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Leclerc M, Tremblay C, Bourassa P, Schneider JA, Bennett DA, Calon F. Lower GLUT1 and unchanged MCT1 in Alzheimer's disease cerebrovasculature. J Cereb Blood Flow Metab 2024; 44:1417-1432. [PMID: 38441044 PMCID: PMC11342728 DOI: 10.1177/0271678x241237484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 12/21/2023] [Accepted: 01/16/2024] [Indexed: 03/06/2024]
Abstract
The brain is a highly demanding organ, utilizing mainly glucose but also ketone bodies as sources of energy. Glucose transporter-1 (GLUT1) and monocarboxylates transporter-1 (MCT1) respectively transport glucose and ketone bodies across the blood-brain barrier. While reduced glucose uptake by the brain is one of the earliest signs of Alzheimer's disease (AD), no change in the uptake of ketone bodies has been evidenced yet. To probe for changes in GLUT1 and MCT1, we performed Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders Study. Participants clinically diagnosed with AD had lower cerebrovascular levels of GLUT1, whereas MCT1 remained unchanged. GLUT1 reduction was associated with lower cognitive scores. No such association was found for MCT1. GLUT1 was inversely correlated with neuritic plaques and cerebrovascular β-secretase-derived fragment levels. No other significant associations were found between both transporters, markers of Aβ and tau pathologies, sex, age at death or apolipoprotein-ε4 genotype. These results suggest that, while a deficit of GLUT1 may underlie the reduced transport of glucose to the brain in AD, no such impairment occurs for MCT1. This study thus supports the exploration of ketone bodies as an alternative energy source for the aging brain.
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Affiliation(s)
- Manon Leclerc
- Faculté de pharmacie, Université Laval, Québec, Canada
- Axe Neurosciences, Centre de recherche du CHU de Québec – Université Laval, Québec, Canada
| | - Cyntia Tremblay
- Axe Neurosciences, Centre de recherche du CHU de Québec – Université Laval, Québec, Canada
| | - Philippe Bourassa
- Faculté de pharmacie, Université Laval, Québec, Canada
- Axe Neurosciences, Centre de recherche du CHU de Québec – Université Laval, Québec, Canada
| | - Julie A Schneider
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - David A Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Frédéric Calon
- Faculté de pharmacie, Université Laval, Québec, Canada
- Axe Neurosciences, Centre de recherche du CHU de Québec – Université Laval, Québec, Canada
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Pereira VM, Pradhanang S, Prather JF, Nair S. Role of Metalloproteinases in Diabetes-associated Mild Cognitive Impairment. Curr Neuropharmacol 2024; 23:58-74. [PMID: 38963109 PMCID: PMC11519823 DOI: 10.2174/1570159x22666240517090855] [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] [Received: 11/16/2023] [Revised: 01/24/2024] [Accepted: 02/14/2024] [Indexed: 07/05/2024] Open
Abstract
Diabetes has been linked to an increased risk of mild cognitive impairment (MCI), a condition characterized by a subtle cognitive decline that may precede the development of dementia. The underlying mechanisms connecting diabetes and MCI involve complex interactions between metabolic dysregulation, inflammation, and neurodegeneration. A critical mechanism implicated in diabetes and MCI is the activation of inflammatory pathways. Chronic low-grade inflammation, as observed in diabetes, can lead to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and interferon-gamma (IFNγ), each of which can exacerbate neuroinflammation and contribute to cognitive decline. A crucial enzyme involved in regulating inflammation is ADAM17, a disintegrin, and metalloproteinase, which can cleave and release TNF-α from its membrane-bound precursor and cause it to become activated. These processes, in turn, activate additional inflammation-related pathways, such as AKT, NF-κB, NLP3, MAPK, and JAK-STAT pathways. Recent research has provided novel insights into the role of ADAM17 in diabetes and neurodegenerative diseases. ADAM17 is upregulated in both diabetes and Alzheimer's disease, suggesting a shared mechanism and implicating inflammation as a possible contributor to much broader forms of pathology and pointing to a possible link between inflammation and the emergence of MCI. This review provides an overview of the different roles of ADAM17 in diabetes-associated mild cognitive impairment diseases. It identifies mechanistic connections through which ADAM17 and associated pathways may influence the emergence of mild cognitive impairment.
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Affiliation(s)
- Vitoria Mattos Pereira
- School of Pharmacy, College of Health Sciences, Biomedical Sciences, Interdisciplinary Graduate Program, University of Wyoming, Laramie, WY 82071, USA
| | - Suyasha Pradhanang
- School of Pharmacy, College of Health Sciences, Biomedical Sciences, Interdisciplinary Graduate Program, University of Wyoming, Laramie, WY 82071, USA
| | - Jonathan F. Prather
- Department of Zoology and Physiology, Program in Neuroscience, University of Wyoming, Laramie, WY 82071, USA
| | - Sreejayan Nair
- School of Pharmacy, College of Health Sciences, Biomedical Sciences, Interdisciplinary Graduate Program, University of Wyoming, Laramie, WY 82071, USA
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3
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Dong L, Zhao L, Tian L, Zhao W, Xiong C, Zheng Y. AsHC 360 Exposure Influence on Epileptiform Discharges in Hippocampus of Infantile Male Rats In Vitro. Int J Mol Sci 2023; 24:16806. [PMID: 38069126 PMCID: PMC10705907 DOI: 10.3390/ijms242316806] [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: 08/31/2023] [Revised: 11/06/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
Arsenic-containing hydrocarbons (AsHCs) are typical arsenolipids found in various marine organisms. They can penetrate the blood-brain barrier, specifically affecting synaptic plasticity and the learning and memory ability of hippocampal neurons. Temporal lobe epilepsy often occurs in the hippocampus. Thus, the possible influence of AsHCs exposure to temporal lobe epilepsy garnered attention. The present study investigated the effects of epileptiform discharges (EDs) signals introduced by low-magnesium ACSF in the hippocampus of infantile male rats in vitro, using electrophysiological techniques with multi-electrode arrays under AsHC 360 exposure. In our study of the effects of AsHC 360 on EDs signals, we found that inter-ictal discharges (IIDs) were not significantly impacted. When AsHC 360 was removed, any minor effects observed were reversed. However, when we examined the impact of AsHC 360 on ictal discharges (IDs), distinct patterns emerged based on the concentration levels. For low-concentration groups (5, 20, 60 μg As L-1), both the frequency and duration effects on IDs returned to normal post-elimination of AsHC 360. However, this recovery was not evident for concentrations of 100 μg As L-1 or higher. IDs were only observed in EDs signals during exposures to AsHC 360 concentrations up to 60 μg As L-1. In these conditions, ID frequencies significantly enhanced with the increased of AsHC 360 concentration. At high concentrations of AsHC 360 (≥100 μg As L-1), the transition from IIDs or pre-ictal discharges (PIDs) to IDs was notably inhibited. Additional study on co-exposure of AsHC 360 (100 μg As L-1) and agonist (10 nM (S)-(-)-Bay-K-8644) indicated that the regulation of EDs signals under AsHC 360 exposure could be due to directly interference with the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) expression which influences the binding of excitatory glutamate neurotransmitter to AMPAR. The results suggest that EDs activities in the hippocampus of infantile Sprague Dawley rats are concentration-dependent on AsHC 360 exposure. Thus, it provides a basis for the seafood intake with AsHCs for epileptic patients and those with potential seizures.
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Affiliation(s)
- Lei Dong
- School of Life Sciences, Tiangong University, Tianjin 300387, China; (L.D.); (L.Z.); (L.T.); (W.Z.)
| | - Ling Zhao
- School of Life Sciences, Tiangong University, Tianjin 300387, China; (L.D.); (L.Z.); (L.T.); (W.Z.)
| | - Lei Tian
- School of Life Sciences, Tiangong University, Tianjin 300387, China; (L.D.); (L.Z.); (L.T.); (W.Z.)
| | - Wenjun Zhao
- School of Life Sciences, Tiangong University, Tianjin 300387, China; (L.D.); (L.Z.); (L.T.); (W.Z.)
| | - Chan Xiong
- Institute of Chemistry, NAWI Graz, University of Graz, Graz 8010, Austria
| | - Yu Zheng
- School of Life Sciences, Tiangong University, Tianjin 300387, China; (L.D.); (L.Z.); (L.T.); (W.Z.)
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Kim DY, Park J, Han IO. Hexosamine biosynthetic pathway and O-GlcNAc cycling of glucose metabolism in brain function and disease. Am J Physiol Cell Physiol 2023; 325:C981-C998. [PMID: 37602414 DOI: 10.1152/ajpcell.00191.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/03/2023] [Accepted: 08/03/2023] [Indexed: 08/22/2023]
Abstract
Impaired brain glucose metabolism is considered a hallmark of brain dysfunction and neurodegeneration. Disruption of the hexosamine biosynthetic pathway (HBP) and subsequent O-linked N-acetylglucosamine (O-GlcNAc) cycling has been identified as an emerging link between altered glucose metabolism and defects in the brain. Myriads of cytosolic and nuclear proteins in the nervous system are modified at serine or threonine residues with a single N-acetylglucosamine (O-GlcNAc) molecule by O-GlcNAc transferase (OGT), which can be removed by β-N-acetylglucosaminidase (O-GlcNAcase, OGA). Homeostatic regulation of O-GlcNAc cycling is important for the maintenance of normal brain activity. Although significant evidence linking dysregulated HBP metabolism and aberrant O-GlcNAc cycling to induction or progression of neuronal diseases has been obtained, the issue of whether altered O-GlcNAcylation is causal in brain pathogenesis remains uncertain. Elucidation of the specific functions and regulatory mechanisms of individual O-GlcNAcylated neuronal proteins in both normal and diseased states may facilitate the identification of novel therapeutic targets for various neuronal disorders. The information presented in this review highlights the importance of HBP/O-GlcNAcylation in the neuronal system and summarizes the roles and potential mechanisms of O-GlcNAcylated neuronal proteins in maintaining normal brain function and initiation and progression of neurological diseases.
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Affiliation(s)
- Dong Yeol Kim
- Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, South Korea
| | - Jiwon Park
- Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, South Korea
| | - Inn-Oc Han
- Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, South Korea
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Yang L, Wang Y, Li Z, Wu X, Mei J, Zheng G. Brain targeted peptide-functionalized chitosan nanoparticles for resveratrol delivery: Impact on insulin resistance and gut microbiota in obesity-related Alzheimer's disease. Carbohydr Polym 2023; 310:120714. [PMID: 36925241 DOI: 10.1016/j.carbpol.2023.120714] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023]
Abstract
The pathology of Alzheimer's disease (AD) is highly correlated with obesity-induced insulin resistance. Resveratrol (Res) is a natural phenol that demonstrates a neuroprotective effect, but the bioactivity of Res is low in vivo. Here, chitosan (CS) was cross-linked with sodium tripolyphosphate (TPP) to encapsulate low water solubility Res. Next, a brain-targeted peptide (TG: TGNYKALHPHNG) was modified on the surface of Res-loaded CS/TPP nanoparticles (TG-Res-CS/TPP-NPs) to specifically deliver Res to the brain. Morris water maze results indicated that cognitive impairments were ameliorated by TG-Res-CS/TPP-NPs in obesity-related AD mice. Obesity-related insulin resistance promotes Tau phosphorylation and Aβ aggregation in the brain. Administration of TG-Res-CS/TPP-NPs alleviated lipid deposition-induced insulin resistance and decreased the level of phosphorylated Tau and Aβ aggregation via the JNK/AKT/GSK3β pathway. Additionally, TG-Res-CS/TPP-NPs transported across blood-brain barrier which in turn increased glucose transporter expression levels, antioxidant enzyme activity and inhibited microglial cell activation. Thus, TG-Res-CS/TPP-NPs were more effective than Res-CS/TPP-NPs at regulating glucose homeostasis, oxidative stress and neuroinflammation in the brain. Moreover, inflammatory, lipid metabolism and oxidative stress-related gut microbiota including Helicobacter, Colidextribacter, Anaerotruncus, Parasutterella, Allobaculum, Alloprevotella, Alistipes, Bifidobacterium and Candidatus_Saccharimonas were also regulated by TG-Res-CS/TPP-NPs. This work indicates the potential use of TG-Res-CS/TPP-NPs for the delivery of Res.
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Affiliation(s)
- Licong Yang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, China.
| | - Yabin Wang
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Zhiwei Li
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Xiaohua Wu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, China
| | - Jingtao Mei
- College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, China
| | - Guodong Zheng
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China.
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Zhao T, Miao H, Song Z, Li Y, Xia N, Zhang Z, Zhang H. Metformin alleviates the cognitive impairment induced by benzo[a]pyrene via glucolipid metabolism regulated by FTO/FoxO6 pathway in mice. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:69192-69204. [PMID: 37133670 DOI: 10.1007/s11356-023-27303-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/25/2023] [Indexed: 05/04/2023]
Abstract
Benzo[a]pyrene (B[a]P) is neurotoxic; however, the mechanism and prevention are still unclear. In this study, we assessed the intervention effect of metformin (MET) on cognitive dysfunction in mice induced by B[a]P from the perspective of glucolipid metabolism. Forty-two male healthy ICR mice were randomly categorized into 6 groups and were gavaged with B[a]P (0, 2.5, 5, or 10 mg/kg), 45 times for 90 days. The controls were gavaged with edible peanut oil, and the intervention groups were co-treated with B[a]P (10 mg/kg) and MET (200 or 300 mg/kg). We assessed the cognitive function of mice, observed the pathomorphological and ultrastructural changes, and detected neuronal apoptosis and glucolipid metabolism. Results showed that B[a]P dose-dependently induced cognitive impairment, neuronal damage, glucolipid metabolism disorder in mice, and enhanced proteins of fat mass and obesity-associated protein (FTO) and forkhead box protein O6 (FoxO6) in the cerebral cortex and liver, which were alleviated by the MET intervention. The findings indicated the critical role of glucolipid metabolism disorder in the cognitive impairment in mice caused by B[a]P and the prevention of MET against B[a]P neurotoxicity by regulating glucolipid metabolism via restraining FTO/FoxO6 pathway. The finding provides a scientific basis for the neurotoxicity and prevention strategies of B[a]P.
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Affiliation(s)
- Tingyi Zhao
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Huide Miao
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Zhanfei Song
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Yangyang Li
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Na Xia
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Zhiyan Zhang
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Hongmei Zhang
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China.
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China.
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Yan F, Liu J, Chen MX, Zhang Y, Wei SJ, Jin H, Nie J, Fu XL, Shi JS, Zhou SY, Jin F. Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3ΧTg-AD mice. Neural Regen Res 2023; 18:183-188. [PMID: 35799540 PMCID: PMC9241391 DOI: 10.4103/1673-5374.344840] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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8
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Tian Y, Zheng Z, Wang X, Liu S, Gu L, Mu J, Zheng X, Li Y, Shen S. Establishment and evaluation of glucose-modified nanocomposite liposomes for the treatment of cerebral malaria. J Nanobiotechnology 2022; 20:318. [PMID: 35794597 PMCID: PMC9258070 DOI: 10.1186/s12951-022-01493-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 06/03/2022] [Indexed: 11/10/2022] Open
Abstract
Cerebral malaria (CM) is a life-threatening neurological complication caused by Plasmodium falciparum. About 627,000 patients died of malaria in 2020. Currently, artemisinin and its derivatives are the front-line drugs used for the treatment of cerebral malaria. However, they cannot target the brain, which decreases their effectiveness. Therefore, increasing their ability to target the brain by the nano-delivery system with brain-targeted materials is of great significance for enhancing the effects of antimalarials and reducing CM mortality. This study used glucose transporter 1 (GLUT1) on the blood-brain barrier as a target for a synthesized cholesterol-undecanoic acid-glucose conjugate. The molecular dynamics simulation found that the structural fragment of glucose in the conjugate faced the outside the phospholipid bilayers, which was conducive to the recognition of brain-targeted liposomes by GLUT1. The fluorescence intensity of the brain-targeted liposomes (na-ATS/TMP@lipoBX) in the mouse brain was significantly higher than that of the non-targeted liposomes (na-ATS/TMP@lipo) in vivo (P < 0.001) after intranasal administration. The infection and recurrence rate of the mice receiving na-ATS/TMP@lipoBX treatment were significantly decreased, which had more advantages than those of other administration groups. The analysis of pharmacokinetic data showed that na-ATS/TMP@lipoBX could enter the brain in both systemic circulation and nasal-brain pathway to treat malaria. Taken together, these results in this study provide a new approach to the treatment of cerebral malaria.
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Affiliation(s)
- Ya Tian
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
- The Hospital of Nanbu County, Sichuan, People's Republic of China
| | - Zhongyuan Zheng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Xi Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Shuzhi Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Liwei Gu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Jing Mu
- Chinese Traditional Medicine Resource Center, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China
| | - Xiaojun Zheng
- Pharmacy Department of the first hospital of Shanxi Medical University, Shanxi, 10114, People's Republic of China
| | - Yujie Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China.
| | - Shuo Shen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China.
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Sharma V, Singh TG, Mannan A. Therapeutic implications of glucose transporters (GLUT) in cerebral ischemia. Neurochem Res 2022; 47:2173-2186. [PMID: 35596882 DOI: 10.1007/s11064-022-03620-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 01/05/2023]
Abstract
Cerebral ischemia is a leading cause of death in the globe, with a large societal cost. Deprivation of blood flow, together with consequent glucose and oxygen shortage, activates a variety of pathways that result in permanent brain damage. As a result, ischemia raises energy demand, which is linked to significant alterations in brain energy metabolism. Even at the low glucose levels reported in plasma during ischemia, glucose transport activity may adjust to assure the supply of glucose to maintain normal cellular function. Glucose transporters in the brain are divided into two groups: sodium-independent glucose transporters (GLUTs) and sodium-dependent glucose cotransporters (SGLTs).This review assess the GLUT structure, expression, regulation, pathobiology of GLUT in cerebral ischemia and regulators of GLUT and it also provides the synopsis of the literature exploring the relationship between GLUT and the various downstream signalling pathways for e.g., AMP-activated protein kinase (AMPK), CREB (cAMP response element-binding protein), Hypoxia-inducible factor 1 (HIF)-1, Phosphatidylinositol 3-kinase (PI3-K), Mitogen-activated protein kinase (MAPK) and adenylate-uridylate-rich elements (AREs). Therefore, the aim of the present review was to elaborate the therapeutic implications of GLUT in the cerebral ischemia.
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Affiliation(s)
- Veerta Sharma
- Chitkara College of Pharmacy, Chitkara University, 140401, Patiala, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, 140401, Patiala, Punjab, India.
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, 140401, Patiala, Punjab, India
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10
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Zhou J, Guo P, Guo Z, Sun X, Chen Y, Feng H. Fluid metabolic pathways after subarachnoid hemorrhage. J Neurochem 2021; 160:13-33. [PMID: 34160835 DOI: 10.1111/jnc.15458] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/12/2021] [Accepted: 06/20/2021] [Indexed: 01/05/2023]
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular disease with high mortality and morbidity. In recent years, a large number of studies have focused on the mechanism of early brain injury (EBI) and delayed cerebral ischemia (DCI), including vasospasm, neurotoxicity of hematoma and neuroinflammatory storm, after aSAH. Despite considerable efforts, no novel drugs have significantly improved the prognosis of patients in phase III clinical trials, indicating the need to further re-examine the multifactorial pathophysiological process that occurs after aSAH. The complex pathogenesis is reflected by the destruction of the dynamic balance of the energy metabolism in the nervous system after aSAH, which prevents the maintenance of normal neural function. This review focuses on the fluid metabolic pathways of the central nervous system (CNS), starting with ruptured aneurysms, and discusses the dysfunction of blood circulation, cerebrospinal fluid (CSF) circulation and the glymphatic system during disease progression. It also proposes a hypothesis on the metabolic disorder mechanism and potential therapeutic targets for aSAH patients.
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Affiliation(s)
- Jiru Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Peiwen Guo
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zongduo Guo
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaochuan Sun
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yujie Chen
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Hua Feng
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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11
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Rojas M, Chávez-Castillo M, Bautista J, Ortega Á, Nava M, Salazar J, Díaz-Camargo E, Medina O, Rojas-Quintero J, Bermúdez V. Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links. World J Diabetes 2021; 12:745-766. [PMID: 34168725 PMCID: PMC8192246 DOI: 10.4239/wjd.v12.i6.745] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/20/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
At present, Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are two highly prevalent disorders worldwide, especially among elderly individuals. T2DM appears to be associated with cognitive dysfunction, with a higher risk of developing neurocognitive disorders, including AD. These diseases have been observed to share various pathophysiological mechanisms, including alterations in insulin signaling, defects in glucose transporters (GLUTs), and mitochondrial dysfunctions in the brain. Therefore, the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic alternatives. In this context, the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain, increase in reactive oxygen species, and production of mitochondrial alterations that occur in T2DM. These findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs, or, more recently, azeliragon, amylin, among others, which have shown possible beneficial effects in diabetic patients diagnosed with AD.
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Affiliation(s)
- Milagros Rojas
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Mervin Chávez-Castillo
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Jordan Bautista
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Ángel Ortega
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Manuel Nava
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Juan Salazar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Edgar Díaz-Camargo
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Oscar Medina
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Joselyn Rojas-Quintero
- Pulmonary and Critical Care Medicine Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02155, United States
| | - Valmore Bermúdez
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia
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12
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Taccola C, Barneoud P, Cartot-Cotton S, Valente D, Schussler N, Saubaméa B, Chasseigneaux S, Cochois V, Mignon V, Curis E, Lochus M, Nicolic S, Dodacki A, Cisternino S, Declèves X, Bourasset F. Modifications of physical and functional integrity of the blood-brain barrier in an inducible mouse model of neurodegeneration. Neuropharmacology 2021; 191:108588. [PMID: 33940010 DOI: 10.1016/j.neuropharm.2021.108588] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 04/10/2021] [Accepted: 04/20/2021] [Indexed: 12/28/2022]
Abstract
The inducible p25 overexpression mouse model recapitulate many hallmark features of Alzheimer's disase including progressive neuronal loss, elevated Aβ, tau pathology, cognitive dysfunction, and impaired synaptic plasticity. We chose p25 mice to evaluate the physical and functional integrity of the blood-brain barrier (BBB) in a context of Tau pathology (pTau) and severe neurodegeneration, at an early (3 weeks ON) and a late (6 weeks ON) stage of the pathology. Using in situ brain perfusion and confocal imaging, we found that the brain vascular surface area and the physical integrity of the BBB were unaltered in p25 mice. However, there was a significant 14% decrease in cerebrovascular volume in 6 weeks ON mice, possibly explained by a significant 27% increase of collagen IV in the basement membrane of brain capillaries. The function of the BBB transporters GLUT1 and LAT1 was evaluated by measuring brain uptake of d-glucose and phenylalanine, respectively. In 6 weeks ON p25 mice, d-glucose brain uptake was significantly reduced by about 17% compared with WT, without any change in the levels of GLUT1 protein or mRNA in brain capillaries. The brain uptake of phenylalanine was not significantly reduced in p25 mice compared with WT. Lack of BBB integrity, impaired BBB d-glucose transport have been observed in several mouse models of AD. In contrast, reduced cerebrovascular volume and an increased basement membrane thickness may be more specifically associated with pTau in mouse models of neurodegeneration.
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Affiliation(s)
- Camille Taccola
- Pharmacokinetics, Dynamics and Metabolism, Translational Medicine & Early Development, Sanofi, 3 Digue d'Alfortville, 94140, Alfortville, France; INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Pascal Barneoud
- Rare and Neurologic Diseases Research Therapeutic Area, Sanofi, 1 Avenue Pierre Brossolette, 91380, Chilly-Mazarin, France
| | - Sylvaine Cartot-Cotton
- Pharmacokinetics, Dynamics and Metabolism, Translational Medicine & Early Development, Sanofi, 3 Digue d'Alfortville, 94140, Alfortville, France
| | - Delphine Valente
- Drug Metabolism & Pharmacokinetics, Research platform, Sanofi, 3 Digue d'Alfortville, 94140, Alfortville, France
| | - Nathalie Schussler
- Rare and Neurologic Diseases Research Therapeutic Area, Sanofi, 1 Avenue Pierre Brossolette, 91380, Chilly-Mazarin, France
| | - Bruno Saubaméa
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Stéphanie Chasseigneaux
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Véronique Cochois
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Virginie Mignon
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Emmanuel Curis
- Laboratoire de biomathématiques, plateau iB(2), EA 7537 « BioSTM », UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France; Service de bioinformatique et statistique médicale, hôpital Saint-Louis, APHP, 1, avenue Claude Vellefaux, 75010, Paris, France
| | - Murielle Lochus
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Sophie Nicolic
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Agnès Dodacki
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Salvatore Cisternino
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Xavier Declèves
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Fanchon Bourasset
- Laboratoire de Recherches Intégratives en Neurosciences et Psychologie Cognitive, Université Bourgogne Franche-Comté, 19 rue Ambroise Paré, 25000, Besançon, France.
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13
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Kaya M, Ahishali B. Basic physiology of the blood-brain barrier in health and disease: a brief overview. Tissue Barriers 2021; 9:1840913. [PMID: 33190576 PMCID: PMC7849738 DOI: 10.1080/21688370.2020.1840913] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/18/2020] [Accepted: 10/19/2020] [Indexed: 12/18/2022] Open
Abstract
The blood-brain barrier (BBB), a dynamic interface between blood and brain constituted mainly by endothelial cells of brain microvessels, robustly restricts the entry of potentially harmful blood-sourced substances and cells into the brain, however, many therapeutically active agents concurrently cannot gain access into the brain at effective doses in the presence of an intact barrier. On the other hand, breakdown of BBB integrity may involve in the pathogenesis of various neurodegenerative diseases. Besides, certain diseases/disorders such as Alzheimer's disease, hypertension, and epilepsy are associated with varying degrees of BBB disruption. In this review, we aim to highlight the current knowledge on the cellular and molecular composition of the BBB with special emphasis on the major transport pathways across the barrier type endothelial cells. We further provide a discussion on the innovative brain drug delivery strategies in which the obstacle formed by BBB interferes with effective pharmacological treatment of neurodegenerative diseases/disorders.
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Affiliation(s)
- Mehmet Kaya
- Koç University School of Medicine Department of Physiology, Koç University Research Center for Translational Medicine, Istanbul, Turkey
| | - Bulent Ahishali
- Koç University School of Medicine Department of Histology and Embryology, Koç University Research Center for Translational Medicine, Istanbul, Turkey
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14
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Bonfili L, Cecarini V, Gogoi O, Berardi S, Scarpona S, Angeletti M, Rossi G, Eleuteri AM. Gut microbiota manipulation through probiotics oral administration restores glucose homeostasis in a mouse model of Alzheimer's disease. Neurobiol Aging 2019; 87:35-43. [PMID: 31813629 DOI: 10.1016/j.neurobiolaging.2019.11.004] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 11/04/2019] [Accepted: 11/04/2019] [Indexed: 01/07/2023]
Abstract
Cerebral glucose homeostasis deregulation has a role in the pathogenesis and the progression of Alzheimer's disease (AD). Current therapies delay symptoms without definitively curing AD. We have previously shown that probiotics counteract AD progression in 3xTg-AD mice modifying gut microbiota and inducing energy metabolism and glycolysis-gluconeogenesis. Ameliorated cognition is based on higher neuroprotective gut hormones concentrations, reduced amyloid-β burden, and restored proteolytic pathways. Here, we demonstrate that probiotics oral administration improves glucose uptake in 3xTg-AD mice by restoring the brain expression levels of key glucose transporters (GLUT3, GLUT1) and insulin-like growth factor receptor β, in accordance with the diminished phosphorylation of adenosine monophosphate-activated protein kinase and protein-kinase B (Akt). In parallel, phosphorylated tau aggregates decrease in treated mice. Probiotics counteract the time-dependent increase of glycated hemoglobin and the accumulation of advanced glycation end products in AD mice, consistently with memory improvement. Collectively, our data elucidate the mechanism through which gut microbiota manipulation ameliorates impaired glucose metabolism in AD, finally delaying the disease progression.
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Affiliation(s)
- Laura Bonfili
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino (MC), Italy.
| | - Valentina Cecarini
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino (MC), Italy
| | - Olee Gogoi
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino (MC), Italy
| | - Sara Berardi
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino (MC), Italy
| | - Silvia Scarpona
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino (MC), Italy
| | - Mauro Angeletti
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino (MC), Italy
| | - Giacomo Rossi
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino (MC), Italy
| | - Anna Maria Eleuteri
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino (MC), Italy
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15
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Dias C, Matos AM, Blásquez-Sanchez MT, Calado P, Martins A, Dätwyler P, Ernst B, Macedo MP, Colabufo N, Rauter AP. 2-Deoxyglycosylation towards more effective and bioavailable neuroprotective molecules inspired by nature. PURE APPL CHEM 2019. [DOI: 10.1515/pac-2019-0303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Abstract
The neuroprotective role of natural polyphenols is well established but phenolics poor water solubility affects their bioavailability and bioactivity. Aiming to overcome this issue, we were encouraged to investigate the 2-deoxyglycosylation of natural or nature inspired neuroprotective molecules, using glycals as easily accessed glycosyl donors. This robust methodology allowed the generation of a set of new resveratrol and caffeic acid ester glycosides, envisioning more effective and bioavailable compounds. Resveratrol 2-deoxyglycosides were more effective at protecting the neuronal cells from peroxide-induced cytotoxicity than resveratrol itself, while the caffeic acid ester glycoside also showed extraordinary neuroprotection activity. Coefficient partition measurements demonstrated the moderate lipophilicity of resveratrol glycosides, which Log D values are typical of a central nervous system (CNS) drug and ideal for blood-brain barrier (BBB) penetration. Passive permeation assessed by the parallel artificial membrane permeability assay (PAMPA) revealed that 2,6-dideoxy-l-arabino-hexopyranosides were more effective than 2-deoxy-d-arabino-hexopyranosides. The lack of toxicity of the neuroprotective glycosides and their promising physicochemical properties revealed the usefulness of sugar coupling towards the modulation of natural product properties and bioactivity.
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Affiliation(s)
- Catarina Dias
- Centro de Química e Bioquímica, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
- Centro de Química Estrutural, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
| | - Ana M. Matos
- Centro de Química e Bioquímica, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
- Centro de Química Estrutural, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
- Centro de Estudos de Doenҫas Crónicas (CEDOC), Chronic Disease Research Center, NOVA Medical School/Faculdade de Ciências Médicas , Universidade Nova de Lisboa , Lisboa , Portugal
| | - Maria T. Blásquez-Sanchez
- Centro de Química e Bioquímica, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
- Centro de Química Estrutural, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
| | - Patrícia Calado
- Centro de Química e Bioquímica, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
- Centro de Química Estrutural, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
| | - Alice Martins
- Centro de Química e Bioquímica, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
- Centro de Química Estrutural, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
| | - Philipp Dätwyler
- Department of Pharmaceutical Sciences, Pharmacenter , University of Basel , Klingelbergstrasse 50 , CH-4056 Basel , Switzerland
| | - Beat Ernst
- Department of Pharmaceutical Sciences, Pharmacenter , University of Basel , Klingelbergstrasse 50 , CH-4056 Basel , Switzerland
| | - M. Paula Macedo
- Centro de Estudos de Doenҫas Crónicas (CEDOC), Chronic Disease Research Center, NOVA Medical School/Faculdade de Ciências Médicas , Universidade Nova de Lisboa , Lisboa , Portugal
- Department of Medical Sciences, Institute of Biomedicine , University of Aveiro , Aveiro , Portugal
| | - Nicola Colabufo
- Università degli Studi di Bari, Biofordrug , Via Edoardo Orabona, 4 , 70125 Bari , Italy
| | - Amélia P. Rauter
- Centro de Química e Bioquímica, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
- Centro de Química Estrutural, Faculdade de Ciências , Universidade de Lisboa, Ed. C8, Campo Grande , 1749-016 Lisboa , Portugal
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16
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Mechanisms Associated with Type 2 Diabetes as a Risk Factor for Alzheimer-Related Pathology. Mol Neurobiol 2019; 56:5815-5834. [PMID: 30684218 DOI: 10.1007/s12035-019-1475-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 01/10/2019] [Indexed: 12/19/2022]
Abstract
Current evidence suggests dementia and pathology in Alzheimer's Disease (AD) are both dependent and independent of amyloid processing and can be induced by multiple 'hits' on vital neuronal functions. Type 2 diabetes (T2D) poses the most important risk factor for developing AD after ageing and dysfunctional IR/PI3K/Akt signalling is a major contributor in both diseases. We developed a model of T2D, coupling subdiabetogenic doses of streptozotocin (STZ) with a human junk food (HJF) diet to more closely mimic the human condition. Over 35 weeks, this induced classic signs of T2D (hyperglycemia and insulin dysfunction) and a modest, but stable deficit in spatial recognition memory, with very little long-term modification of proteins in or associated with IR/PI3K/Akt signalling in CA1 of the hippocampus. Intracerebroventricular infusion of soluble amyloid beta 42 (Aβ42) to mimic the early preclinical rise in Aβ alone induced a more severe, but short-lasting deficits in memory and deregulation of proteins. Infusion of Aβ on the T2D phenotype exacerbated and prolonged the memory deficits over approximately 4 months, and induced more severe aberrant regulation of proteins associated with autophagy, inflammation and glucose uptake from the periphery. A mild form of environmental enrichment transiently rescued memory deficits and could reverse the regulation of some, but not all protein changes. Together, these data identify mechanisms by which T2D could create a modest dysfunctional neuronal milieu via multiple and parallel inputs that permits the development of pathological events identified in AD and memory deficits when Aβ levels are transiently effective in the brain.
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17
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Nuñez MT, Chana-Cuevas P. New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases. Pharmaceuticals (Basel) 2018; 11:ph11040109. [PMID: 30347635 PMCID: PMC6316457 DOI: 10.3390/ph11040109] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 07/31/2018] [Accepted: 08/03/2018] [Indexed: 02/07/2023] Open
Abstract
Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results. Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction. In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micromolar range, but not high enough to disrupt physiological iron homeostasis. Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment. Here, on the basis of a number of clinical trials, we discuss critically the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component. The list includes Parkinson’s disease, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease and Alzheimer’s disease. We also review the upsurge of new multifunctional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Marco T Nuñez
- Faculty of Sciences, Universidad de Chile, Las Palmeras 3425, Santiago 7800024, Chile.
| | - Pedro Chana-Cuevas
- Center for the Treatment of Movement Disorders, Universidad de Santiago de Chile, Belisario Prat 1597, Santiago 83800000, Chile.
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18
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Expression profile of glucose transport-related genes under chronic and acute exposure to growth hormone in zebrafish. Comp Biochem Physiol A Mol Integr Physiol 2018. [DOI: 10.1016/j.cbpa.2018.02.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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19
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Ahn KC, Learman CR, Dunbar GL, Maiti P, Jang WC, Cha HC, Song MS. Characterization of Impaired Cerebrovascular Structure in APP/PS1 Mouse Brains. Neuroscience 2018; 385:246-254. [PMID: 29777753 DOI: 10.1016/j.neuroscience.2018.05.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 04/27/2018] [Accepted: 05/02/2018] [Indexed: 01/01/2023]
Abstract
Alzheimer's disease (AD) is defined by senile plaques, tauopathy and neuronal cell death in specific area of the brain. Recent studies suggest that neurovascular dysfunction may be an integral part of AD pathogenesis, contributing to the onset and development of AD pathologies such as neuronal death, inflammatory response, and breakdown of blood-brain barrier (BBB). In addition, vascular complications caused by age-related metabolic diseases such as diabetes and high blood pressure have high incidence in development of dementia and AD. We previously reported that astrocytes, essential components of BBB, were chronically activated and some deteriorated in the brain of 5xFAD, an amyloid precursor protein/presenilin1 (APP/PS1) transgenic mouse model. Thus, it is rational to investigate if any vascular dysfunction is associated with considerable activation of astrocytes in APP/PS1 mouse model. In this study, we observed that cerebrovascular pathology was associated with large scale of reactive astrocytes and neurodegeneration in an Aβ plague-generating mouse model. Using 5xFAD mouse brains, we demonstrate damaged brain vessels and reduced expression of glucose transporter 1 (GLUT1), the main glucose transporter, and a tight junction protein zonula occludens-1 (ZO-1) of cerebrovascular endothelial cells. This vascular pathology was closely associated with astrocytic deterioration and neuronal loss due to buildup of Aβ plaques in 5xFAD mouse brains.
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Affiliation(s)
- Kee-Chan Ahn
- University of British Columbia, Vancouver, BC, Canada; EnviroBrain, Edmonton, AB, Canada
| | - Cameron R Learman
- Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, USA; Neuroscience Program, Central Michigan University, Mt Pleasant, MI, USA
| | - Gary L Dunbar
- Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, USA; Neuroscience Program, Central Michigan University, Mt Pleasant, MI, USA
| | - Panchanan Maiti
- Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, USA; Neuroscience Program, Central Michigan University, Mt Pleasant, MI, USA
| | | | - Hyeon-Cheol Cha
- Department of Biological Sciences, Dankook University, Cheonan, Chungnam, South Korea
| | - Mee-Sook Song
- Department of Biological Sciences, Dankook University, Cheonan, Chungnam, South Korea.
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20
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Murata M, Kang JH. Bisphenol A (BPA) and cell signaling pathways. Biotechnol Adv 2018; 36:311-327. [DOI: 10.1016/j.biotechadv.2017.12.002] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 12/01/2017] [Accepted: 12/07/2017] [Indexed: 01/09/2023]
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21
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Cerebrospinal fluid and brain extracellular fluid in severe brain trauma. HANDBOOK OF CLINICAL NEUROLOGY 2018; 146:237-258. [DOI: 10.1016/b978-0-12-804279-3.00014-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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22
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Hegen H, Walde J, Auer M, Deisenhammer F. Cerebrospinal fluid:serum glucose ratio in the ventricular and lumbar compartments: implications for clinical practice. Eur J Neurol 2017; 25:373-379. [DOI: 10.1111/ene.13513] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 11/02/2017] [Indexed: 11/30/2022]
Affiliation(s)
- H. Hegen
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
| | - J. Walde
- Department of Statistics Faculty of Economics and Statistics University of Innsbruck Innsbruck Austria
| | - M. Auer
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
| | - F. Deisenhammer
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
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23
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Theodorakis PE, Müller EA, Craster RV, Matar OK. Physical insights into the blood-brain barrier translocation mechanisms. Phys Biol 2017; 14:041001. [PMID: 28586313 DOI: 10.1088/1478-3975/aa708a] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The number of individuals suffering from diseases of the central nervous system (CNS) is growing with an aging population. While candidate drugs for many of these diseases are available, most of these pharmaceutical agents cannot reach the brain rendering most of the drug therapies that target the CNS inefficient. The reason is the blood-brain barrier (BBB), a complex and dynamic interface that controls the influx and efflux of substances through a number of different translocation mechanisms. Here, we present these mechanisms providing, also, the necessary background related to the morphology and various characteristics of the BBB. Moreover, we discuss various numerical and simulation approaches used to study the BBB, and possible future directions based on multi-scale methods. We anticipate that this review will motivate multi-disciplinary research on the BBB aiming at the design of effective drug therapies.
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24
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Szablewski L. Glucose Transporters in Brain: In Health and in Alzheimer’s Disease. J Alzheimers Dis 2016; 55:1307-1320. [DOI: 10.3233/jad-160841] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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25
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Abstract
A constant supply of glucose to the brain is critical for normal cerebral metabolism. The dysglycemia of type 1 diabetes (T1D) can affect activity, survival, and function of neural cells. Clinical studies in T1D have shown impairments in brain morphology and function. The most neurotoxic milieu seems to be young age and/or diabetic ketoacidosis at onset, severe hypoglycemia under the age of 6 years followed by chronic hyperglycemia. Adverse cognitive outcomes seem to be associated with poorer mental health outcomes. It is imperative to improve outcomes by investigating the mechanisms of injury so that neuroprotective strategies independent of glycemia can be identified.
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Affiliation(s)
- Fergus J Cameron
- Department of Endocrinology and Diabetes, Royal Children's Hospital, Murdoch Childrens Research Institute, 50 Flemington Road, Parkville, Melbourne 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne 3010, Australia.
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26
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Abstract
The mass transport or flux of neurochemicals in the brain and how this flux affects chemical measurements and their interpretation is reviewed. For all endogenous neurochemicals found in the brain, the flux of each of these neurochemicals exists between sources that produce them and the sites that consume them all within μm distances. Principles of convective-diffusion are reviewed with a significant emphasis on the tortuous paths and discrete point sources and sinks. The fundamentals of the primary methods of detection, microelectrodes and microdialysis sampling of brain neurochemicals are included in the review. Special attention is paid to the change in the natural flux of the neurochemicals caused by implantation and consumption at microelectrodes and uptake by microdialysis. The detection of oxygen, nitric oxide, glucose, lactate, and glutamate, and catecholamines by both methods are examined and where possible the two techniques (electrochemical vs. microdialysis) are compared. Non-invasive imaging methods: magnetic resonance, isotopic fluorine MRI, electron paramagnetic resonance, and positron emission tomography are also used for different measurements of the above-mentioned solutes and these are briefly reviewed. Although more sophisticated, the imaging techniques are unable to track neurochemical flux on short time scales, and lack spatial resolution. Where possible, determinations of flux using imaging are compared to the more classical techniques of microdialysis and microelectrodes.
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Affiliation(s)
- David W Paul
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA.
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27
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Dias C, Rauter AP. Carbohydrates and Glycomimetics in Alzheimer's Disease Therapeutics and Diagnosis. CARBOHYDRATES IN DRUG DESIGN AND DISCOVERY 2015. [DOI: 10.1039/9781849739993-00180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Alzheimer's disease is the most prevalent form of late-life dementia, affecting millions worldwide. The devastating nature of the disease, unsuccessful treatment options and high socio-economic impact has inspired scientists to develop new structures with neuroprotective properties. Although currently available drugs target cholinergic neurotransmission, investigation towards disease-modifying therapies has been growing and carbohydrates have been playing an active role in the latest discoveries. Sugars, as polyfunctional compounds particularly important in biology and widely involved in human health and disease, have great potential to generate bioactive and bioavailable interesting molecules. Herein we discuss the importance of carbohydrates and glycomimetic structures, addressing different aspects of neuroprotection under investigation, targeting amyloid, tau and cholinergic hypotheses. The potential of carbohydrates in diagnosis is also discussed.
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Affiliation(s)
- Catarina Dias
- Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 1749-016 Lisbon Portugal
| | - Amélia P. Rauter
- Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande 1749-016 Lisbon Portugal
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Brain and behavioral perturbations in rats following Western diet access. Appetite 2015; 93:35-43. [PMID: 25862980 DOI: 10.1016/j.appet.2015.03.037] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Revised: 03/21/2015] [Accepted: 03/25/2015] [Indexed: 11/22/2022]
Abstract
Energy dense "Western" diets (WD) are known to cause obesity as well as learning and memory impairments, blood-brain barrier damage, and psychological disturbances. Impaired glucose (GLUT1) and monocarboxylate (MCT1) transport may play a role in diet-induced dementia development. In contrast, ketogenic diets (KD) have been shown to be neuroprotective. We assessed the effect of 10, 40 and 90 days WD, KD and Chow maintenance on spontaneous alternation (SA) and vicarious trial and error (VTE) behaviors in male rats, then analyzed blood glucose, insulin, and ketone levels; and hippocampal GLUT1 and MCT1 mRNA. Compared to Chow and KD, rats fed WD had increased 90 day insulin levels. SA was decreased in WD rats at 10, but not 40 or 90 days. VTE was perturbed in WD-fed rats, particularly at 10 and 90 days, indicating hippocampal deficits. WD rats had lower hippocampal GLUT1 and MCT1 expression compared to Chow and KD, and KD rats had increased 90 day MCT1 expression compared to Chow and WD. These data suggest that WD reduces glucose and monocarboxylate transport at the hippocampus, which may result in learning and memory deficits. Further, KD consumption may be useful for MCT1 transporter recovery, which may benefit cognition.
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29
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Bürgi S, Seuwen A, Keist R, Vom Berg J, Grandjean J, Rudin M. In vivo imaging of hypoxia-inducible factor regulation in a subcutaneous and orthotopic GL261 glioma tumor model using a reporter gene assay. Mol Imaging 2015; 13. [PMID: 25248521 DOI: 10.2310/7290.2014.00029] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Intratumoral hypoxia changes the metabolism of gliomas, leading to a more aggressive phenotype with increased resistance to radio- and chemotherapy. Hypoxia triggers a signaling cascade with hypoxia-inducible factor (HIF) as a key regulator. We monitored activation of the HIF pathway longitudinally in murine glioma tumors. GL261 cells, stably transfected with a luciferase reporter driven under the control of a promoter comprising the HIF target gene motive hypoxia response element, were implanted either subcutaneously or orthotopically. In vivo experiments were carried out using bioluminescence imaging. Tumors were subsequently analyzed using immunofluorescence staining for hypoxia, endothelial cells, tumor perfusion, and glucose transporter expression. Transient upregulation of the HIF signaling was observed in both subcutaneous and orthotopic gliomas. Immunofluorescence staining confirmed hypoxic regions in subcutaneous and, to a lesser extent, intracranial tumors. Subcutaneous tumors showed substantial necrosis, which might contribute to the decreased bioluminescence output observed toward the end of the experiment. Orthotopic tumors were less hypoxic than subcutaneous ones and did not develop extensive necrotic areas. Although this may be the result of the overall smaller size of orthotopic tumors, it might also reflect differences in the local environment, such as the better intrinsic vascularization of brain tissue compared to the subcutaneous tissue compartment.
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30
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Rowinska-Zyrek M, Salerno M, Kozlowski H. Neurodegenerative diseases – Understanding their molecular bases and progress in the development of potential treatments. Coord Chem Rev 2015. [DOI: 10.1016/j.ccr.2014.03.026] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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31
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Kosse C, Gonzalez A, Burdakov D. Predictive models of glucose control: roles for glucose-sensing neurones. Acta Physiol (Oxf) 2015; 213:7-18. [PMID: 25131833 PMCID: PMC5767106 DOI: 10.1111/apha.12360] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 05/08/2014] [Accepted: 08/01/2014] [Indexed: 12/17/2022]
Abstract
The brain can be viewed as a sophisticated control module for stabilizing blood glucose. A review of classical behavioural evidence indicates that central circuits add predictive (feedforward/anticipatory) control to the reactive (feedback/compensatory) control by peripheral organs. The brain/cephalic control is constructed and engaged, via associative learning, by sensory cues predicting energy intake or expenditure (e.g. sight, smell, taste, sound). This allows rapidly measurable sensory information (rather than slowly generated internal feedback signals, e.g. digested nutrients) to control food selection, glucose supply for fight-or-flight responses or preparedness for digestion/absorption. Predictive control is therefore useful for preventing large glucose fluctuations. We review emerging roles in predictive control of two classes of widely projecting hypothalamic neurones, orexin/hypocretin (ORX) and melanin-concentrating hormone (MCH) cells. Evidence is cited that ORX neurones (i) are activated by sensory cues (e.g. taste, sound), (ii) drive hepatic production, and muscle uptake, of glucose, via sympathetic nerves, (iii) stimulate wakefulness and exploration via global brain projections and (iv) are glucose-inhibited. MCH neurones are (i) glucose-excited, (ii) innervate learning and reward centres to promote synaptic plasticity, learning and memory and (iii) are critical for learning associations useful for predictive control (e.g. using taste to predict nutrient value of food). This evidence is unified into a model for predictive glucose control. During associative learning, inputs from some glucose-excited neurones may promote connections between the 'fast' senses and reward circuits, constructing neural shortcuts for efficient action selection. In turn, glucose-inhibited neurones may engage locomotion/exploration and coordinate the required fuel supply. Feedback inhibition of the latter neurones by glucose would ensure that glucose fluxes they stimulate (from liver, into muscle) are balanced. Estimating nutrient challenges from indirect sensory cues may become more difficult when the cues become complex and variable (e.g. like human foods today). Consequent errors of predictive glucose control may contribute to obesity and diabetes.
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Affiliation(s)
- C. Kosse
- Division of Neurophysiology MRC National Institute for Medical Research London UK
| | - A. Gonzalez
- Division of Neurophysiology MRC National Institute for Medical Research London UK
| | - D. Burdakov
- Division of Neurophysiology MRC National Institute for Medical Research London UK
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Jesus AR, Dias C, Matos AM, de Almeida RFM, Viana AS, Marcelo F, Ribeiro RT, Macedo MP, Airoldi C, Nicotra F, Martins A, Cabrita EJ, Jiménez-Barbero J, Rauter AP. Exploiting the Therapeutic Potential of 8-β-d-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity, and Molecular Interaction with Islet Amyloid Polypeptide and Amyloid β-Peptide (1–42). J Med Chem 2014; 57:9463-72. [DOI: 10.1021/jm501069h] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Ana R. Jesus
- Center
of Chemistry and Biochemistry, Department of Chemistry and Biochemistry,
Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso
5, Campo Grande, 1749−016 Lisboa, Portugal
| | - Catarina Dias
- Center
of Chemistry and Biochemistry, Department of Chemistry and Biochemistry,
Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso
5, Campo Grande, 1749−016 Lisboa, Portugal
| | - Ana M. Matos
- Center
of Chemistry and Biochemistry, Department of Chemistry and Biochemistry,
Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso
5, Campo Grande, 1749−016 Lisboa, Portugal
- CEDOC
Chronic Diseases Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Rua Câmara Pestana, 6,
6a, 1150-082, Lisboa, Portugal
| | - Rodrigo F. M. de Almeida
- Center
of Chemistry and Biochemistry, Department of Chemistry and Biochemistry,
Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso
5, Campo Grande, 1749−016 Lisboa, Portugal
| | - Ana S. Viana
- Center
of Chemistry and Biochemistry, Department of Chemistry and Biochemistry,
Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso
5, Campo Grande, 1749−016 Lisboa, Portugal
| | - Filipa Marcelo
- REQUIMTE,
CQFB, Department of Chemistry, Faculdade de Ciências e Tecnologias, Universidade Nova de Lisboa, Quinta da Torre, 2829-516 Caparica, Portugal
| | - Rogério T. Ribeiro
- CEDOC
Chronic Diseases Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Rua Câmara Pestana, 6,
6a, 1150-082, Lisboa, Portugal
- APDP, Diabetes
Portugal Education and Research Center, APDP-ERC, Rua do Salitre, 118-120, 1250-203 Lisboa, Portugal
| | - Maria P. Macedo
- CEDOC
Chronic Diseases Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Rua Câmara Pestana, 6,
6a, 1150-082, Lisboa, Portugal
- APDP, Diabetes
Portugal Education and Research Center, APDP-ERC, Rua do Salitre, 118-120, 1250-203 Lisboa, Portugal
| | - Cristina Airoldi
- Department
of Biotechnology and Biosciences, University Milano Bicocca, Piaza
della Sciencia 2-4, 20126, Milano, Italy
| | - Francesco Nicotra
- Department
of Biotechnology and Biosciences, University Milano Bicocca, Piaza
della Sciencia 2-4, 20126, Milano, Italy
| | - Alice Martins
- Center
of Chemistry and Biochemistry, Department of Chemistry and Biochemistry,
Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso
5, Campo Grande, 1749−016 Lisboa, Portugal
| | - Eurico J. Cabrita
- REQUIMTE,
CQFB, Department of Chemistry, Faculdade de Ciências e Tecnologias, Universidade Nova de Lisboa, Quinta da Torre, 2829-516 Caparica, Portugal
| | - Jesús Jiménez-Barbero
- Centro de Investigaciones
Biológicas, C.S.I.C., Ramiro
de Maeztu 9, 28040 Madrid, Spain
| | - Amélia P. Rauter
- Center
of Chemistry and Biochemistry, Department of Chemistry and Biochemistry,
Faculdade de Ciências, Universidade de Lisboa, Ed C8, Piso
5, Campo Grande, 1749−016 Lisboa, Portugal
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Molino Y, Jabès F, Lacassagne E, Gaudin N, Khrestchatisky M. Setting-up an in vitro model of rat blood-brain barrier (BBB): a focus on BBB impermeability and receptor-mediated transport. J Vis Exp 2014:e51278. [PMID: 24998179 PMCID: PMC4208856 DOI: 10.3791/51278] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The blood brain barrier (BBB) specifically regulates molecular and cellular flux between the blood and the nervous tissue. Our aim was to develop and characterize a highly reproducible rat syngeneic in vitro model of the BBB using co-cultures of primary rat brain endothelial cells (RBEC) and astrocytes to study receptors involved in transcytosis across the endothelial cell monolayer. Astrocytes were isolated by mechanical dissection following trypsin digestion and were frozen for later co-culture. RBEC were isolated from 5-week-old rat cortices. The brains were cleaned of meninges and white matter, and mechanically dissociated following enzymatic digestion. Thereafter, the tissue homogenate was centrifuged in bovine serum albumin to separate vessel fragments from nervous tissue. The vessel fragments underwent a second enzymatic digestion to free endothelial cells from their extracellular matrix. The remaining contaminating cells such as pericytes were further eliminated by plating the microvessel fragments in puromycin-containing medium. They were then passaged onto filters for co-culture with astrocytes grown on the bottom of the wells. RBEC expressed high levels of tight junction (TJ) proteins such as occludin, claudin-5 and ZO-1 with a typical localization at the cell borders. The transendothelial electrical resistance (TEER) of brain endothelial monolayers, indicating the tightness of TJs reached 300 ohm·cm2 on average. The endothelial permeability coefficients (Pe) for lucifer yellow (LY) was highly reproducible with an average of 0.26 ± 0.11 x 10-3 cm/min. Brain endothelial cells organized in monolayers expressed the efflux transporter P-glycoprotein (P-gp), showed a polarized transport of rhodamine 123, a ligand for P-gp, and showed specific transport of transferrin-Cy3 and DiILDL across the endothelial cell monolayer. In conclusion, we provide a protocol for setting up an in vitro BBB model that is highly reproducible due to the quality assurance methods, and that is suitable for research on BBB transporters and receptors.
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Chen Y, Zhao Y, Dai CL, Liang Z, Run X, Iqbal K, Liu F, Gong CX. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Aβ level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol 2014; 261:610-9. [PMID: 24918340 DOI: 10.1016/j.expneurol.2014.06.004] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 05/31/2014] [Accepted: 06/03/2014] [Indexed: 12/23/2022]
Abstract
Decreased brain insulin signaling has been found recently in Alzheimer's disease (AD). Intranasal administration of insulin, which delivers the drug directly into the brain, improves memory and cognition in both animal studies and small clinical trials. However, the underlying mechanisms are unknown. Here, we treated 9-month-old 3xTg-AD mice, a commonly used mouse model of AD, with daily intranasal administration of insulin for seven days and then studied brain abnormalities of the mice biochemically and immunohistochemically. We found that intranasal insulin restored insulin signaling, increased the levels of synaptic proteins, and reduced Aβ40 level and microglia activation in the brains of 3xTg-AD mice. However, this treatment did not affect the levels of glucose transporters and O-GlcNAcylation or tau phosphorylation. Our findings provide a mechanistic insight into the beneficial effects of intranasal insulin treatment and support continuous clinical trials of intranasal insulin for the treatment of AD.
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Affiliation(s)
- Yanxing Chen
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yang Zhao
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; Department of Neurology, The First Hospital of Jilin University, Xinmin Street, Changchun, Jilin, China
| | - Chun-Ling Dai
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
| | - Zhihou Liang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China
| | - Xiaoqin Run
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China
| | - Khalid Iqbal
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
| | - Fei Liu
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
| | - Cheng-Xin Gong
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
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35
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Jauch-Chara K, Oltmanns KM. Glycemic control after brain injury: boon and bane for the brain. Neuroscience 2014; 283:202-9. [PMID: 24814022 DOI: 10.1016/j.neuroscience.2014.04.059] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 04/22/2014] [Accepted: 04/28/2014] [Indexed: 01/10/2023]
Abstract
Hyperglycemia is a common phenomenon in the early phase of brain injury (BI). The management of blood glucose levels after BI, however, is subject of a growing debate. The occurrence of elevated blood glucose concentrations is linked to increased mortality and worse neurologic outcomes indicating the necessity for therapeutic glucose-lowering. Intensive glucose-lowering therapy, on the other hand, inevitably results in an increased rate of hypoglycemic episodes with detrimental effects on the injured brain. In this review, we give an overview on the current knowledge about causes and pathophysiological consequences of dysglycemia in patients with BI and offer some suggestions for clinical glucose management.
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Affiliation(s)
- K Jauch-Chara
- Division of Psychoneurobiology, Department of Psychiatry and Psychotherapy, University of Luebeck, Luebeck, Germany.
| | - K M Oltmanns
- Division of Psychoneurobiology, Department of Psychiatry and Psychotherapy, University of Luebeck, Luebeck, Germany
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36
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Do TM, Alata W, Dodacki A, Traversy MT, Chacun H, Pradier L, Scherrmann JM, Farinotti R, Calon F, Bourasset F. Altered cerebral vascular volumes and solute transport at the blood-brain barriers of two transgenic mouse models of Alzheimer's disease. Neuropharmacology 2014; 81:311-7. [PMID: 24631967 DOI: 10.1016/j.neuropharm.2014.02.010] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 02/11/2014] [Accepted: 02/13/2014] [Indexed: 11/30/2022]
Abstract
We evaluated the integrity and function of the blood-brain barrier in 3xTg-AD mice aged 3-18 months and in APP/PS1 mice aged 8-months to determine the impacts of changes in amyloid and tau proteins on the brain vascular changes. The vascular volume (Vvasc) was sub-normal in 3xTg-AD mice aged from 6 to 18 months, but not in the APP/PS1 mice. The uptakes of [(3)H]-diazepam by the brains of 3xTg-AD, APP/PS1 and their age-matched control mice were similar at all the times studied, suggesting that the simple diffusion of small solutes is unchanged in transgenic animals. The uptake of d-glucose by the brains of 18-month old 3xTg-AD mice, but not by those of 8-month old APP/PS1 mice, was reduced compared to their age-matched controls. Accordingly, the amount of Glut-1 protein was 1.4 times lower in the brain capillaries of 18 month-old 3xTg-AD mice than in those of age-matched control mice. We conclude that the brain vascular volume is reduced early in 3xTg-AD mice, 6 months before the appearance of pathological lesions, and that this reduction persists until they are at least 18 months old. The absence of alterations in the BBB of APP/PS1 mice suggests that hyperphosphorylated tau proteins contribute to the vascular changes that occur in AD.
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Affiliation(s)
- Tuan Minh Do
- Laboratoire de Pharmacie Clinique et pharmacocinétique, EA 4123, Université Paris-Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Wael Alata
- Faculty of Pharmacy, Laval University, Quebec, QC, Canada
| | - Agnès Dodacki
- Inserm, U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France
| | | | - Hélène Chacun
- CNRS UMR 8612, Université Paris Sud, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Laurent Pradier
- Sanofi-Aventis Therapeutic Strategy Unit Aging, Chilly-Mazarin, France
| | - Jean-Michel Scherrmann
- Inserm, U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France
| | - Robert Farinotti
- Laboratoire de Pharmacie Clinique et pharmacocinétique, EA 4123, Université Paris-Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Frédéric Calon
- Faculty of Pharmacy, Laval University, Quebec, QC, Canada
| | - Fanchon Bourasset
- Inserm, U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France.
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Zhao Y, Gu JH, Dai CL, Liu Q, Iqbal K, Liu F, Gong CX. Chronic cerebral hypoperfusion causes decrease of O-GlcNAcylation, hyperphosphorylation of tau and behavioral deficits in mice. Front Aging Neurosci 2014; 6:10. [PMID: 24575038 PMCID: PMC3918671 DOI: 10.3389/fnagi.2014.00010] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Accepted: 01/16/2014] [Indexed: 11/13/2022] Open
Abstract
Chronic cerebral hypoperfusion (CCH) is one of the causes of vascular dementia (VaD) and is also an etiological factor for Alzheimer’s disease (AD). However, how CCH causes cognitive impairment and contributes to Alzheimer’s pathology is poorly understood. Here we produced a mouse model of CCH by unilateral common carotid artery occlusion (UCCAO) and studied the behavioral changes and brain abnormalities in mice 2.5 months after UCCAO. We found that CCH caused significant short-term memory deficits and mild long-term spatial memory impairment, as well as decreased level of protein O-GlcNAcylation, increased level of tau phosphorylation, dysregulated synaptic proteins and insulin signaling, and selective neurodegeneration in the brain. These findings provide mechanistic insight into the effects of CCH on memory and cognition and the likely link between AD and VaD.
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Affiliation(s)
- Yang Zhao
- Department of Neurology, The First Hospital of Jilin University, Changchun Jilin, China ; Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities Staten Island, NY, USA
| | - Jin-Hua Gu
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities Staten Island, NY, USA ; Department of Pharmacology, Medical School, Nantong University Nantong, Jiangsu, China
| | - Chun-Ling Dai
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities Staten Island, NY, USA
| | - Qun Liu
- Department of Neurology, The First Hospital of Jilin University, Changchun Jilin, China
| | - Khalid Iqbal
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities Staten Island, NY, USA
| | - Fei Liu
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities Staten Island, NY, USA
| | - Cheng-Xin Gong
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities Staten Island, NY, USA
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Anderson RA, Qin B, Canini F, Poulet L, Roussel AM. Cinnamon counteracts the negative effects of a high fat/high fructose diet on behavior, brain insulin signaling and Alzheimer-associated changes. PLoS One 2013; 8:e83243. [PMID: 24349472 PMCID: PMC3862724 DOI: 10.1371/journal.pone.0083243] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 10/22/2013] [Indexed: 11/18/2022] Open
Abstract
Insulin resistance leads to memory impairment. Cinnamon (CN) improves peripheral insulin resistance but its effects in the brain are not known. Changes in behavior, insulin signaling and Alzheimer-associated mRNA expression in the brain were measured in male Wistar rats fed a high fat/high fructose (HF/HFr) diet to induce insulin resistance, with or without CN, for 12 weeks. There was a decrease in insulin sensitivity associated with the HF/HFr diet that was reversed by CN. The CN fed rats were more active in a Y maze test than rats fed the control and HF/HFr diets. The HF/HFr diet fed rats showed greater anxiety in an elevated plus maze test that was lessened by feeding CN. The HF/HFr diet also led to a down regulation of the mRNA coding for GLUT1 and GLUT3 that was reversed by CN in the hippocampus and cortex. There were increases in Insr, Irs1 and Irs2 mRNA in the hippocampus and cortex due to the HF/HFr diet that were not reversed by CN. Increased peripheral insulin sensitivity was also associated with increased glycogen synthase in both hippocampus and cortex in the control and HF/HFr diet animals fed CN. The HF/HFr diet induced increases in mRNA associated with Alzheimers including PTEN, Tau and amyloid precursor protein (App) were also alleviated by CN. In conclusion, these data suggest that the negative effects of a HF/HFr diet on behavior, brain insulin signaling and Alzheimer-associated changes were alleviated by CN suggesting that neuroprotective effects of CN are associated with improved whole body insulin sensitivity and related changes in the brain.
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Affiliation(s)
- Richard A. Anderson
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland, United States of America
- * E-mail:
| | - Bolin Qin
- Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland, United States of America
- Integrity Nutraceuticals International, Spring Hill, Tennessee, United States of America
| | - Frederic Canini
- Army Institute for Research in Biology, Grenoble, France
- Ecole du Val de Grâce, 1 place Laveran, Paris, France
| | - Laurent Poulet
- Army Institute for Research in Biology, Grenoble, France
- National Institute for Health, Joseph Fourier University, Grenoble, France
| | - Anne Marie Roussel
- National Institute for Health, Joseph Fourier University, Grenoble, France
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Li X, Qu B, Jin X, Hai L, Wu Y. Design, synthesis and biological evaluation for docetaxel-loaded brain targeting liposome with “lock-in” function. J Drug Target 2013; 22:251-261. [DOI: 10.3109/1061186x.2013.865032] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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40
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Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention. PLoS One 2013; 8:e79977. [PMID: 24244584 PMCID: PMC3823655 DOI: 10.1371/journal.pone.0079977] [Citation(s) in RCA: 196] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 10/07/2013] [Indexed: 01/10/2023] Open
Abstract
We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3–15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6–9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain.
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Gupta RK, Przekwas A. Mathematical Models of Blast-Induced TBI: Current Status, Challenges, and Prospects. Front Neurol 2013; 4:59. [PMID: 23755039 PMCID: PMC3667273 DOI: 10.3389/fneur.2013.00059] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Accepted: 05/09/2013] [Indexed: 01/13/2023] Open
Abstract
Blast-induced traumatic brain injury (TBI) has become a signature wound of recent military activities and is the leading cause of death and long-term disability among U.S. soldiers. The current limited understanding of brain injury mechanisms impedes the development of protection, diagnostic, and treatment strategies. We believe mathematical models of blast wave brain injury biomechanics and neurobiology, complemented with in vitro and in vivo experimental studies, will enable a better understanding of injury mechanisms and accelerate the development of both protective and treatment strategies. The goal of this paper is to review the current state of the art in mathematical and computational modeling of blast-induced TBI, identify research gaps, and recommend future developments. A brief overview of blast wave physics, injury biomechanics, and the neurobiology of brain injury is used as a foundation for a more detailed discussion of multiscale mathematical models of primary biomechanics and secondary injury and repair mechanisms. The paper also presents a discussion of model development strategies, experimental approaches to generate benchmark data for model validation, and potential applications of the model for prevention and protection against blast wave TBI.
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Affiliation(s)
- Raj K Gupta
- Department of Defense Blast Injury Research Program Coordinating Office, U.S. Army Medical Research and Materiel Command , Fort Detrick, MD , USA
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DiNuzzo M, Giove F, Maraviglia B, Mangia S. Glucose metabolism down-regulates the uptake of 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (6-NBDG) mediated by glucose transporter 1 isoform (GLUT1): theory and simulations using the symmetric four-state carrier model. J Neurochem 2013; 125:236-46. [PMID: 23336592 DOI: 10.1111/jnc.12164] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 01/18/2013] [Accepted: 01/18/2013] [Indexed: 11/27/2022]
Abstract
The non-metabolizable fluorescent glucose analogue 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (6-NBDG) is increasingly used to study cellular transport of glucose. Intracellular accumulation of exogenously applied 6-NBDG is assumed to reflect concurrent gradient-driven glucose uptake by glucose transporters (GLUTs). Here, theoretical considerations are provided that put this assumption into question. In particular, depending on the microscopic parameters of the carrier proteins, theory proves that changes in glucose transport can be accompanied by opposite changes in flow of 6-NBDG. Simulations were carried out applying the symmetric four-state carrier model on the GLUT1 isoform, which is the only isoform whose kinetic parameters are presently available. Results show that cellular 6-NBDG uptake decreases with increasing rate of glucose utilization under core-model conditions, supported by literature, namely where the transporter is assumed to work in regime of slow reorientation of the free-carrier compared with the ligand-carrier complex. To observe an increase of 6-NBDG uptake with increasing rate of glucose utilization, and thus interpret 6-NBDG increase as surrogate of glucose uptake, the transporter must be assumed to operate in regime of slow ligand-carrier binding, a condition that is currently not supported by literature. Our findings suggest that the interpretation of data obtained with NBDG derivatives is presently ambiguous and should be cautious because the underlying transport kinetics are not adequately established.
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Affiliation(s)
- Mauro DiNuzzo
- MARBILab, Museo storico della fisica e Centro di studi e ricerche "Enrico Fermi", Rome, Italy
| | - Federico Giove
- MARBILab, Museo storico della fisica e Centro di studi e ricerche "Enrico Fermi", Rome, Italy.,Dipartimento di Fisica, Sapienza Università di Roma, Rome, Italy
| | - Bruno Maraviglia
- MARBILab, Museo storico della fisica e Centro di studi e ricerche "Enrico Fermi", Rome, Italy.,Fondazione Santa Lucia IRCCS, Rome, Italy
| | - Silvia Mangia
- Center for Magnetic Resonance Research, Dept. of Radiology, University of Minneapolis, Minnesota, USA
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Rodriguez M, Sabate M, Rodriguez-Sabate C, Morales I. The role of non-synaptic extracellular glutamate. Brain Res Bull 2012; 93:17-26. [PMID: 23149167 DOI: 10.1016/j.brainresbull.2012.09.018] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Revised: 09/07/2012] [Accepted: 09/12/2012] [Indexed: 12/21/2022]
Abstract
Although there are some mechanisms which allow the direct crossing of substances between the cytoplasm of adjacent cells (gap junctions), most substances use the extracellular space to diffuse between brain cells. The present work reviews the behavior and functions of extracellular glutamate (GLU). There are two extracellular pools of glutamate (GLU) in the brain, a synaptic pool whose functions in the excitatory neurotransmission has been widely studied and an extrasynaptic GLU pool although less known nonetheless is gaining attention among a growing number of researchers. Evidence accumulated over the last years shows a number of mechanisms capable of releasing glial GLU to the extracellular medium, thus modulating neurons, microglia and oligodendrocytes, and regulating the immune response, cerebral blood flow, neuronal synchronization and other brain functions. This new scenario is expanding present knowledge regarding the role of GLU in the brain under different physiological and pathological conditions. This article is part of a Special Issue entitled 'Extrasynaptic ionotropic receptors'.
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Affiliation(s)
- Manuel Rodriguez
- Laboratory of Neurobiology and Experimental Neurology, Department of Physiology, Faculty of Medicine, University of La Laguna, La Laguna, Tenerife, Canary Islands, Spain.
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Rodríguez-Rodríguez C, Telpoukhovskaia M, Orvig C. The art of building multifunctional metal-binding agents from basic molecular scaffolds for the potential application in neurodegenerative diseases. Coord Chem Rev 2012. [DOI: 10.1016/j.ccr.2012.03.008] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Coulter DA, Eid T. Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 2012; 60:1215-26. [PMID: 22592998 PMCID: PMC3375386 DOI: 10.1002/glia.22341] [Citation(s) in RCA: 215] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Accepted: 03/16/2012] [Indexed: 12/18/2022]
Abstract
Astrocytes play a critical role in regulation of extracellular neurotransmitter levels in the central nervous system. This function is particularly prominent for the excitatory amino acid glutamate, with estimates that 80-90% of extracellular glutamate uptake in brain is through astrocytic glutamate transporters. This uptake has significance both in regulation of the potential toxic accumulation of extracellular glutamate and in normal resupply of inhibitory and excitatory synapses with neurotransmitter. This resupply of neurotransmitter is accomplished by astroglial uptake of glutamate, transformation of glutamate to glutamine by the astrocytic enzyme glutamine synthetase (GS), and shuttling of glutamine back to excitatory and inhibitory neurons via specialized transporters. Once in neurons, glutamine is enzymatically converted back to glutamate, which is utilized for synaptic transmission, either directly, or following decarboxylation to γ-aminobutyric acid. Many neurologic and psychiatric conditions, particularly epilepsy, are accompanied by the development of reactive gliosis, a pathology characterized by anatomical and biochemical plasticity in astrocytes, accompanied by proliferation of these cells. Among the biochemical changes evident in reactive astrocytes is a downregulation of several of the important regulators of the glutamine-glutamate cycle, including GS, and possibly also glutamate transporters. This downregulation may have significance in contributing both to the aberrant excitability and to the altered neuropathology characterizing epilepsy. In the present review, we provide an overview of the normal function of astrocytes in regulating extracellular glutamate homeostasis, neurotransmitter supply, and excitotoxicity. We further discuss the potential role reactive gliosis may play in the pathophysiology of epilepsy.
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Affiliation(s)
- Douglas A Coulter
- Departments of Pediatrics and Neuroscience, University of Pennsylvania School of Medicine and the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Tore Eid
- Departments of Laboratory Medicine and Neurosurgery, Yale University School of Medicine and the Clinical Chemistry Laboratory, Yale-New Haven Hospital, New Haven, Connecticut
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Kiyatkin EA, Lenoir M. Rapid fluctuations in extracellular brain glucose levels induced by natural arousing stimuli and intravenous cocaine: fueling the brain during neural activation. J Neurophysiol 2012; 108:1669-84. [PMID: 22723672 DOI: 10.1152/jn.00521.2012] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Glucose, a primary energetic substrate for neural activity, is continuously influenced by two opposing forces that tend to either decrease its extracellular levels due to enhanced utilization in neural cells or increase its levels due to entry from peripheral circulation via enhanced cerebral blood flow. How this balance is maintained under physiological conditions and changed during neural activation remains unclear. To clarify this issue, enzyme-based glucose sensors coupled with high-speed amperometry were used in freely moving rats to evaluate fluctuations in extracellular glucose levels induced by brief audio stimulus, tail pinch (TP), social interaction with another rat (SI), and intravenous cocaine (1 mg/kg). Measurements were performed in nucleus accumbens (NAcc) and substantia nigra pars reticulata (SNr), which drastically differ in neuronal activity. In NAcc, where most cells are powerfully excited after salient stimulation, glucose levels rapidly (latency 2-6 s) increased (30-70 μM or 6-14% over baseline) by all stimuli; the increase differed in magnitude and duration for each stimulus. In SNr, where most cells are transiently inhibited by salient stimuli, TP, SI, and cocaine induced a biphasic glucose response, with the initial decrease (-20-40 μM or 5-10% below baseline) followed by a reboundlike increase. The critical role of neuronal activity in mediating the initial glucose response was confirmed by monitoring glucose currents after local microinjections of glutamate (GLU) or procaine (PRO). While intra-NAcc injection of GLU transiently increased glucose levels in this structure, intra-SNr PRO injection resulted in rapid, transient decreases in SNr glucose. Therefore, extracellular glucose levels in the brain change very rapidly after physiological and pharmacological stimulation, the response is structure specific, and the pattern of neuronal activity appears to be a critical factor determining direction and magnitude of physiological fluctuations in glucose levels.
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Affiliation(s)
- Eugene A Kiyatkin
- In-Vivo Electrophysiology Unit, Behavioral Neuroscience Branch, National Institute on Drug Abuse-Intramural Research Program, NIH, DHHS, 333 Cassell Dr., Baltimore, MD 21224, USA.
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Xie F, Yao N, Qin Y, Zhang Q, Chen H, Yuan M, Tang J, Li X, Fan W, Zhang Q, Wu Y, Hai L, He Q. Investigation of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers for brain targeting. Int J Nanomedicine 2012; 7:163-75. [PMID: 22275832 PMCID: PMC3263409 DOI: 10.2147/ijn.s23771] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND An intimidating challenge to transporting drugs into the brain parenchyma is the presence of the blood-brain barrier (BBB). Glucose is an essential nutritional substance for brain function sustenance, which cannot be synthesized by the brain. Its transport primarily depends on the glucose transporters on the brain capillary endothelial cells. In this paper, the brain-targeted properties of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers were compared and evaluated to establish an optimized drug-delivery system. METHODS Coumarin 6-loaded liposomes (GLU200-LIP, GLU400-LIP, GLU1000-LIP, and GLU2000-LIP) composed of phospholipids and glucose-derived cholesterols were prepared by thin-film dispersion-ultrasound method. The BBB model in vitro was developed to evaluate the transendothelial ability of the different liposomes crossing the BBB. The biodistribution of liposomes in the mice brains was identified by in vivo and ex vivo nearinfrared fluorescence imaging and confocal laser scanning microscopy and further analyzed quantitatively by high-performance liquid chromatography. RESULTS Glucose-derived cholesterols were synthesized and identified, and coumarin 6-loaded liposomes were prepared successfully. The particle sizes of the four types of glucose-modified liposomes were around or smaller than 100 nm with a polydispersity index less than 0.300. GLU400-LIP, GLU1000-LIP, and GLU2000-LIP achieved higher cumulative cleared volumes on BBB model in vitro after 6 hours compared with GLU200-LIP (P < 0.05) and were significantly higher than that of the conventional liposome (P < 0.001). The qualitative and quantitative biodistribution results in the mice showed that the accumulation of GLU1000-LIP in the brain was the highest among all the groups (P < 0.01 versus LIP). CONCLUSION The data indicated that GLU400-LIP, GLU1000-LIP, and GLU2000-LIP all possess the potential of brain targeting, among which GLU1000-LIP, as a promising drug-delivery system, exhibited the strongest brain delivery capacity.
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Affiliation(s)
- Fulan Xie
- Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17 Block 3 Southern Renmin Road, Chengdu, People's Republic of China
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Gantt RW, Peltier-Pain P, Thorson JS. Enzymatic methods for glyco(diversification/randomization) of drugs and small molecules. Nat Prod Rep 2011; 28:1811-53. [DOI: 10.1039/c1np00045d] [Citation(s) in RCA: 194] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Qin Y, Fan W, Chen H, Yao N, Tang W, Tang J, Yuan W, Kuai R, Zhang Z, Wu Y, He Q. In vitro and in vivo investigation of glucose-mediated brain-targeting liposomes. J Drug Target 2010; 18:536-49. [PMID: 20132091 DOI: 10.3109/10611861003587235] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
New glycosyl derivative of cholesterol was synthesized as a material for preparing novel liposome to overcome the ineffective delivery of normal drug formulations to brain by targeting the (glucose transporters) GLUTs on the BBB. Coumarin-6 was used as fluorescent probe. The results have shown that the cytotoxicity for the brain capillary endothelial cells (BCECs) of the glucose-mediated brain targeting liposome containing coumarin-6 was less than that of conventional liposome. The BBB model in vitro was established by coculturing of BCECs and astrocytes (ACs) of rat to test the transendothelial ability crossing the BBB. The transendothelial ability was confirmed strengthen alone with the amount of the new glycosyl derivative of cholesterol used in liposome. After i.v. administration of LIP, control liposome (CLP), and GLP-4, the AUC(0-t) of coumarin-6 for GLP-4 was 2.85 times higher than that of LIP, and 3.33 times higher than that of CLP. The C(max) of CLP-4 was 1.43 times higher than that of LIP, and 3.10 times higher than that of CLP. Both pharmacokinetics and distribution in mice were also investigated to show that this novel brain targeting drug delivery system was promising.
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Affiliation(s)
- Yao Qin
- Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China
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Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer's disease. J Neurochem 2009; 111:242-9. [PMID: 19659459 PMCID: PMC2760012 DOI: 10.1111/j.1471-4159.2009.06320.x] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Type 2 diabetes mellitus (T2DM) increases the risk for Alzheimer's disease (AD), but the underlying mechanism is unknown. In this study, we determined the levels of major brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in the postmortem brain tissue from frontal cortices of 7 controls, 11 T2DM subjects, 10 AD subjects and 8 additional subjects who had both T2DM and AD. We found that the neuronal glucose transporter 3 was decreased to a bigger extent in T2DM brain than in AD brain. The O-GlcNAcylation levels of global proteins and of tau were also decreased in T2DM brain as seen in AD brain. Phosphorylation of tau at some of the AD abnormal hyperphosphorylation sites was increased in T2DM brain. These results suggest that T2DM may contribute to the increased risk for AD by impairing brain glucose uptake/metabolism and, consequently, down-regulation of O-GlcNAcylation, which facilitates abnormal hyperphosphorylation of tau.
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Affiliation(s)
- Ying Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang District, Wuhan, Hubei 430060, PR China
| | | | | | | | - Cheng-Xin Gong
- Address correspondence and reprint requests to Dr. Cheng-Xin Gong, Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA. Phone: 1-718-494-5248; Fax: 1-718-494-1080; or
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