarez LG, Coirini H. Regulation of the expression of LXR in rat hypothalamic and hippocampal explants. Neurosci Lett 2017; 639:53-58. [DOI: 10.1016/j.neulet.2016.12.065] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/16/2016] [Accepted: 12/26/2016] [Indexed: 01/08/2023]
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Hami J, Vafaei-Nezhad S, Sadeghi A, Ghaemi K, Taheri MMH, Fereidouni M, Ivar G, Hosseini M. Synaptogenesis in the Cerebellum of Offspring Born to Diabetic Mothers. J Pediatr Neurosci 2017; 12:215-221. [PMID: 29204194 PMCID: PMC5696656 DOI: 10.4103/jpn.jpn_144_16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
There is increasing evidence that maternal diabetes mellitus during the pregnancy is associated with a higher risk of neurodevelopmental and neurofunctional anomalies including motor dysfunctions, learning deficits, and behavioral problems in offspring. The cerebellum is a part of the brain that has long been recognized as a center of movement balance and motor coordination. Moreover, recent studies in humans and animals have also implicated the cerebellum in cognitive processing, sensory discrimination, attention, and learning and memory. Synaptogenesis is one of the most crucial events during the development of the central nervous system. Synaptophysin (SYP) is an integral membrane protein of synaptic vesicles and is considered to be a marker for synaptic density and synaptogenesis. Here, we review the manuscripts focusing on the negative impacts of maternal diabetes in pregnancy on the expression or localization of SYP in the developing cerebellar cortex. We believe that the alteration in synaptogenesis or synapse density may be part of the cascade of events through which diabetes in pregnant women affects the newborn's cerebellum.
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Affiliation(s)
- Javad Hami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.,Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Vafaei-Nezhad
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.,Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Akram Sadeghi
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.,Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Kazem Ghaemi
- Department of Neurosurgery, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Mohammad Fereidouni
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.,Department of Immunology, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Ghasem Ivar
- Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mehran Hosseini
- Department of Public Health, Research Centre of Experimental Medicine, Birjand University of Medical Sciences, Birjand, Iran
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24
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Hami J, Vafaei-Nezhad S, Ivar G, Sadeghi A, Ghaemi K, Mostafavizadeh M, Hosseini M. Altered expression and localization of synaptophysin in developing cerebellar cortex of neonatal rats due to maternal diabetes mellitus. Metab Brain Dis 2016; 31:1369-1380. [PMID: 27389246 DOI: 10.1007/s11011-016-9864-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Accepted: 06/28/2016] [Indexed: 12/30/2022]
Abstract
There is sufficient evidence that diabetes during pregnancy is associated with a higher risk of neurodevelopmental anomalies including learning deficits, behavioral problems and motor dysfunctions in the offspring. Synaptophysin (SYP) is an integral membrane protein of synaptic vesicles and is considered as a marker for synaptogenesis and synaptic density. This study aimed to examine the effects of maternal diabetes in pregnancy on the expression and localization of SYP in the developing rat cerebellum. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was euthanized at postnatal day (P) 0, 7, and 14. The results revealed a significant down-regulation in the mRNA expression of SYP in the offspring born to diabetic animals at both P7 and P14 (P < 0.05 each). One week after birth, there was a significant reduction in the localization of SYP expression in the external granular (EGL) and in the molecular (ML) layers of neonates born to diabetic animals (P < 0.05 each). We also found a marked decrease in the expression of SYP in all of the cerebellar cortical layers of STZ-D group pups at P14 (P < 0.05 each). Moreover, our results revealed no significant changes in either expression or localization of SYP in insulin-treated group pups when compared with the controls (P ≥ 0.05 each). The present study demonstrated that maternal diabetes has adverse effects on the synaptogenesis in the offspring's cerebellum. Furthermore, the rigid maternal blood glucose control in the most cases normalized these negative impacts.
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Affiliation(s)
- Javad Hami
- Department of Anatomical Sciences, School of Medicine, Birjand University of Medical Sciences, Ghaffari St, Birjand, Iran
| | - Saeed Vafaei-Nezhad
- Department of Anatomical Sciences, School of Medicine, Birjand University of Medical Sciences, Ghaffari St, Birjand, Iran.
| | - Ghasem Ivar
- Department of Anatomical Sciences, School of Medicine, Birjand University of Medical Sciences, Ghaffari St, Birjand, Iran
| | - Akram Sadeghi
- Department of Anatomy and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Kazem Ghaemi
- Department of Neurosurgery, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Mehran Hosseini
- Department of Public Health, Deputy of Research and Technology, Research Centre of Experimental Medicine, Birjand University of Medical Sciences, Birjand, Iran
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25
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Hami J, Vafaei-Nezhad S, Ghaemi K, Sadeghi A, Ivar G, Shojae F, Hosseini M. Stereological study of the effects of maternal diabetes on cerebellar cortex development in rat. Metab Brain Dis 2016; 31:643-52. [PMID: 26842601 DOI: 10.1007/s11011-016-9802-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 01/27/2016] [Indexed: 10/22/2022]
Abstract
Diabetes during pregnancy is associated with the deficits in balance and motor coordination and altered social behaviors in offspring. In the present study, we have investigated the effect of maternal diabetes and insulin treatment on the cerebellar volume and morphogenesis of the cerebellar cortex of rat neonates during the first two postnatal weeks. Sprague Dawley female rats were maintained diabetic from a week before pregnancy through parturition. At the end of pregnancy, the male offspring euthanized on postnatal days (P) 0, 7, and 14. Cavalieri's principle and fractionator methods were used to estimate the cerebellar volume, the thickness and the number of cells in the different layers of the cerebellar cortex. In spite of P0, there was a significant reduction in the cerebellar volume and the thickness of the external granule, molecular, and internal granule layers between the diabetic and the control animals. In diabetic group, the granular and purkinje cell densities were increased at P0. Moreover, the number of granular and purkinje cells in the cerebellum of diabetic neonates was reduced in comparison with the control group at P7 and P14. There were no significant differences in either the volume and thickness or the number of cells in the different layers of the cerebellar cortex between the insulin-treated diabetic group and controls. Our data indicate that diabetes in pregnancy disrupts the morphogenesis of cerebellar cortex. This dysmorphogenesis may be part of the cascade of events through which diabetes during pregnancy affects motor coordination and social behaviors in offspring.
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Affiliation(s)
- Javad Hami
- Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Vafaei-Nezhad
- Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Kazem Ghaemi
- Department of Neurosurgery, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Akram Sadeghi
- Department of Anatomy and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ghasem Ivar
- Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Fatemeh Shojae
- Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mehran Hosseini
- Department of Public Health, Research Centre of Experimental Medicine, Deputy of Research and Technology, Birjand University of Medical Sciences, Birjand, Iran.
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Diabetes during pregnancy enhanced neuronal death in the hippocampus of rat offspring. Int J Dev Neurosci 2016; 51:28-35. [DOI: 10.1016/j.ijdevneu.2016.04.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 03/29/2016] [Accepted: 04/20/2016] [Indexed: 12/30/2022] Open
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The impacts of diabetes in pregnancy on hippocampal synaptogenesis in rat neonates. Neuroscience 2016; 318:122-33. [DOI: 10.1016/j.neuroscience.2016.01.025] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 12/28/2015] [Accepted: 01/11/2016] [Indexed: 11/21/2022]
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Hami J, Kerachian MA, Karimi R, Haghir H, Sadr-Nabavi A. Effects of streptozotocin-induced type 1 maternal diabetes on PI3K/AKT signaling pathway in the hippocampus of rat neonates. J Recept Signal Transduct Res 2015; 36:254-60. [DOI: 10.3109/10799893.2015.1086884] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Insulin-Like Growth Factor-1 Receptor Is Differentially Distributed in Developing Cerebellar Cortex of Rats Born to Diabetic Mothers. J Mol Neurosci 2015; 58:221-32. [DOI: 10.1007/s12031-015-0661-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 09/30/2015] [Indexed: 01/04/2023]
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Hami J, Karimi R, Haghir H, Gholamin M, Sadr-Nabavi A. Diabetes in Pregnancy Adversely Affects the Expression of Glycogen Synthase Kinase-3β in the Hippocampus of Rat Neonates. J Mol Neurosci 2015; 57:273-81. [PMID: 26242887 DOI: 10.1007/s12031-015-0617-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 07/07/2015] [Indexed: 12/18/2022]
Abstract
Diabetes during pregnancy causes a wide range of neurodevelopmental and neurocognitive abnormalities in offspring. Glycogen synthase kinase-3 (GSK-3) is widely expressed during brain development and regulates multiple cellular processes, and its dysregulation is implicated in the pathogenesis of diverse neurodegenerative and psychological diseases. This study was designed to examine the effects of maternal diabetes on GSK-3β messenger RNA (mRNA) expression and phosphorylation in the developing rat hippocampus. Female rats were maintained diabetic from a week before pregnancy through parturition, and male offspring was killed immediately after birth. We found a significant bilateral upregulation of GSK-3β mRNA expression in the hippocampus of pups born to diabetic mothers at P0, compared to controls. Moreover, at the same time point, there was a marked bilateral increase in the phosphorylation level of GSK-3β in the diabetic group. Unlike phosphorylation levels, there was a significant upregulation in hippocampal GSK-3β mRNA expression in the insulin-treated group, when compared to controls. The present study revealed that diabetes during pregnancy strongly influences the regulation of GSK-3β in the right/left developing hippocampi. These dysregulations may be part of the cascade of events through which diabetes during pregnancy affects the newborn's hippocampal structure and function.
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Affiliation(s)
- Javad Hami
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Razieh Karimi
- Medical Genetics Research Center (MGRC), School of Medicine, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences (MUMS), Azadi Square, Mashhad, Iran
| | - Hossein Haghir
- Medical Genetics Research Center (MGRC), School of Medicine, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran.,Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran
| | - Mehran Gholamin
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ariane Sadr-Nabavi
- Medical Genetics Research Center (MGRC), School of Medicine, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran. .,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences (MUMS), Azadi Square, Mashhad, Iran. .,Molecular Medicine Research Department, Iranian Academic Centers for Education, Culture and Research (ACECR)-Khorasan Razavi Branch, Mashhad, Iran.
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Hami J, Shojae F, Vafaee-Nezhad S, Lotfi N, Kheradmand H, Haghir H. Some of the experimental and clinical aspects of the effects of the maternal diabetes on developing hippocampus. World J Diabetes 2015; 6:412-422. [PMID: 25897352 PMCID: PMC4398898 DOI: 10.4239/wjd.v6.i3.412] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 10/25/2014] [Accepted: 01/12/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus during pregnancy is associated with an increased risk of multiple congenital anomalies in progeny. There are sufficient evidence suggesting that the children of diabetic women exhibit intellectual and behavioral abnormalities accompanied by modification of hippocampus structure and function. Although, the exact mechanism by which maternal diabetes affects the developing hippocampus remains to be defined. Multiple biological alterations, including hyperglycemia, hyperinsulinemia, oxidative stress, hypoxia, and iron deficiency occur in pregnancies with diabetes and affect the development of central nervous system (CNS) of the fetus. The conclusion from several studies is that disturbance in glucose and insulin homeostasis in mothers and infants are major teratogenic factor in the development of CNS. Insulin and Insulin-like growth factor-1 (IGF-1) are two key regulators of CNS function and development. Insulin and IGF-1 receptors (IR and IGF1R, respectively) are distributed in a highly specific pattern with the high density in some brain regions such as hippocampus. Recent researches have clearly established that maternal diabetes disrupts the regulation of both IR and IGF1R in the hippocampus of rat newborn. Dissecting out the mechanisms responsible for maternal diabetes-related changes in the development of hippocampus is helping to prevent from impaired cognitive and memory functions in offspring.
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Dempsey KM, Ali HH. Identifying aging-related genes in mouse hippocampus using gateway nodes. BMC SYSTEMS BIOLOGY 2014; 8:62. [PMID: 24886704 PMCID: PMC4057599 DOI: 10.1186/1752-0509-8-62] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Accepted: 05/12/2014] [Indexed: 12/16/2022]
Abstract
Background High-throughput studies continue to produce volumes of metadata representing valuable sources of information to better guide biological research. With a stronger focus on data generation, analysis models that can readily identify actual signals have not received the same level of attention. This is due in part to high levels of noise and data heterogeneity, along with a lack of sophisticated algorithms for mining useful information. Networks have emerged as a powerful tool for modeling high-throughput data because they are capable of representing not only individual biological elements but also different types of relationships en masse. Moreover, well-established graph theoretic methodology can be applied to network models to increase efficiency and speed of analysis. In this project, we propose a network model that examines temporal data from mouse hippocampus at the transcriptional level via correlation of gene expression. Using this model, we formally define the concept of “gateway” nodes, loosely defined as nodes representing genes co-expressed in multiple states. We show that the proposed network model allows us to identify target genes implicated in hippocampal aging-related processes. Results By mining gateway genes related to hippocampal aging from networks made from gene expression in young and middle-aged mice, we provide a proof-of-concept of existence and importance of gateway nodes. Additionally, these results highlight how network analysis can act as a supplement to traditional statistical analysis of differentially expressed genes. Finally, we use the gateway nodes identified by our method as well as functional databases and literature to propose new targets for study of aging in the mouse hippocampus. Conclusions This research highlights the need for methods of temporal comparison using network models and provides a systems biology approach to extract information from correlation networks of gene expression. Our results identify a number of genes previously implicated in the aging mouse hippocampus related to synaptic plasticity and apoptosis. Additionally, this model identifies a novel set of aging genes previously uncharacterized in the hippocampus. This research can be viewed as a first-step for identifying the processes behind comparative experiments in aging that is applicable to any type of temporal multi-state network.
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Affiliation(s)
| | - Hesham H Ali
- Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, USA.
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Haghir H, Rezaee AAR, Sankian M, Kheradmand H, Hami J. The effects of induced type-I diabetes on developmental regulation of insulin & insulin like growth factor-1 (IGF-1) receptors in the cerebellum of rat neonates. Metab Brain Dis 2013; 28:397-410. [PMID: 23397157 DOI: 10.1007/s11011-013-9386-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 02/01/2013] [Indexed: 12/24/2022]
Abstract
Diabetes during pregnancy impairs brain development in offspring, leading to behavioral problems, motor dysfunction and learning deficits. Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. Aim of the present study was to examine the effects of maternal diabetes on insulin receptor (InsR) and IGF-1 receptor (IGF-1R) expression in the developing rat cerebellum. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was killed at P0, P7, and P14, an active neurogenesis period in brain development equivalent to the third trimester in human. The expression of InsR and IGF-1R in cerebelli was evaluated using real-time PCR and western blot analysis. We found a significant upregulation of both IGF-1R and InsR transcripts in cerebellum of pups born to diabetic mothers at P0, compared to controls. However, at the same time point, the results of western blot analysis revealed only a slight change in their protein levels. In contrast to InsR, which does not show any difference, there was a markedly reduction in cerebellar expression of IGF-1R mRNA and protein level in the diabetic group of newborns at P7. Moreover, 2 weeks after birth, mRNA expression and protein levels of both InsR and IGF-1R in cerebellum of the diabetic group was significantly downregulated. Compared to controls, we did not find any difference in cerebellar InsR or IGF-1R mRNA and protein levels in the insulin treated group. The present study revealed that diabetes during pregnancy strongly influences the regulation of both InsR and IGF-1R in the developing cerebellum. Furthermore, optimal maternal glycaemia control by insulin administration normalized these effects.
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MESH Headings
- Actins/metabolism
- Animals
- Animals, Newborn
- Blood Glucose/metabolism
- Blotting, Western
- Cerebellum/metabolism
- DNA, Complementary/biosynthesis
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 1/chemically induced
- Diabetes Mellitus, Type 1/metabolism
- Female
- Gene Expression/drug effects
- Male
- Pregnancy
- RNA/biosynthesis
- RNA/isolation & purification
- Rats
- Rats, Wistar
- Real-Time Polymerase Chain Reaction
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism
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Affiliation(s)
- Hossein Haghir
- Department of Anatomy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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