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Sourij H, Azhar K, Aberer F, Sourij C, Tripolt NJ, Kojzar H, Pferschy PN, Buchmann A, Aziz F, Khalil M. Impact of level 2 hypoglycaemia on neuroaxonal damage biomarker in individuals with type 2 diabetes: A stepwise hypoglycaemic clamp study. Diabetes Obes Metab 2025. [PMID: 40091483 DOI: 10.1111/dom.16340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/19/2025]
Affiliation(s)
- Harald Sourij
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Kehkishan Azhar
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Felix Aberer
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Caren Sourij
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
- Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Norbert J Tripolt
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Harald Kojzar
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Peter N Pferschy
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | | | - Faisal Aziz
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Michael Khalil
- Department of Neurology, Medical University of Graz, Graz, Austria
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Lin L, Chen Z, Huang C, Wu Y, Huang L, Wang L, Ke S, Liu L. Mito-TEMPO, a Mitochondria-Targeted Antioxidant, Improves Cognitive Dysfunction due to Hypoglycemia: an Association with Reduced Pericyte Loss and Blood-Brain Barrier Leakage. Mol Neurobiol 2023; 60:672-686. [PMID: 36357613 DOI: 10.1007/s12035-022-03101-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/23/2022] [Indexed: 11/12/2022]
Abstract
Hypoglycemia is associated with cognitive dysfunction, but the exact mechanisms have not been elucidated. Our previous study found that severe hypoglycemia could lead to cognitive dysfunction in a type 1 diabetes (T1D) mouse model. Thus, the aim of this study was to further investigate whether the mechanism of severe hypoglycemia leading to cognitive dysfunction is related to oxidative stress-mediated pericyte loss and blood-brain barrier (BBB) leakage. A streptozotocin T1D model (150 mg/kg, one-time intraperitoneal injection), using male C57BL/6J mice, was used to induce hypoglycemia. Brain tissue was extracted to examine for neuronal damage, permeability of BBB was investigated through Evans blue staining and electron microscopy, reactive oxygen species and adenosine triphosphate in brain tissue were assayed, and the functional changes of pericytes were determined. Cognitive function was tested using Morris water maze. Also, an in vitro glucose deprivation model was constructed. The results showed that BBB leakage after hypoglycemia is associated with excessive activation of oxidative stress and mitochondrial dysfunction due to glucose deprivation/reperfusion. Interventions using the mitochondria-targeted antioxidant Mito-TEMPO in both in vivo and in vitro models reduced mitochondrial oxidative stress, decreased pericyte loss and apoptosis, and attenuated BBB leakage and neuronal damage, ultimately leading to improved cognitive function.
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Affiliation(s)
- Lu Lin
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Zhou Chen
- School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Cuihua Huang
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Yubin Wu
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Lishan Huang
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Lijing Wang
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Sujie Ke
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Libin Liu
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China.
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3
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Stephenson L, van den Heuvel C, Humphries M, Byard RW. Characteristics of fatal insulin overdoses. Forensic Sci Med Pathol 2022; 18:429-441. [PMID: 35943711 PMCID: PMC9636090 DOI: 10.1007/s12024-022-00511-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2022] [Indexed: 12/14/2022]
Abstract
This study was undertaken to review fatal cases of insulin overdose in South Australia (SA) over a 20-year period to assess rates and characteristics of insulin-related deaths among insulin-dependent diabetics and non-diabetics for all manners of death. Records from the National Coronial Information System (NCIS) and Forensic Science SA (FSSA) were searched for all cases of fatal insulin overdose in South Australia (SA) between 2000 and 2019. Collected variables included age, sex, cause of death, scene findings, manner of death, decedent medical and personal histories, biochemistry, toxicology, histopathology, and autopsy findings. Statistical analyses were performed using R (version 4.1.2). Forty cases of insulin overdose were identified in SA between 2000 and 2019. Twenty-nine cases (72.5%) were suicides, with the remaining cases classified as accidental or undetermined intent. Thirteen of the 22 insulin-dependent diabetics (59%) had a history of depression, 10 of whom had previously demonstrated suicidal ideation. The current study has shown that suicides using insulin among insulin-dependent diabetics are equally as prevalent, if not more so than fatal accidental insulin overdoses. This can largely be attributed to insulin-dependent diabetic access to a potentially lethal substance. Suicide prevention strategies should focus on insulin-dependent diabetics with a history of depression, particularly for those with access to rapid-acting insulin.
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Affiliation(s)
- Lilli Stephenson
- School of Biomedicine, The University of Adelaide, Adelaide, South Australia, 5000, Australia.
| | - Corinna van den Heuvel
- School of Biomedicine, The University of Adelaide, Adelaide, South Australia, 5000, Australia
| | - Melissa Humphries
- School of Mathematical Sciences, The University of Adelaide, Adelaide, South Australia, 5000, Australia
| | - Roger W Byard
- School of Biomedicine, The University of Adelaide, Adelaide, South Australia, 5000, Australia
- Forensic Science SA (FSSA), Adelaide, South Australia, 5000, Australia
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Sreedharan R, Martini A, Das G, Aftab N, Khanna S, Ruetzler K. Clinical challenges of glycemic control in the intensive care unit: A narrative review. World J Clin Cases 2022; 10:11260-11272. [PMID: 36387820 PMCID: PMC9649548 DOI: 10.12998/wjcc.v10.i31.11260] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/15/2022] [Accepted: 09/27/2022] [Indexed: 02/05/2023] Open
Abstract
Glucose control in patient admitted to the intensive care unit has been a topic of much debate over the past 20 years. The harmful effects of uncontrolled hyperglycemia and hypoglycemia in critically ill patients is well established. Although a large clinical trial in 2001 demonstrated significant mortality and morbidity benefits with tight glucose control in this patient population, the results could not be replicated by other investigators. The “Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation” trial in 2009 established that tight glucose control was not only of no benefit, but in fact harmful due to the significant risk of hypoglycemia. The current guidelines suggest a moderate approach with the initiation of intravenous insulin therapy in critically ill patients when the blood glucose level is above 180 mg/dL. The most important factor that underpins glycemic management in intensive care unit patients is the consequent prevention of hypoglycemia. Robust glucose monitoring strategies and insulin protocols need to be implemented in order to achieve this goal.
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Affiliation(s)
- Roshni Sreedharan
- Anesthesiology Institute, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Adriana Martini
- Anesthesiology Institute, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Gyan Das
- Anesthesiology Institute, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Nida Aftab
- Anesthesiology Institute, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Sandeep Khanna
- Anesthesiology Institute, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Kurt Ruetzler
- Anesthesiology Institute, Cleveland Clinic, Cleveland, OH 44195, United States
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Administration of an Acidic Sphingomyelinase (ASMase) Inhibitor, Imipramine, Reduces Hypoglycemia-Induced Hippocampal Neuronal Death. Cells 2022; 11:cells11040667. [PMID: 35203316 PMCID: PMC8869983 DOI: 10.3390/cells11040667] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/31/2022] [Accepted: 02/12/2022] [Indexed: 01/27/2023] Open
Abstract
Severe hypoglycemia (below 35 mg/dL) appears most often in diabetes patients who continuously inject insulin. To rapidly cease the hypoglycemic state in this study, glucose reperfusion was conducted, which can induce a secondary neuronal death cascade following hypoglycemia. Acid sphingomyelinase (ASMase) hydrolyzes sphingomyelin into ceramide and phosphorylcholine. ASMase activity can be influenced by cations, pH, redox, lipids, and other proteins in the cells, and there are many changes in these factors in hypoglycemia. Thus, we expect that ASMase is activated excessively after hypoglycemia. Ceramide is known to cause free radical production, excessive inflammation, calcium dysregulation, and lysosomal injury, resulting in apoptosis and the necrosis of neurons. Imipramine is mainly used in the treatment of depression and certain anxiety disorders, and it is particularly known as an ASMase inhibitor. We hypothesized that imipramine could decrease hippocampal neuronal death by reducing ceramide via the inhibition of ASMase after hypoglycemia. In the present study, we confirmed that the administration of imipramine significantly reduced hypoglycemia-induced neuronal death and improved cognitive function. Therefore, we suggest that imipramine may be a promising therapeutic tool for preventing hypoglycemia-induced neuronal death.
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Abstract
The discovery of insulin and its subsequent mass manufacture transformed the lives of people with type 1 and 2 diabetes. Insulin, however, was a drug with a 'dark side'. It brought with it the risk of iatrogenic hypoglycaemia. In this short review, the cellular consequences of recurrent hypoglycaemia, with a particular focus on the brain, are discussed. Using the ventromedial hypothalamus as an exemplar, this review highlights how recurrent hypoglycaemia has an impact on the specialised cells in the brain that are critical to the regulation of glucose homeostasis and the counterregulatory response to hypoglycaemia. In these cells, recurrent hypoglycaemia initiates a series of adaptations that ensure that they are more resilient to subsequent hypoglycaemia, but this leads to impaired hypoglycaemia awareness and a paradoxical increased risk of severe hypoglycaemia. This review also highlights how hypoglycaemia, as an oxidative stressor, may also exacerbate chronic hyperglycaemia-induced increases in oxidative stress and inflammation, leading to damage to vulnerable brain regions (and other end organs) and accelerating cognitive decline. Pre-clinical research indicates that glucose recovery following hypoglycaemia is considered a period where reactive oxygen species generation and oxidative stress are pronounced and can exacerbate the longer-term consequence of chronic hypoglycaemia. It is proposed that prior glycaemic control, hypoglycaemia and the degree of rebound hyperglycaemia interact synergistically to accelerate oxidative stress and inflammation, which may explain why increased glycaemic variability is now increasingly considered a risk factor for the complications of diabetes.
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Affiliation(s)
- Rory J McCrimmon
- Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
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Kho AR, Hong DK, Kang BS, Park WJ, Choi KC, Park KH, Suh SW. The Effects of Atorvastatin on Global Cerebral Ischemia-Induced Neuronal Death. Int J Mol Sci 2021; 22:ijms22094385. [PMID: 33922266 PMCID: PMC8122811 DOI: 10.3390/ijms22094385] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 11/16/2022] Open
Abstract
(1) Background and Purpose: Global cerebral ischemia-induced severe hypoxic brain damage is one of the main causes of mortality and long-term neurologic disability even after receiving early blood reperfusion. This study aimed to test the hypothesis that atorvastatin potentially has neuroprotective effects in global cerebral ischemia (GCI). (2) Methods: We performed two sets of experiments, analyzing acute (1-week) and chronic (4-week) treatments. For the vehicle (Veh) and statin treatments, 1 mL of 0.9% saline and 5 mg/kg of atorvastatin (ATOR) were administered orally. For histological analysis, we used the following staining protocols: Fluoro-Jade B and NeuN, 4-hydroxynonenal, CD11b and GFAP, IgG, SMI71, and vWF. Finally, we evaluated the cognitive function with a battery of behavioral tests. (3) Results: The GCI-ATOR group showed significantly reduced neuronal death, oxidative stress, inflammation, and BBB disruption compared with the GCI-Veh group. Moreover, the GCI-ATOR group showed decreased endothelial damage and VV proliferation and had significantly improved cognitive function compared with the GCI-Veh group in both models. (4) Conclusions: ATOR has neuroprotective effects and helps recover the cognitive function after GCI in rats. Therefore, administration of atorvastatin may be a therapeutic option in managing GCI after CA.
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Affiliation(s)
- A Ra Kho
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea; (A.R.K.); (D.K.H.); (B.S.K.)
| | - Dae Ki Hong
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea; (A.R.K.); (D.K.H.); (B.S.K.)
| | - Beom Seok Kang
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea; (A.R.K.); (D.K.H.); (B.S.K.)
| | - Woo-Jung Park
- Division of Cardiovascular Disease, Hallym University Medical Center, Anyang 14068, Korea;
| | - Kyung Chan Choi
- Department of Pathology, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon 24252, Korea;
| | - Kyoung-Ha Park
- Division of Cardiovascular Disease, Hallym University Medical Center, Anyang 14068, Korea;
- Correspondence: (K.-H.P.); (S.W.S.); Tel.: +82-31-380-1725 (K.-H.P.); +82-10-8573-6364 (S.W.S.); Fax: +82-31-386-2269 (K.-H.P.); +82-33-248-2580 (S.W.S.)
| | - Sang Won Suh
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea; (A.R.K.); (D.K.H.); (B.S.K.)
- Correspondence: (K.-H.P.); (S.W.S.); Tel.: +82-31-380-1725 (K.-H.P.); +82-10-8573-6364 (S.W.S.); Fax: +82-31-386-2269 (K.-H.P.); +82-33-248-2580 (S.W.S.)
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Wang X, Hu X, Zhang L, Xu X, Sakurai T. Nicotinamide mononucleotide administration after sever hypoglycemia improves neuronal survival and cognitive function in rats. Brain Res Bull 2020; 160:98-106. [PMID: 32380185 DOI: 10.1016/j.brainresbull.2020.04.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/23/2020] [Accepted: 04/27/2020] [Indexed: 10/24/2022]
Abstract
Hypoglycemia-induced brain injury is a potential complication of insulin therapy in diabetic patients. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that may lead to neuronal death and cognitive impairment even after glucose normalization. Oxidative stress and the activation of poly (ADP-ribose) polymerase-1 (PARP-1) are key events in this cascade. The production of reactive oxygen species (ROS) induces DNA damage and the consequent PARP-1 activation, which depletes NAD+ and ATP, resulting in brain injury. One of the key precursors of NAD+ is nicotinamide mononucleotide (NMN), which is converted to NAD+ and reduces production of ROS. Here we investigated whether NMN could reduce brain injury after severe hypoglycemia. We used a rat model of insulin-induced severe hypoglycemia and injected NMN (500 mmg/kg, i.p., one week) following 30 min of severe hypoglycemia, at the time of glucose administration. One week after severe hypoglycemia, hippocampal long-term potentiation (LTP), an electrophysiogic assay of synaptic plasticity, was examined and neuronal damage was assessed by Hematoxylin-Eosin staining. ROS accumulation, PARP-1 activation, NAD+ and ATP levels in hippocampus were also measured. Cognitive function was assessed using the Morris water maze 6 weeks after severe hypoglycemia. The addition of NMN reduced neuron death by 83 ± 3% (P < 0.05) after severe hypoglycemia. The hippocampal LTP was significantly reduced by severe hypoglycemia but showed recovery in the NMN addition group. NMN treatment also attenuated the severe hypoglycemia-induced spatial learning and memory impairment. Mechanically, we showed that NMN administration decreased ROS accumulation, suppressed PARP-1 activation, and restored levels of NAD+ and ATP in hippocampus. All these protective effects were reversed by 3-acetylpyridine (3-AP), which generates inactive NAD+. In summary, NMN administration following severe hypoglycemia could ameliorate neuronal damage and cognitive impairment caused by severe hypoglycemia. These results suggest that NMN may be a promising therapeutic drug to prevent hypoglycemia-induced brain injury.
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Affiliation(s)
- Xiaonan Wang
- Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China.
| | - Xuejun Hu
- Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Li Zhang
- Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xi Xu
- Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China
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Tomita N, Nakamura T, Sunden Y, Miyata H, Morita T. Temporal analysis of histopathology and cytokine expression in the rat cerebral cortex after insulin-induced hypoglycemia. Neuropathology 2020; 40:240-250. [PMID: 32080930 DOI: 10.1111/neup.12643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/24/2019] [Accepted: 12/25/2019] [Indexed: 11/30/2022]
Abstract
Hypoglycemic coma causes neuronal death in the cerebral neocortex; however, its unclear pathogenesis prevents the establishment of preventive measures. Inflammation plays a pivotal role in neuronal damage in the hypoglycemic state; however, the dynamics of glial cell activation or cytokine expression remain unknown. Here, we aimed to elucidate the spatiotemporal morphological changes of microglia and time-course cytokine expression profiles in the rat cerebral cortex after hypoglycemic coma. We performed histopathological and immunohistochemical (Iba1, neuronal nuclei, glial fibrillary acidic protein) analyses in the cingulate cortex and four areas of the neocortex: hindlimb area (HL), parietal cortex area 1 (Par1), parietal cortex area 2 (Par2), and perirhinal cortex (PRh). We measured tumor necrosis factor alpha (TNFα) and interleukin-6 messenger RNA (mRNA) expression by real-time reverse transcriptase-polymerase chain reaction. Necrotic neurons appeared in the neocortex as early as 3 h after hypoglycemic coma, while they were absent in the cingulate cortex. Neuronal nuclei-immunopositive neurons in the HL, Par2, and PRh were significantly less abundant than in the control at day 1. In Iba1 immunostaining, large rod-shaped cells were detected at 3-6 h after hypoglycemia, and commonly observed in the HL, Par2, and PRh. After 6 h, rod-shaped cells were rarely observed; instead, there was a prominent infiltration of hypertrophic and ameboid-shaped cells until day 7. The mRNA expression of TNFα was significantly higher than the control at 3-6 h after hypoglycemia in the neocortex, while it was significantly higher only at 3 h in the cingulate cortex. Our results indicate that early and transient appearance of rod-shaped microglia and persisting high TNFα expression levels characterize inflammatory responses to hypoglycemic neuronal damage in the cerebral neocortex, which might contribute to neuronal necrosis in response to transient hypoglycemic coma.
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Affiliation(s)
- Nagi Tomita
- Laboratory of Veterinary Pathology, Tottori University, Tottori, Japan.,The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| | - Tomoki Nakamura
- Laboratory of Veterinary Pathology, Tottori University, Tottori, Japan
| | - Yuji Sunden
- Laboratory of Veterinary Pathology, Tottori University, Tottori, Japan
| | - Hajime Miyata
- Department of Neuropathology, Research Institute for Brain and Blood Vessels, Akita Cerebrospinal and Cardiovascular Center, Akita, Japan
| | - Takehito Morita
- Laboratory of Veterinary Pathology, Tottori University, Tottori, Japan
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Tomita N, Nakamura T, Sunden Y, Morita T. Histopathological and immunohistochemical analysis of the cerebral white matter after transient hypoglycemia in rat. J Vet Med Sci 2019; 82:68-76. [PMID: 31787662 PMCID: PMC6983658 DOI: 10.1292/jvms.19-0502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Patients with hypoglycemic coma show abnormal signals in the white matter on magnetic resonance imaging. However, the precise pathological changes in the white matter caused by hypoglycemic
coma remain unclear in humans and experimental animals. This study aimed to reveal the distribution and time course of histopathological and immunohistochemical changes occurring in the
white matter during the early stages of hypoglycemic coma in rats. Insulin-induced hypoglycemic coma of 15–30-min duration was induced in rats, followed by recovery using a glucose solution.
Rat brains were collected after 6 and 24 hr and after 3, 5, 7, and 14 days. The brains were submitted for histological and immunohistochemical analysis for neurofilament 200 kDa (NF), myelin
basic protein, olig-2, Iba-1, and glial fibrillary acidic protein (GFAP). Vacuolation was observed in the fiber bundles of the globus pallidus on days 1–14. Most of the vacuoles were located
in GFAP-positive astrocytic processes or the extracellular space and appeared to be edematous. Additionally, myelin pallor and a decrease in NF-positive signals were observed on day 14.
Microgliosis and astrogliosis were also detected. Observations similar to the globus pallidus, except for edema, were noted in the internal capsule. In the corpus callosum, a mild decrease
in NF-positive signals, microgliosis, and astrogliosis were observed. These results suggest that after transient hypoglycemic coma, edema and/or degeneration occurred in the white matter,
especially in the globus pallidus, internal capsule, and corpus callosum in the early stages.
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Affiliation(s)
- Nagi Tomita
- Laboratory of Veterinary Pathology, Tottori University, Tottori, Tottori 680-8553, Japan.,The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Yamaguchi 753-8511, Japan
| | - Tomoki Nakamura
- Laboratory of Veterinary Pathology, Tottori University, Tottori, Tottori 680-8553, Japan
| | - Yuji Sunden
- Laboratory of Veterinary Pathology, Tottori University, Tottori, Tottori 680-8553, Japan
| | - Takehito Morita
- Laboratory of Veterinary Pathology, Tottori University, Tottori, Tottori 680-8553, Japan
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The Effects of Sodium Dichloroacetate on Mitochondrial Dysfunction and Neuronal Death Following Hypoglycemia-Induced Injury. Cells 2019; 8:cells8050405. [PMID: 31052436 PMCID: PMC6562710 DOI: 10.3390/cells8050405] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/17/2019] [Accepted: 05/01/2019] [Indexed: 12/15/2022] Open
Abstract
Our previous studies demonstrated that some degree of neuronal death is caused by hypoglycemia, but a subsequent and more severe wave of neuronal cell death occurs due to glucose reperfusion, which results from the rapid restoration of low blood glucose levels. Mitochondrial dysfunction caused by hypoglycemia leads to increased levels of pyruvate dehydrogenase kinase (PDK) and suppresses the formation of ATP by inhibiting pyruvate dehydrogenase (PDH) activation, which can convert pyruvate into acetyl-coenzyme A (acetyl-CoA). Sodium dichloroacetate (DCA) is a PDK inhibitor and activates PDH, the gatekeeper of glucose oxidation. However, no studies about the effect of DCA on hypoglycemia have been published. In the present study, we hypothesized that DCA treatment could reduce neuronal death through improvement of glycolysis and prevention of reactive oxygen species production after hypoglycemia. To test this, we used an animal model of insulin-induced hypoglycemia and injected DCA (100 mg/kg, i.v., two days) following hypoglycemic insult. Histological evaluation was performed one week after hypoglycemia. DCA treatment reduced hypoglycemia-induced oxidative stress, microglial activation, blood–brain barrier disruption, and neuronal death compared to the vehicle-treated hypoglycemia group. Therefore, our findings suggest that DCA may have the therapeutic potential to reduce hippocampal neuronal death after hypoglycemia.
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12
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Brown AM, Evans RD, Smith PA, Rich LR, Ransom BR. Hypothermic neuroprotection during reperfusion following exposure to aglycemia in central white matter is mediated by acidification. Physiol Rep 2019; 7:e14007. [PMID: 30834716 PMCID: PMC6399195 DOI: 10.14814/phy2.14007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 01/30/2019] [Indexed: 11/24/2022] Open
Abstract
Hypoglycemia is a common iatrogenic consequence of type 1 diabetes therapy that can lead to central nervous system injury and even death if untreated. In the absence of clinically effective neuroprotective drugs we sought to quantify the putative neuroprotective effects of imposing hypothermia during the reperfusion phase following aglycemic exposure to central white matter. Mouse optic nerves (MONs), central white matter tracts, were superfused with oxygenated artificial cerebrospinal fluid (aCSF) containing 10 mmol/L glucose at 37°C. The supramaximal compound action potential (CAP) was evoked and axon conduction was assessed as the CAP area. Extracellular lactate was measured using an enzyme biosensor. Exposure to aglycemia, simulated by omitting glucose from the aCSF, resulted in axon injury, quantified by electrophysiological recordings, electron microscopic analysis confirming axon damage, the extent of which was determined by the duration of aglycemia exposure. Hypothermia attenuated injury. Exposing MONs to hypothermia during reperfusion resulted in improved CAP recovery compared with control recovery measured at 37°C, an effect attenuated in alkaline aCSF. Hypothermia decreases pH implying that the hypothermic neuroprotection derives from interstitial acidification. These results have important clinical implications demonstrating that hypothermic intervention during reperfusion can improve recovery in central white matter following aglycemia.
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Affiliation(s)
- Angus M. Brown
- School of Life SciencesQueens Medical CentreUniversity of NottinghamNottinghamUnited Kingdom
- Department of NeurologySchool of MedicineUniversity of WashingtonSeattleWashington
| | - Richard D. Evans
- School of Life SciencesQueens Medical CentreUniversity of NottinghamNottinghamUnited Kingdom
| | - Paul A. Smith
- School of Life SciencesQueens Medical CentreUniversity of NottinghamNottinghamUnited Kingdom
| | - Laura R. Rich
- School of Life SciencesQueens Medical CentreUniversity of NottinghamNottinghamUnited Kingdom
| | - Bruce R. Ransom
- Department of NeurologySchool of MedicineUniversity of WashingtonSeattleWashington
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Lin SY, Lin CL, Hsu WH, Lin CC, Fu YC. Association of attention deficit hyperactivity disorder with recurrent hypoglycemia in type 1 diabetes mellitus. Pediatr Diabetes 2019; 20:189-196. [PMID: 29938875 DOI: 10.1111/pedi.12716] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 05/22/2018] [Accepted: 06/07/2018] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE Data regarding the association between hypoglycemia and attention deficit hyperactivity disorder (ADHD) in children and adolescents with type 1 diabetes mellitus (T1DM) are limited. This study investigated whether hypoglycemia was associated with the risk of ADHD in young people with T1DM. METHODS Children and adolescents with a diagnosis of T1DM were identified from the Longitudinal National Health Insurance Database in Taiwan from 1998 to 2011. Among them who were newly diagnosed with hypoglycemia during 2000 to 2007 were selected for the hypoglycemia cohort. The hypoglycemia diagnosis date was defined as the index date. Those who were diagnosed with ADHD before the index date were excluded. The main outcome was the development of ADHD. In total, 726 participants with hypoglycemia and 2852 participants without hypoglycemia were included in this study. RESULTS The overall incidence density of ADHD was markedly increased among cohort with hypoglycemia compared with cohort without hypoglycemia (4.74 vs 1.65 per 1000 person-years), with an adjusted hazard ratio (aHR) of 2.73 (95% confidence interval [CI] = 1.50-4.98). Cohort with hypoglycemia who had experienced a hypoglycemic coma had a significantly higher risk of ADHD (aHR = 6.54, 95% CI = 1.89-22.7) compared with cohort without hypoglycemia. CONCLUSIONS Hypoglycemia, especially hypoglycemic coma, is significantly associated with a subsequent risk of ADHD in young people with T1DM.
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Affiliation(s)
- Shih-Yi Lin
- Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.,Department of Nephrology, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Wu-Huei Hsu
- Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.,Department of Chest, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Chieh Lin
- Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.,Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yun-Ching Fu
- China Medical University Children's Hospital, Taichung, Taiwan.,Department of Pediatrics and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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14
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Yager JY. Glucose and Perinatal Brain Injury—Questions and Controversies. Neurology 2019. [DOI: 10.1016/b978-0-323-54392-7.00009-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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15
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Abstract
West syndrome (WS) is an early life epileptic encephalopathy associated with infantile spasms, interictal electroencephalography (EEG) abnormalities including high amplitude, disorganized background with multifocal epileptic spikes (hypsarrhythmia), and often neurodevelopmental impairments. Approximately 64% of the patients have structural, metabolic, genetic, or infectious etiologies and, in the rest, the etiology is unknown. Here we review the contribution of etiologies due to various metabolic disorders in the pathology of WS. These may include metabolic errors in organic molecules involved in amino acid and glucose metabolism, fatty acid oxidation, metal metabolism, pyridoxine deficiency or dependency, or acidurias in organelles such as mitochondria and lysosomes. We discuss the biochemical, clinical, and EEG features of these disorders as well as the evidence of how they may be implicated in the pathogenesis and treatment of WS. The early recognition of these etiologies in some cases may permit early interventions that may improve the course of the disease.
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Affiliation(s)
- Seda Salar
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Solomon L. Moshé
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Department of PediatricsMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Aristea S. Galanopoulou
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
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16
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Effects of Protocatechuic Acid (PCA) on Global Cerebral Ischemia-Induced Hippocampal Neuronal Death. Int J Mol Sci 2018; 19:ijms19051420. [PMID: 29747437 PMCID: PMC5983751 DOI: 10.3390/ijms19051420] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 05/08/2018] [Accepted: 05/08/2018] [Indexed: 12/31/2022] Open
Abstract
Global cerebral ischemia (GCI) is one of the main causes of hippocampal neuronal death. Ischemic damage can be rescued by early blood reperfusion. However, under some circumstances reperfusion itself can trigger a cell death process that is initiated by the reintroduction of blood, followed by the production of superoxide, a blood⁻brain barrier (BBB) disruption and microglial activation. Protocatechuic acid (PCA) is a major metabolite of the antioxidant polyphenols, which have been discovered in green tea. PCA has been shown to have antioxidant effects on healthy cells and anti-proliferative effects on tumor cells. To test whether PCA can prevent ischemia-induced hippocampal neuronal death, rats were injected with PCA (30 mg/kg/day) per oral (p.o) for one week after global ischemia. To evaluate degenerating neurons, oxidative stress, microglial activation and BBB disruption, we performed Fluoro-Jade B (FJB), 4-hydroxynonenal (4HNE), CD11b, GFAP and IgG staining. In the present study, we found that PCA significantly decreased degenerating neuronal cell death, oxidative stress, microglial activation, astrocyte activation and BBB disruption compared with the vehicle-treated group after ischemia. In addition, an ischemia-induced reduction in glutathione (GSH) concentration in hippocampal neurons was recovered by PCA administration. Therefore, the administration of PCA may be further investigated as a promising tool for decreasing hippocampal neuronal death after global cerebral ischemia.
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17
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Xi C, Pan C, Li T. Abnormally low Bispectral index and severe hypoglycemia during maintenance of and recovery from general anesthesia in diabetic retinopathy surgery: two case reports. BMC Anesthesiol 2018; 18:45. [PMID: 29678142 PMCID: PMC5910559 DOI: 10.1186/s12871-018-0510-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 04/13/2018] [Indexed: 11/25/2022] Open
Abstract
Background Hypoglycemia is one of the most fatal complications during the perioperative period. General anesthesia or sedation can mask a hypoglycemia-altered mental status. Acute hypoglycemia might result in permanent brain injury. There is no way to detect hypoglycemia during general anesthesia, except for intermittent blood glucose monitoring. Case presentation Hypoglycemia is associated with changes in electroencephalogram readings. Here, we report two cases of patients with an abnormally low Bispectral Index (BIS) associated with diabetic retinopathy surgery, one in the recovery stage of general anesthesia and the other in the maintenance of general anesthesia. Hemodynamics were stable. Severe hypoglycemia (1.6 mmol/L and 2.2 mmol/L) was then detected. BIS increased with the correction of severe hypoglycemia. Conclusions For diabetic patients, when the intraoperative BIS value is abnormally low, hypoglycemia should be considered. Severe hypoglycemia may be presented in BIS monitoring during general anesthesia.
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Affiliation(s)
- Chunhua Xi
- Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Dongjiaominxiang 1, Dongchen District, Beijing, 100730, China
| | - Chuxiong Pan
- Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Dongjiaominxiang 1, Dongchen District, Beijing, 100730, China
| | - Tianzuo Li
- Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Tieyilu 10, Yangfangdian, Haidian District, Beijing, 100038, China.
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18
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Kim JH, Choi BY, Kho AR, Lee SH, Jeong JH, Hong DK, Lee SH, Sohn M, Ryu OH, Choi MG, Suh SW. Acetylcholine precursor, citicoline (cytidine 5'-diphosphocholine), reduces hypoglycaemia-induced neuronal death in rats. J Neuroendocrinol 2018; 30. [PMID: 29247563 DOI: 10.1111/jne.12567] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 11/23/2017] [Accepted: 12/11/2017] [Indexed: 01/21/2023]
Abstract
Citicoline (cytidine 5'-diphosphocholine) is an important precursor for the synthesis of neuronal plasma membrane phospholipids, mainly phosphatidylcholine. The administration of citicoline serves as a choline donor for the synthesis of acetylcholine. Citicoline has been shown to reduce the neuronal injury in animal models with cerebral ischaemia and in clinical trials of stroke patients. Citicoline is currently being investigated in a multicentre clinical trial. However, citicoline has not yet been examined the context of hypoglycaemia-induced neuronal death. To clarify the therapeutic impact of citicoline in hypoglycaemia-induced neuronal death, we used a rat model with insulin-induced hypoglycaemia. Acute hypoglycaemia was induced by i.p. injection of regular insulin (10 U kg-1 ) after overnight fasting, after which iso-electricity was maintained for 30 minutes. Citicoline injections (500 mg/kg, i.p.) were started immediately after glucose reperfusion. We found that post-treatment of citicoline resulted in significantly reduced neuronal death, oxidative injury and microglial activation in the hippocampus compared to vehicle-treated control groups at 7 days after induced hypoglycaemia. Citicoline administration after hypoglycaemia decreased immunoglobulin leakage via blood-brain barrier disruption in the hippocampus compared to the vehicle group. Citicoline increased choline acetyltransferase expression for phosphatidylcholine synthesis after hypoglycaemia. Altogether, the present findings suggest that neuronal membrane stabilisation by citicoline administration can save neurones from the degeneration process after hypoglycaemia, as seen in several studies of ischaemia. Therefore, the results suggest that citicoline may have therapeutic potential to reduce hypoglycaemia-induced neuronal death.
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Affiliation(s)
- J H Kim
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - B Y Choi
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - A R Kho
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - S H Lee
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - J H Jeong
- Department of Medical Life Science, College of Medicine, Hallym University, Chuncheon, Korea
| | - D K Hong
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - S H Lee
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - M Sohn
- Department of Nursing, Inha University, Incheon, Korea
| | - O H Ryu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University, College of Medicine, Chuncheon, Korea
| | - M-G Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University, College of Medicine, Chuncheon, Korea
| | - S W Suh
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
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19
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20
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Shukla V, Shakya AK, Perez-Pinzon MA, Dave KR. Cerebral ischemic damage in diabetes: an inflammatory perspective. J Neuroinflammation 2017; 14:21. [PMID: 28115020 PMCID: PMC5260103 DOI: 10.1186/s12974-016-0774-5] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 12/07/2016] [Indexed: 12/16/2022] Open
Abstract
Stroke is one of the leading causes of death worldwide. A strong inflammatory response characterized by activation and release of cytokines, chemokines, adhesion molecules, and proteolytic enzymes contributes to brain damage following stroke. Stroke outcomes are worse among diabetics, resulting in increased mortality and disabilities. Diabetes involves chronic inflammation manifested by reactive oxygen species generation, expression of proinflammatory cytokines, and activation/expression of other inflammatory mediators. It appears that increased proinflammatory processes due to diabetes are further accelerated after cerebral ischemia, leading to increased ischemic damage. Hypoglycemia is an intrinsic side effect owing to glucose-lowering therapy in diabetics, and is known to induce proinflammatory changes as well as exacerbate cerebral damage in experimental stroke. Here, we present a review of available literature on the contribution of neuroinflammation to increased cerebral ischemic damage in diabetics. We also describe the role of hypoglycemia in neuroinflammation and cerebral ischemic damage in diabetics. Understanding the role of neuroinflammatory mechanisms in worsening stroke outcome in diabetics may help limit ischemic brain injury and improve clinical outcomes.
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Affiliation(s)
- Vibha Shukla
- Cerebral Vascular Disease Research Laboratories, University of Miami School of Medicine, Miami, FL, 33136, USA.,Department of Neurology (D4-5), University of Miami Miller School of Medicine, 1420 NW 9th Ave, NRB/203E, Miami, FL, 33136, USA
| | - Akhalesh Kumar Shakya
- Present address: Department of Microbiology and Immunology, and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Miguel A Perez-Pinzon
- Cerebral Vascular Disease Research Laboratories, University of Miami School of Medicine, Miami, FL, 33136, USA.,Department of Neurology (D4-5), University of Miami Miller School of Medicine, 1420 NW 9th Ave, NRB/203E, Miami, FL, 33136, USA.,Neuroscience Program, University of Miami School of Medicine, Miami, FL, 33136, USA
| | - Kunjan R Dave
- Cerebral Vascular Disease Research Laboratories, University of Miami School of Medicine, Miami, FL, 33136, USA. .,Department of Neurology (D4-5), University of Miami Miller School of Medicine, 1420 NW 9th Ave, NRB/203E, Miami, FL, 33136, USA. .,Neuroscience Program, University of Miami School of Medicine, Miami, FL, 33136, USA.
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21
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Jensen VFH, Mølck AM, Chapman M, Alifrangis L, Andersen L, Lykkesfeldt J, Bøgh IB. Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain. Int J Endocrinol 2017; 2017:7861236. [PMID: 28421113 PMCID: PMC5379133 DOI: 10.1155/2017/7861236] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 12/19/2016] [Accepted: 12/26/2016] [Indexed: 12/18/2022] Open
Abstract
The brain is vulnerable to hypoglycaemia due to a continuous need of energy substrates to meet its high metabolic demands. Studies have shown that severe acute insulin-induced hypoglycaemia results in oxidative stress in the rat brain, when neuroglycopenia cannot be evaded despite increased levels of cerebral glucose transporters. Compensatory measures in the brain during chronic insulin-induced hypoglycaemia are less well understood. The present study investigated how the brain of nondiabetic rats copes with chronic insulin-induced hypoglycaemia for up to eight weeks. Brain level of different substrate transporters and redox homeostasis was evaluated. Hyperinsulinaemia for 8 weeks consistently lowered blood glucose levels by 30-50% (4-6 mM versus 7-9 mM in controls). The animals had increased food consumption, body weights, and hyperleptinaemia. During infusion, protein levels of the brain neuronal glucose transporter were decreased, whereas levels of lipid peroxidation products were unchanged. Discontinued infusion was followed by transient systemic hyperglycaemia and decreased food consumption and body weight. After 4 weeks, plasma levels of lipid peroxidation products were increased, possibly as a consequence of hyperglycaemia-induced oxidative stress. The present data suggests that chronic moderate hyperinsulinaemic hypoglycaemia causes increased body weight and hyperleptinaemia. This is accompanied by decreased neuronal glucose transporter levels, which may be leptin-induced.
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Affiliation(s)
- Vivi F. H. Jensen
- Department of Veterinary Disease Biology, Section for Experimental Animal Models, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Toxicology, Safety Pharm and Pathology, Novo Nordisk A/S, Maaloev, Denmark
- *Vivi F. H. Jensen:
| | - Anne-Marie Mølck
- Department of Toxicology, Safety Pharm and Pathology, Novo Nordisk A/S, Maaloev, Denmark
| | | | - Lene Alifrangis
- Department of Development DMPK, Novo Nordisk A/S, Maaloev, Denmark
| | - Lene Andersen
- Department of Development Bioanalysis, Novo Nordisk A/S, Maaloev, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary Disease Biology, Section for Experimental Animal Models, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ingrid B. Bøgh
- Department of Toxicology, Safety Pharm and Pathology, Novo Nordisk A/S, Maaloev, Denmark
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22
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Fusco FR, Paldino E. Role of Phosphodiesterases in Huntington’s Disease. ADVANCES IN NEUROBIOLOGY 2017; 17:285-304. [DOI: 10.1007/978-3-319-58811-7_11] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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23
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Kho AR, Choi BY, Kim JH, Lee SH, Hong DK, Lee SH, Jeong JH, Sohn M, Suh SW. Prevention of hypoglycemia-induced hippocampal neuronal death by N-acetyl-L-cysteine (NAC). Amino Acids 2016; 49:367-378. [PMID: 27990559 DOI: 10.1007/s00726-016-2370-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 11/22/2016] [Indexed: 12/25/2022]
Abstract
Type 1 and type 2 diabetic patients who are treated with insulin or other blood glucose reducing agents for tight control of blood glucose levels are frequently at risk of experiencing severe hypoglycemia which can lead to seizures, loss of consciousness and death. Hypoglycemic neuronal cell death is not a simple result of low glucose supply to the brain, but, instead, results from a cell death signaling pathway that is started by the re-administration of glucose after glucose deprivation. Zinc is a biologically important element for physiological function of central nervous system. However, excessive zinc release from the presynaptic terminals and subsequent translocation into the postsynaptic neurons may contribute to neuronal death following hypoglycemia. N-acetyl-L-cysteine (NAC) acts as a zinc chelator that alleviates zinc-induced neuronal death processes. In addition, NAC restores levels of neuronal glutathione (GSH), a potent antioxidant, by providing a cell-permeable source of cysteine. Thus, we hypothesized that NAC treatment can reduce neuronal cell death, not only by increasing GSH concentration but also by zinc chelation. As a result, we found that NAC decreased the oxidative stress, zinc release and translocation, and improved the level of glutathione. Therefore, NAC administration alleviated hippocampal neuron death in hypoglycemia-induced rats.
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Affiliation(s)
- A Ra Kho
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Bo Young Choi
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Jin Hee Kim
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Song Hee Lee
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Dae Ki Hong
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Sang Hwon Lee
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Jeong Hyun Jeong
- Department of Neurology, College of Medicine, Hallym University, Chuncheon, Korea
| | - Min Sohn
- Department of Nursing, Inha University, Incheon, Korea
| | - Sang Won Suh
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea.
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24
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Frost PA, Chen S, Mezzles MJ, Voruganti VS, Nava-Gonzalez EJ, Arriaga-Cazares HE, Freed KA, Comuzzie AG, DeFronzo RA, Kent JW, Grayburn PA, Bastarrachea RA. Successful pharmaceutical-grade streptozotocin (STZ)-induced hyperglycemia in a conscious tethered baboon (Papio hamadryas) model. J Med Primatol 2015; 44:202-17. [PMID: 26122701 DOI: 10.1111/jmp.12182] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND Non-human primate (NHP) diabetic models using chemical ablation of β-cells with STZ have been achieved by several research groups. Chemotherapeutic STZ could lead to serious adverse events including nephrotoxicity, hepatotoxicity, and mortality. METHODS We implemented a comprehensive therapeutic strategy that included the tether system, permanent indwelling catheter implants, an aggressive hydration protocol, management for pain with IV nubain and anxiety with IV midazolam, moment-by-moment monitoring of glucose levels post-STZ administration, and continuous intravenous insulin therapy. RESULTS A triphasic response in blood glucose after STZ administration was fully characterized. A dangerous hypoglycemic phase was also detected in all baboons. Other significant findings were hyperglycemia associated with low levels of plasma leptin, insulin and C-peptide concentrations, hyperglucagonemia, and elevated non-esterified fatty acids (NEFA) concentrations. CONCLUSIONS We successfully induced frank diabetes by IV administering a single dose of pharmaceutical-grade STZ safely and without adverse events in conscious tethered baboons.
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Affiliation(s)
- Patrice A Frost
- Southwest National Primate Research Center, San Antonio, TX, USA
| | | | - Marguerite J Mezzles
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | | | - Edna J Nava-Gonzalez
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.,University of Nuevo Leon School of Nutrition and Public Health, Monterrey, Mexico
| | - Hector E Arriaga-Cazares
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.,Hospital Infantil de Tamaulipas, Ciudad Victoria, México
| | - Katy A Freed
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Anthony G Comuzzie
- Southwest National Primate Research Center, San Antonio, TX, USA.,Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Ralph A DeFronzo
- The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jack W Kent
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Paul A Grayburn
- Baylor Research Institute, Dallas, TX, USA.,Baylor University Medical Center, Dallas, TX, USA
| | - Raul A Bastarrachea
- Southwest National Primate Research Center, San Antonio, TX, USA.,Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
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25
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Florez CM, Lukankin V, Sugumar S, McGinn R, Zhang ZJ, Zhang L, Carlen PL. Hypoglycemia-induced alterations in hippocampal intrinsic rhythms: Decreased inhibition, increased excitation, seizures and spreading depression. Neurobiol Dis 2015; 82:213-225. [PMID: 26093168 DOI: 10.1016/j.nbd.2015.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Revised: 06/09/2015] [Accepted: 06/12/2015] [Indexed: 12/16/2022] Open
Abstract
UNLABELLED Seizures are the most common clinical presentation of severe hypoglycemia, usually as a side effect of insulin treatment for juvenile onset type 1 diabetes mellitus and advanced type 2 diabetes. We used the mouse thick hippocampal slice preparation to study the pathophysiology of hypoglycemia-induced seizures and the effects of severe glucose depletion on the isolated hippocampal rhythms from the CA3 circuitry. METHODS AND RESULTS Dropping the glucose perfusate concentration from the standard 10 mM to 1 mM produced epileptiform activity in 14/16 of the slices. Seizure-like events (SLEs) originated in the CA3 region and then spread into the CA1 region. Following the SLE, a spreading-depression (SD)-like event occurred (12/16 slices) with irreversible synaptic failure in the CA1 region (8/12 slices). CA3 SD-like events followed ~30 s after the SD-like event in the CA1 region. Less commonly, SD-like events originated in the CA3 region (4/12). Additionally, prior to the onset of the SLE in the CA3 area, there was decreased GABA correlated baseline SPW activity (bSPW), while there was increased large-amplitude sharp wave (LASW) activity, thought to originate from synchronous pyramidal cell firing. CA3 pyramidal cells displayed progressive tonic depolarization prior to the seizure which was resistant to synaptic transmission blockade. The initiation of hypoglycemic seizures and SD was prevented by AMPA/kainate or NMDA receptor blockade. CONCLUSIONS Severe glucose depletion induces rapid changes initiated in the intrinsic CA3 rhythms of the hippocampus including depressed inhibition and enhanced excitation, which may underlie the mechanisms of seizure generation and delayed spreading depression.
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Affiliation(s)
- C M Florez
- Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada; Division of Fundamental Neurobiology, TWRI, UHN, Toronto, Canada
| | - V Lukankin
- Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada
| | - S Sugumar
- Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada
| | - R McGinn
- Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada
| | - Z J Zhang
- Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada
| | - L Zhang
- Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada
| | - P L Carlen
- Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Canada; Division of Fundamental Neurobiology, TWRI, UHN, Toronto, Canada.
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26
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Ikeda T, Takahashi T, Tsujita M, Kanazawa M, Toriyabe M, Koyama M, Itoh K, Nakada T, Nishizawa M, Shimohata T. Effects of Alda-1, an Aldehyde Dehydrogenase-2 Agonist, on Hypoglycemic Neuronal Death. PLoS One 2015; 10:e0128844. [PMID: 26083658 PMCID: PMC4471358 DOI: 10.1371/journal.pone.0128844] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Accepted: 04/30/2015] [Indexed: 11/23/2022] Open
Abstract
Hypoglycemic encephalopathy (HE) is caused by a lack of glucose availability to neuronal cells, and no neuroprotective drugs have been developed as yet. Studies on the pathogenesis of HE and the development of new neuroprotective drugs have been conducted using animal models such as the hypoglycemic coma model and non-coma hypoglycemia model. However, both models have inherent problems, and establishment of animal models that mimic clinical situations is desirable. In this study, we first developed a short-term hypoglycemic coma model in which rats could be maintained in an isoelectric electroencephalogram (EEG) state for 2 min and subsequent hyperglycemia without requiring anti-seizure drugs and an artificial ventilation. This condition caused the production of 4-hydroxy-2-nonenal (4-HNE), a cytotoxic aldehyde, in neurons of the hippocampus and cerebral cortex, and a marked increase in neuronal death as evaluated by Fluoro-Jade B (FJB) staining. We also investigated whether N-(1,3-benzodioxole-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1), a small-molecule agonist of aldehyde dehydrogenase-2, could attenuate 4-HNE levels and reduce hypoglycemic neuronal death. After confirming that EEG recordings remained isoelectric for 2 min, Alda-1 (8.5 mg/kg) or vehicle (dimethyl sulfoxide; DMSO) was administered intravenously with glucose to maintain a blood glucose level of 250 to 270 mg/dL. Fewer 4-HNE and FJB-positive cells were observed in the cerebral cortex of Alda-1-treated rats than in DMSO-treated rats 24 h after glucose administration (P = 0.002 and P = 0.020). Thus, activation of the ALDH2 pathway could be a molecular target for HE treatment, and Alda-1 is a potentially neuroprotective agent that exerts a beneficial effect on neurons when intravenously administered simultaneously with glucose.
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Affiliation(s)
- Tetsuhiko Ikeda
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Tetsuya Takahashi
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Mika Tsujita
- Department of Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masato Kanazawa
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masafumi Toriyabe
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Misaki Koyama
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Kosuke Itoh
- Department of Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata, Japan
| | - Tsutomu Nakada
- Department of Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masatoyo Nishizawa
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Takayoshi Shimohata
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
- * E-mail:
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McNeilly AD, McCrimmon RJ. The Scylla and Charybdis of glucose control in childhood type 1 diabetes? Pediatr Diabetes 2015; 16:235-41. [PMID: 25727089 DOI: 10.1111/pedi.12270] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 02/05/2015] [Accepted: 02/05/2015] [Indexed: 11/27/2022] Open
Abstract
Glucose control in childhood type 1 diabetes is difficult and often characterized by significant glucose variability, including periods of prolonged hyperglycemia and intermittent episodes of hypoglycemia that can be severe. The brain of the developing child is thought to be more susceptible to metabolic insults because of its relatively high demand for glucose to fuel neuronal growth and differentiation. In this review we consider the impact of glucose variability, especially when associated with recurrent hypoglycemia, on long-term cognitive function in childhood type 1 diabetes. At present, this indicates a subtle effect of type 1 diabetes per se on a number of cognitive modalities. Within the population of children with type 1 diabetes, a history of severe hypoglycemia also appears to have an additional negative effect on cognitive function. However, interpretation of the literature is difficult in that the human studies draw largely from cross-sectional observational epidemiology while more basic work has used models that do not translate well into human disease. Moreover, it is likely to be many years before we will be able to clearly document the effects of recurrent hypoglycemia or chronic hyperglycemia on cognitive function. In the meantime, it seems appropriate to advocate that minimizing glucose variability when achieving glycemic targets should be the therapeutic goal of clinicians involved in the management of childhood type 1 diabetes.
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Affiliation(s)
- Alison D McNeilly
- Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK
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28
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Influence of Glucose Deprivation on Membrane Potentials of Plasma Membranes, Mitochondria and Synaptic Vesicles in Rat Brain Synaptosomes. Neurochem Res 2015; 40:1188-96. [DOI: 10.1007/s11064-015-1579-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 04/02/2015] [Accepted: 04/08/2015] [Indexed: 12/26/2022]
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Schulz JG, Laranjeira A, Van Huffel L, Gärtner A, Vilain S, Bastianen J, Van Veldhoven PP, Dotti CG. Glial β-oxidation regulates Drosophila energy metabolism. Sci Rep 2015; 5:7805. [PMID: 25588812 PMCID: PMC4295106 DOI: 10.1038/srep07805] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 12/03/2014] [Indexed: 12/26/2022] Open
Abstract
The brain's impotence to utilize long-chain fatty acids as fuel, one of the dogmas in neuroscience, is surprising, since the nervous system is the tissue most energy consuming and most vulnerable to a lack of energy. Challenging this view, we here show in vivo that loss of the Drosophila carnitine palmitoyltransferase 2 (CPT2), an enzyme required for mitochondrial β-oxidation of long-chain fatty acids as substrates for energy production, results in the accumulation of triacylglyceride-filled lipid droplets in adult Drosophila brain but not in obesity. CPT2 rescue in glial cells alone is sufficient to restore triacylglyceride homeostasis, and we suggest that this is mediated by the release of ketone bodies from the rescued glial cells. These results demonstrate that the adult brain is able to catabolize fatty acids for cellular energy production.
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Affiliation(s)
- Joachim G Schulz
- VIB Center for the Biology of Disease, Leuven and Center for Human Genetics, KU Leuven, Leuven, Belgium
| | - Antonio Laranjeira
- VIB Center for the Biology of Disease, Leuven and Center for Human Genetics, KU Leuven, Leuven, Belgium
| | - Leen Van Huffel
- VIB Center for the Biology of Disease, Leuven and Center for Human Genetics, KU Leuven, Leuven, Belgium
| | - Annette Gärtner
- VIB Center for the Biology of Disease, Leuven and Center for Human Genetics, KU Leuven, Leuven, Belgium
| | - Sven Vilain
- VIB Center for the Biology of Disease, Leuven and Center for Human Genetics, KU Leuven, Leuven, Belgium
| | - Jarl Bastianen
- VIB Center for the Biology of Disease, Leuven and Center for Human Genetics, KU Leuven, Leuven, Belgium
| | - Paul P Van Veldhoven
- Laboratory of Lipid Biochemistry, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Carlos G Dotti
- 1] VIB Center for the Biology of Disease, Leuven and Center for Human Genetics, KU Leuven, Leuven, Belgium [2] Centro Biología Molecular "Severo Ochoa" CSIC-UAM, Madrid, Spain
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30
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Kim JH, Yoo BH, Won SJ, Choi BY, Lee BE, Kim IY, Kho A, Lee SH, Sohn M, Suh SW. Melatonin Reduces Hypoglycemia-Induced Neuronal Death in Rats. Neuroendocrinology 2015; 102:300-310. [PMID: 26065386 DOI: 10.1159/000434722] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 06/02/2015] [Indexed: 11/19/2022]
Abstract
Melatonin, N-aceyl-5-methoxytryptamine, is the main secretory product of the pineal gland and has neuroprotective effects on several brain injuries, including ischemic stroke. In the present study, we hypothesized that exogenous melatonin may decrease hypoglycemia-induced neuronal death through the prevention of superoxide generation. To test our hypothesis, hypoglycemia was induced by injecting human insulin (10 U/kg, i.p.) in rats. Melatonin injection was started immediately after hypoglycemia (10 mg/kg, i.p.). The first melatonin injection was performed at the end of a 30-min isoelectric EEG period. The second and third injections were administered at 1 and 3 h after the first injection. Reactive oxygen species generation, as detected by dihydroethidium staining, was significantly reduced by melatonin treatment. Neuronal injury was reduced by the treatment of melatonin in the hippocampal CA1 and dentate granule cells. Microglia activation was robust in the hippocampus after hypoglycemia, which was almost completely prevented by melatonin treatment. Hypoglycemia-induced cognitive impairment was also significantly prevented by melatonin treatment. The present study suggests that melatonin has therapeutic potential to prevent hypoglycemia-induced brain injury.
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Affiliation(s)
- Jin Hee Kim
- Department of Neurology, University of California, San Francisco, Calif., USA
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31
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Kenny JD, Westover MB, Ching S, Brown EN, Solt K. Propofol and sevoflurane induce distinct burst suppression patterns in rats. Front Syst Neurosci 2014; 8:237. [PMID: 25565990 PMCID: PMC4270179 DOI: 10.3389/fnsys.2014.00237] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 11/27/2014] [Indexed: 12/30/2022] Open
Abstract
Burst suppression is an EEG pattern characterized by alternating periods of high-amplitude activity (bursts) and relatively low amplitude activity (suppressions). Burst suppression can arise from several different pathological conditions, as well as from general anesthesia. Here we review current algorithms that are used to quantify burst suppression, its various etiologies, and possible underlying mechanisms. We then review clinical applications of anesthetic-induced burst suppression. Finally, we report the results of our new study showing clear electrophysiological differences in burst suppression patterns induced by two common general anesthetics, sevoflurane and propofol. Our data suggest that the circuit mechanisms that generate burst suppression activity may differ among general anesthetics.
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Affiliation(s)
- Jonathan D Kenny
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Boston, MA, USA
| | - M Brandon Westover
- Department of Neurology, Harvard Medical School Boston, MA, USA ; Department of Neurology, Massachusetts General Hospital Boston, MA, USA
| | - ShiNung Ching
- Department of Electrical and Systems Engineering, Washington University in St. Louis St. Louis, Missouri, USA
| | - Emery N Brown
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Boston, MA, USA ; Department of Anaesthesia, Harvard Medical School Boston, MA, USA ; Institute for Medical Engineering and Science, Massachusetts Institute of Technology Cambridge, MA, USA ; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology Cambridge, MA, USA
| | - Ken Solt
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Boston, MA, USA ; Department of Anaesthesia, Harvard Medical School Boston, MA, USA
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32
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Sonneville R, Vanhorebeek I, den Hertog HM, Chrétien F, Annane D, Sharshar T, Van den Berghe G. Critical illness-induced dysglycemia and the brain. Intensive Care Med 2014; 41:192-202. [PMID: 25465908 DOI: 10.1007/s00134-014-3577-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 11/19/2014] [Indexed: 01/04/2023]
Abstract
PURPOSE Dysglycemia is a characteristic feature of critical illness associated with adverse outcome. Whether dysglycemia contributes to brain dysfunction during critical illness and long-term neurological complications is unclear. We give an overview of glucose metabolism in the brain and review the literature on critical illness-induced dysglycemia and the brain. METHODS Medline database search using relevant search terms on dysglycemia, critical illness, acute brain injury/dysfunction, and randomized controlled trial. RESULTS Hyperglycemia has been associated with deleterious effects on the nervous system. Underlying mechanisms in critical illness remain largely speculative and are often extrapolated from knowledge in diabetes mellitus. Increased hyperglycemia-induced blood-brain barrier permeability, oxidative stress, and microglia activation may play a role and compromise neuronal and glial cell integrity. Hypoglycemia is feared as critically ill patients cannot recognize or communicate hypoglycemic symptoms, which furthermore are masked by sedation and analgesia. However, observational data on the impact of brief hypoglycemia on the brain in critical illness are controversial. Secondary analysis of two large randomized studies suggested neuroprotection by strict glycemic control with insulin during intensive care, with lowered intracranial pressure, reduction of seizures, and better long-term rehabilitation in patients with isolated brain injury, and reduced incidence of critical illness polyneuromyopathy in the general critically ill patient population. Several subsequent studies failed to reproduce neurological benefit, likely explained by methodological issues, which include divergent achieved glucose levels and inaccurate glucose monitoring tools. CONCLUSIONS Preventing hyperglycemia during critical illness holds promise as a neuroprotective strategy to preserve brain cell viability and prevent acute brain dysfunction and long-term cognitive impairment in survivors.
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Affiliation(s)
- Romain Sonneville
- Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium
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33
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Deng J, Zhao F, Yu X, Zhao Y, Li D, Shi H, Sun Y. Expression of aquaporin 4 and breakdown of the blood-brain barrier after hypoglycemia-induced brain edema in rats. PLoS One 2014; 9:e107022. [PMID: 25264602 PMCID: PMC4180270 DOI: 10.1371/journal.pone.0107022] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 08/05/2014] [Indexed: 11/18/2022] Open
Abstract
Background Hypoglycemia-induced brain edema is a severe clinical event that often results in death. The mechanisms by which hypoglycemia induces brain edema are unclear. Methods In a hypoglycemic injury model established in adult rats, brain edema was verified by measuring brain water content and visualizing water accumulation using hematoxylin and eosin staining. Temporal expression of aquaporin 4 (AQP4) and the integrity of the blood-brain barrier (BBB) were evaluated. We assessed the distribution and expression of AQP4 following glucose deprivation in astrocyte cultures. Results Brain edema was induced immediately after severe hypoglycemia but continued to progress even after recovery from hypoglycemia. Upregulation of AQP4 expression and moderate breakdown of the BBB were observed 24 h after recovery. In vitro, significant redistribution of AQP4 to the plasma membrane was induced following 6 h glucose deprivation. Conclusion Hypoglycemia-induced brain edema is caused by cytotoxic and vasogenic factors. Changes in AQP4 location and expression may play a protective role in edema resolution.
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Affiliation(s)
- Jiangshan Deng
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Fei Zhao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaoyan Yu
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yuwu Zhao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- * E-mail: (YZ); (DL)
| | - Dawei Li
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- * E-mail: (YZ); (DL)
| | - Hong Shi
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yongning Sun
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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34
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Amador-Alvarado L, Montiel T, Massieu L. Differential production of reactive oxygen species in distinct brain regions of hypoglycemic mice. Metab Brain Dis 2014; 29:711-9. [PMID: 24590689 DOI: 10.1007/s11011-014-9508-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 02/12/2014] [Indexed: 01/21/2023]
Abstract
Hypoglycemia is a serious complication of insulin therapy in patients suffering from type 1 Diabetes Mellitus. Severe hypoglycemia leading to coma (isoelectricity) induces massive neuronal death in vulnerable brain regions such as the hippocampus, the striatum and the cerebral cortex. It has been suggested that the production of reactive oxygen species (ROS) and oxidative stress is involved in hypoglycemic brain damage, and that ROS generation is stimulated by glucose reintroduction (GR) after the hypoglycemic coma. However, the distribution of ROS in discrete brain regions has not been studied in detail. Using the oxidation sensitive marker dihydroethidium (DHE) we have investigated the distribution of ROS in different regions of the mouse brain during prolonged severe hypoglycemia without isoelectricity, as well as the effect of GR on ROS levels. Results show that ROS generation increases in the hippocampus, the cerebral cortex and the striatum after prolonged severe hypoglycemia before the coma. The hippocampus showed the largest increases in ROS levels. GR further stimulated ROS production in the hippocampus and the striatum while in the cerebral cortex, only the somatosensory and parietal areas were significantly affected by GR. Results suggest that ROS are differentially produced during the hypoglycemic insult and that a different response to GR is present among distinct brain regions.
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Affiliation(s)
- Leticia Amador-Alvarado
- División de Neurociencias, Departamento de Neuropatología Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México, D.F, 04510, México
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35
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Jensen VFH, Mølck AM, Bøgh IB, Lykkesfeldt J. Effect of insulin-induced hypoglycaemia on the peripheral nervous system: focus on adaptive mechanisms, pathogenesis and histopathological changes. J Neuroendocrinol 2014; 26:482-96. [PMID: 24921897 DOI: 10.1111/jne.12170] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 05/22/2014] [Accepted: 06/05/2014] [Indexed: 12/31/2022]
Abstract
Insulin-induced hypoglycaemia (IIH) is a common acute side effect in type 1 and type 2 diabetic patients, especially during intensive insulin therapy. The peripheral nervous system (PNS) depends on glucose as its primary energy source during normoglycaemia and, consequently, it may be particularly susceptible to IIH damage. Possible mechanisms for adaption of the PNS to IIH include increased glucose uptake, utilisation of alternative energy substrates and the use of Schwann cell glycogen as a local glucose reserve. However, these potential adaptive mechanisms become insufficient when the hypoglycaemic state exceeds a certain level of severity and duration, resulting in a sensory-motor neuropathy with associated skeletal muscle atrophy. Large myelinated motor fibres appear to be particularly vulnerable. Thus, although the PNS is not an obligate glucose consumer, as is the brain, it appears to be more prone to IIH than the central nervous system when hypoglycaemia is not severe (blood glucose level ≤ 2 mm), possibly reflecting a preferential protection of the brain during periods of inadequate glucose availability. With a primary focus on evidence from experimental animal studies investigating nondiabetic IIH, the present review discusses the effect of IIH on the PNS with a focus on adaptive mechanisms, pathogenesis and histological changes.
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Affiliation(s)
- V F H Jensen
- Department of Veterinary Disease, Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Diabetes Toxicology and Safety Pharmacology, Novo Nordisk A/S, Maaloev, Denmark
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36
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Borges AA, El-Batah PN, Yamashita LF, Santana ADS, Lopes AC, Freymuller-Haapalainen E, Coimbra CG, Sinigaglia-Coimbra R. Neuroprotective effect of oral choline administration after global brain ischemia in rats. Nutr Neurosci 2014; 18:265-74. [PMID: 24754536 DOI: 10.1179/1476830514y.0000000125] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Choline - now recognized as an essential nutrient - is the most common polar group found in the outer leaflet of the plasma membrane bilayer. Brain ischemia-reperfusion causes lipid peroxidation triggering multiple cell death pathways involving necrosis and apoptosis. Membrane breakdown is, therefore, a major pathophysiologic event in brain ischemia. The ability to achieve membrane repair is a critical step for survival of ischemic neurons following reperfusion injury. The availability of choline is a rate-limiting factor in phospholipid synthesis and, therefore, may be important for timely membrane repair and cell survival. This work aimed at verifying the effects of 7-day oral administration with different doses of choline on survival of CA1 hippocampal neurons following transient global forebrain ischemia in rats. The administration of 400 mg/kg/day divided into two daily doses for 7 consecutive days significantly improved CA1 pyramidal cell survival, indicating that the local availability of this essential nutrient may limit postischemic neuronal survival.
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37
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Jensen VFH, Bøgh IB, Lykkesfeldt J. Effect of insulin-induced hypoglycaemia on the central nervous system: evidence from experimental studies. J Neuroendocrinol 2014; 26:123-50. [PMID: 24428753 DOI: 10.1111/jne.12133] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 12/13/2013] [Accepted: 01/08/2014] [Indexed: 12/12/2022]
Abstract
Insulin-induced hypoglycaemia (IIH) is a major acute complication in type 1 as well as in type 2 diabetes, particularly during intensive insulin therapy. The brain plays a central role in the counter-regulatory response by eliciting parasympathetic and sympathetic hormone responses to restore normoglycaemia. Brain glucose concentrations, being approximately 15-20% of the blood glucose concentration in humans, are rigorously maintained during hypoglycaemia through adaptions such as increased cerebral glucose transport, decreased cerebral glucose utilisation and, possibly, by using central nervous system glycogen as a glucose reserve. However, during sustained hypoglycaemia, the brain cannot maintain a sufficient glucose influx and, as the cerebral hypoglycaemia becomes severe, electroencephalogram changes, oxidative stress and regional neuronal death ensues. With particular focus on evidence from experimental studies on nondiabetic IIH, this review outlines the central mechanisms behind the counter-regulatory response to IIH, as well as cerebral adaption to avoid sequelae of cerebral neuroglycopaenia, including seizures and coma.
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Affiliation(s)
- V F H Jensen
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Diabetes Toxicology and Safety Pharmacology, Novo Nordisk A/S, Maaloev, Denmark
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38
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Abstract
Hypoglycemia occurs in diabetic patients as a consequence of treatment with hypoglycemic agents, in insulinoma patients as a result of excessive insulin production, and in infants as a result of abnormal regulation of metabolism. Profound hypoglycemia can cause structural and functional disturbances in both the central (CNS) and the peripheral nervous system (PNS). The brain is damaged by a short and severe episode of hypoglycemia, whereas PNS pathology appears after a mild and prolonged episode. In the CNS, damaged mitochondria, elevated intracellular Ca2(+) level, released cytochrome c to the cytosol, extensive production of superoxide, increased caspase-3 activity, release of aspartate and glutamate from presynaptic terminals, and altered biosynthetic machinery can lead to neuronal cell death in the brain. Considering the PNS, chronic hypoglycemia is associated with delayed motor and sensory conduction velocities in peripheral nerves. With respect to pathology, hypoglycemic neuropathy in the PNS is characterized by Wallerian-like axonal degeneration that starts at the nerve terminal and progresses to a more proximal part of the axon, and motor axons to the muscles may be more severely damaged than sensory axons. Since excitatory neurotransmitters primarily involve the neuron in the CNS, this "dying back" pattern of axonal damage in the PNS may involve mechanisms other than excitotoxicity.
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Affiliation(s)
- Simin Mohseni
- Department of Clinical and Experimental Medicine, Division of Cell Biology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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Maheandiran M, Mylvaganam S, Wu C, El-Hayek Y, Sugumar S, Hazrati L, del Campo M, Giacca A, Zhang L, Carlen PL. Severe hypoglycemia in a juvenile diabetic rat model: presence and severity of seizures are associated with mortality. PLoS One 2013; 8:e83168. [PMID: 24386156 PMCID: PMC3875447 DOI: 10.1371/journal.pone.0083168] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 10/31/2013] [Indexed: 01/05/2023] Open
Abstract
It is well accepted that insulin-induced hypoglycemia can result in seizures. However, the effects of the seizures, as well as possible treatment strategies, have yet to be elucidated, particularly in juvenile or insulin-dependent diabetes mellitus (IDDM). Here we establish a model of diabetes in young rats, to examine the consequences of severe hypoglycemia in this age group; particularly seizures and mortality. Diabetes was induced in post-weaned 22-day-old Sprague-Dawley rats by streptozotocin (STZ) administered intraperitoneally (IP). Insulin IP (15 U/kg), in rats fasted (14-16 hours), induced hypoglycemia, defined as <3.5 mM blood glucose (BG), in 68% of diabetic (STZ) and 86% of control rats (CON). Seizures occurred in 86% of STZ and all CON rats that reached hypoglycemic levels with mortality only occurring post-seizure. The fasting BG levels were significantly higher in STZ (12.4 ± 1.3 mM) than in CON rodents (6.3 ± 0.3 mM), resulting in earlier onset of hypoglycemia and seizures in the CON group. However, the BG at seizure onset was statistically similar between STZ (1.8 ± 0.2 mM) and CON animals (1.6 ± 0.1 mM) as well as between those that survived (S+S) and those that died (S+M) post-seizure. Despite this, the S+M group underwent a significantly greater number of seizure events than the S+S group. 25% glucose administered at seizure onset and repeated with recurrent seizures was not sufficient to mitigate these continued convulsions. Combining glucose with diazepam and phenytoin significantly decreased post-treatment seizures, but not mortality. Intracranial electroencephalograms (EEGs) were recorded in 10 CON and 9 STZ animals. Predictive EEG changes were not observed in these animals that underwent seizures. Fluorojade staining revealed damaged cells in non-seizing STZ animals and in STZ and CON animals post-seizure. In summary, this model of hypoglycemia and seizures in juvenile diabetic rats provides a paradigm for further study of underlying mechanisms. Our data demonstrate that severe hypoglycemia (<2.0 mM) is a necessary precondition for seizures, and the increased frequency of these seizures is associated with mortality.
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Affiliation(s)
- Margaret Maheandiran
- Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Shanthini Mylvaganam
- Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Chiping Wu
- Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Youssef El-Hayek
- Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Sonia Sugumar
- Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Lili Hazrati
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario Canada
| | - Martin del Campo
- Department of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Adria Giacca
- Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Liang Zhang
- Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Peter L. Carlen
- Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada
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Choi BY, Kim JH, Kim HJ, Yoo JH, Song HK, Sohn M, Won SJ, Suh SW. Pyruvate administration reduces recurrent/moderate hypoglycemia-induced cortical neuron death in diabetic rats. PLoS One 2013; 8:e81523. [PMID: 24278448 PMCID: PMC3838412 DOI: 10.1371/journal.pone.0081523] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 10/14/2013] [Indexed: 11/24/2022] Open
Abstract
Recurrent/moderate (R/M) hypoglycemia is common in type 1 diabetes patients. Moderate hypoglycemia is not life-threatening, but if experienced recurrently it may present several clinical complications. Activated PARP-1 consumes cytosolic NAD, and because NAD is required for glycolysis, hypoglycemia-induced PARP-1 activation may render cells unable to use glucose even when glucose availability is restored. Pyruvate, however, can be metabolized in the absence of cytosolic NAD. We therefore hypothesized that pyruvate may be able to improve the outcome in diabetic rats subjected to insulin-induced R/M hypoglycemia by terminating hypoglycemia with glucose plus pyruvate, as compared with delivering just glucose alone. In an effort to mimic juvenile type 1 diabetes the experiments were conducted in one-month-old young rats that were rendered diabetic by streptozotocin (STZ, 50mg/kg, i.p.) injection. One week after STZ injection, rats were subjected to moderate hypoglycemia by insulin injection (10U/kg, i.p.) without anesthesia for five consecutive days. Pyruvate (500mg/kg) was given by intraperitoneal injection after each R/M hypoglycemia. Three hours after last R/M hypoglycemia, zinc accumulation was evaluated. Three days after R/M hypoglycemia, neuronal death, oxidative stress, microglial activation and GSH concentrations in the cerebral cortex were analyzed. Sparse neuronal death was observed in the cortex. Zinc accumulation, oxidative injury, microglial activation and GSH loss in the cortex after R/M hypoglycemia were all reduced by pyruvate injection. These findings suggest that when delivered alongside glucose, pyruvate may significantly improve the outcome after R/M hypoglycemia by circumventing a sustained impairment in neuronal glucose utilization resulting from PARP-1 activation.
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Affiliation(s)
- Bo Young Choi
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Jin Hee Kim
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Hyun Jung Kim
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Jin Hyuk Yoo
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Hong Ki Song
- Department of Neurology, Hallym University, College of Medicine, Chuncheon, Korea
| | - Min Sohn
- Department of Nursing, Inha University, Incheon, Korea
| | - Seok Joon Won
- Department of Neurology, University of California San Francisco, San Francisco, California, United States of America
| | - Sang Won Suh
- Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea
- * E-mail:
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Impairment of autophagic flux promotes glucose reperfusion-induced neuro2A cell death after glucose deprivation. PLoS One 2013; 8:e76466. [PMID: 24124562 PMCID: PMC3790699 DOI: 10.1371/journal.pone.0076466] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 08/26/2013] [Indexed: 12/19/2022] Open
Abstract
Hypoglycemia-induced brain injury is a common and serious complication of intensive insulin therapy experienced by Type 1 diabetic patients. We previously reported that hypoglycemic neuronal death is triggered by glucose reperfusion after hypoglycemia rather than as a simple result of glucose deprivation. However, the precise mechanism of neuronal death initiated by glucose reperfusion is still unclear. Autophagy is a self-degradation process that acts through a lysosome-mediated trafficking pathway to degrade and recycle intracellular components, thereby regulating metabolism and energy production. Recent studies suggest that autophagic and lysosomal dysfunction leads to abnormal protein degradation and deposition that may contribute to neuronal death. Here, we focused on the relationship between autophagy and lysosomal dysfunction in hypoglycemia-induced neuronal death. In neuronal cells, glucose reperfusion after glucose deprivation resulted in inhibition of autophagy, which may promote cell death. This cell death was accompanied with activation of caspase3 and the lysosomal proteases cathepsin B and D, which indicated impairment of autophagic flux. Taken together, these results suggest that interplay of autophagy, caspase3 activation and lysosomal proteases serve as a basis for neuronal death after hypoglycemia. Thus, we provide the molecular mechanism of neuronal death by glucose reperfusion and suggest some clues for therapeutic strategies to prevent hypoglycemia-induced neuronal death.
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Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes 2013; 62:3570-81. [PMID: 23835337 PMCID: PMC3781452 DOI: 10.2337/db13-0216] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
For people with insulin-treated diabetes, severe hypoglycemia can be lethal, though potential mechanisms involved are poorly understood. To investigate how severe hypoglycemia can be fatal, hyperinsulinemic, severe hypoglycemic (10-15 mg/dL) clamps were performed in Sprague-Dawley rats with simultaneous electrocardiogram monitoring. With goals of reducing hypoglycemia-induced mortality, the hypotheses tested were that: 1) antecedent glycemic control impacts mortality associated with severe hypoglycemia; 2) with limitation of hypokalemia, potassium supplementation could limit hypoglycemia-associated deaths; 3) with prevention of central neuroglycopenia, brain glucose infusion could prevent hypoglycemia-associated arrhythmias and deaths; and 4) with limitation of sympathoadrenal activation, adrenergic blockers could prevent hypoglycemia-induced arrhythmic deaths. Severe hypoglycemia-induced mortality was noted to be worsened by diabetes, but recurrent antecedent hypoglycemia markedly improved the ability to survive an episode of severe hypoglycemia. Potassium supplementation tended to reduce mortality. Severe hypoglycemia caused numerous cardiac arrhythmias including premature ventricular contractions, tachycardia, and high-degree heart block. Intracerebroventricular glucose infusion reduced severe hypoglycemia-induced arrhythmias and overall mortality. β-Adrenergic blockade markedly reduced cardiac arrhythmias and completely abrogated deaths due to severe hypoglycemia. Under conditions studied, sudden deaths caused by insulin-induced severe hypoglycemia were mediated by lethal cardiac arrhythmias triggered by brain neuroglycopenia and the marked sympathoadrenal response.
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Affiliation(s)
- Candace M. Reno
- Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri
| | - Dorit Daphna-Iken
- Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri
| | - Y. Stefanie Chen
- Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri
| | - Jennifer VanderWeele
- Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri
| | - Krishan Jethi
- Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri
| | - Simon J. Fisher
- Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri
- Corresponding author: Simon J. Fisher,
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43
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Giampà C, Montagna E, Dato C, Melone MAB, Bernardi G, Fusco FR. Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington's disease. PLoS One 2013; 8:e64037. [PMID: 23700454 PMCID: PMC3659095 DOI: 10.1371/journal.pone.0064037] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Accepted: 04/11/2013] [Indexed: 12/20/2022] Open
Abstract
Loss of huntingtin-mediated BDNF gene transcription has been shown to occur in HD and thus contribute to the degeneration of the striatum. Several studies have indicated that an increase in BDNF levels is associated with neuroprotection and amelioration of neurological signs in animal models of HD. In a recent study, an increase in BDNF mRNA and protein levels was recorded in mice administered recombinant BDNF peripherally. Chronic, indwelling osmotic mini-pumps containing either recombinant BDNF or saline were surgically placed in R6/2 or wild-type mice from 4 weeks of age until euthanasia. Neurological evaluation (paw clasping, rotarod performance, locomotor activity in an open field) was performed. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that BDNF- treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as brain volume, striatal atrophy, size and morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. BDNF was effective in increasing significantly the levels of activated CREB and of BDNF the striatal spiny neurons. Moreover, systemically administered BDNF increased the synthesis of BDNF as demonstrated by RT-PCR, and this might account for the beneficial effects observed in this model.
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Affiliation(s)
- Carmela Giampà
- Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Rome, Italy
| | - Elena Montagna
- Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Rome, Italy
| | - Clemente Dato
- Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Rome, Italy
| | - Mariarosa A. B. Melone
- Division of Neurology, Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy
- Institute of Protein Biochemistry, CNR, Naples, Italy
| | - Giorgio Bernardi
- Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Rome, Italy
- Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Romana Fusco
- Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Rome, Italy
- * E-mail:
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44
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Chen HJ, Lee YJ, Yeh GC, Lin HC. Association of attention-deficit/hyperactivity disorder with diabetes: a population-based study. Pediatr Res 2013; 73:492-6. [PMID: 23329200 DOI: 10.1038/pr.2013.5] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Cognitive impairment has been documented in adult diabetes but is unclear in pediatric diabetes. No study had been conducted to explore the relationship between attention-deficit/hyperactivity disorder (ADHD) and diabetes. Using a population-based data set, we aimed to examine the association between ADHD and a prior diagnosis of diabetes mellitus (DM) in Taiwan. METHODS A total of 4,302 patients with ADHD were selected as cases and 21,510 randomly selected subjects as controls. We used conditional logistic regression to calculate the odds ratio (OR) for having previously received a diagnosis of DM between subjects with and without ADHD. RESULTS In this study, 116 of the 25,812 sampled subjects (0.5%) had received a diagnosis of DM prior to their index date. Subjects with ADHD had a higher proportion of prior DM diagnoses than controls (0.9% vs. 0.4%, P < 0.001). After adjusting for age, sex, index year, geographic location, and obesity, ADHD was significantly associated with a prior diagnosis of type 2 DM (OR = 2.75, 95% confidence interval (CI) = 1.82-4.16). However, no significant association was observed between ADHD and type 1 DM. CONCLUSION The findings suggest that ADHD was associated with a previous diagnosis of type 2 DM.
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Affiliation(s)
- Hui-Ju Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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45
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Koranyi L, Bourey RE, James D, Mueckler M, Fiedorek FT, Permutt MA. Glucose transporter gene expression in rat brain: Pretranslational changes associated with chronic insulin-induced hypoglycemia, fasting, and diabetes. Mol Cell Neurosci 2012; 2:244-52. [PMID: 19912805 DOI: 10.1016/1044-7431(91)90051-o] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/1991] [Indexed: 11/24/2022] Open
Abstract
Steady-state levels of the major glucose transporter gene (GLUT-1) of the brain were evaluated under three conditions that induced chronic changes in plasma glucose and insulin in adult rats: (i) repeated injection of insulin for 5 days, resulting in plasma glucose levels of 60-70 mg/dl for at least 3 days; (ii) fasting for 3 days; and (iii) moderate streptozotocin-induced diabetes of 1 week duration. Brain GLUT-1 mRNA was measured by dot blot hybridization with a HepG2/erythrocyte (GLUT1) [(32)P]cRNA probe, and GLUT-1 protein by immunoblot analysis with a polyclonal antibody (11493). Insulin injection resulted in hypoglycemia, increased GLUT-1 mRNA (143 +/- 15%, P < 0.05), and increased GLUT-1 protein (141 +/- 6%, P < 0.05). The increase in GLUT-1 mRNA was specific for brain, as no change was observed in liver or kidney. Fasting resulted in mild hypoglycemia, lower plasma insulin, increased GLUT-1 mRNA (131 +/- 17%, P < 0.05 vs control), and no change in GLUT-1 protein (125 +/- 9%, N.S.). Mild streptozotocin diabetes resulted in hyperglycemia, undetectable plasma insulin, decreased GLUT-1 mRNA (65 +/- 6%, P < 0.05 vs control), and no change in GLUT-1 protein (84 +/- 9%, N.S.). A negative correlation (r = -0.61, P < .0001) between GLUT-1 mRNA levels in brain and plasma glucose concentrations was observed among the three experimental groups and control animals, suggesting that the plasma glucose concentration may be at least one determinant of GLUT-1 levels in rat brain. The importance of these results is the finding that GLUT-1 gene expression in rat brain is regulated in vivo by the nutritional and endocrine status of the animal.
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Affiliation(s)
- L Koranyi
- Department of Internal Medicine, Division of Metabolism, Washington University School of Medicine, St. Louis, Missouri 63110, USA
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Affiliation(s)
- Jun Su
- Department of Pediatrics, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Li Wang
- Department of Pediatrics, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
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47
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Won SJ, Kim JH, Yoo BH, Sohn M, Kauppinen TM, Park MS, Kwon HJ, Liu J, Suh SW. Prevention of hypoglycemia-induced neuronal death by minocycline. J Neuroinflammation 2012; 9:225. [PMID: 22998689 PMCID: PMC3511289 DOI: 10.1186/1742-2094-9-225] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 09/14/2012] [Indexed: 02/03/2023] Open
Abstract
Diabetic patients who attempt strict management of blood glucose levels frequently experience hypoglycemia. Severe and prolonged hypoglycemia causes neuronal death and cognitive impairment. There is no effective tool for prevention of these unwanted clinical sequelae. Minocycline, a second-generation tetracycline derivative, has been recognized as an anti-inflammatory and neuroprotective agent in several animal models such as stroke and traumatic brain injury. In the present study, we tested whether minocycline also has protective effects on hypoglycemia-induced neuronal death and cognitive impairment. To test our hypothesis we used an animal model of insulin-induced acute hypoglycemia. Minocycline was injected intraperitoneally at 6 hours after hypoglycemia/glucose reperfusion and injected once per day for the following 1 week. Histological evaluation for neuronal death and microglial activation was performed from 1 day to 1 week after hypoglycemia. Cognitive evaluation was conducted 6 weeks after hypoglycemia. Microglial activation began to be evident in the hippocampal area at 1 day after hypoglycemia and persisted for 1 week. Minocycline injection significantly reduced hypoglycemia-induced microglial activation and myeloperoxidase (MPO) immunoreactivity. Neuronal death was significantly reduced by minocycline treatment when evaluated at 1 week after hypoglycemia. Hypoglycemia-induced cognitive impairment is also significantly prevented by the same minocycline regimen when subjects were evaluated at 6 weeks after hypoglycemia. Therefore, these results suggest that delayed treatment (6 hours post-insult) with minocycline protects against microglial activation, neuronal death and cognitive impairment caused by severe hypoglycemia. The present study suggests that minocycline has therapeutic potential to prevent hypoglycemia-induced brain injury in diabetic patients.
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Affiliation(s)
- Seok Joon Won
- Department of Neurology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA
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48
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Won SJ, Yoo BH, Kauppinen TM, Choi BY, Kim JH, Jang BG, Lee MW, Sohn M, Liu J, Swanson RA, Suh SW. Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats. J Neuroinflammation 2012; 9:182. [PMID: 22830525 PMCID: PMC3458941 DOI: 10.1186/1742-2094-9-182] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Accepted: 07/06/2012] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Recurrent/moderate (R/M) hypoglycemia is common in type 1 diabetes. Although mild or moderate hypoglycemia is not life-threatening, if recurrent, it may cause cognitive impairment. In the present study, we sought to determine whether R/M hypoglycemia leads to neuronal death, dendritic injury, or cognitive impairment. METHODS The experiments were conducted in normal and in diabetic rats. Rats were subjected to moderate hypoglycemia by insulin without anesthesia. Oxidative stress was evaluated by 4-Hydroxy-2-nonenal immunostaining and neuronal death was determined by Fluoro-Jade B staining 7 days after R/M hypoglycemia. To test whether oxidative injury caused by NADPH oxidase activation, an NADPH oxidase inhibitor, apocynin, was used. Cognitive function was assessed by Barnes maze and open field tests at 6 weeks after R/M hypoglycemia. RESULTS The present study found that oxidative injury was detected in the dendritic area of the hippocampus after R/M hypoglycemia. Sparse neuronal death was found in the cortex, but no neuronal death was detected in the hippocampus. Significant cognitive impairment and thinning of the CA1 dendritic region was detected 6 weeks after hypoglycemia. Oxidative injury, cognitive impairment, and hippocampal thinning after R/M hypoglycemia were more severe in diabetic rats than in non-diabetic rats. Oxidative damage in the hippocampal CA1 dendritic area and microglial activation were reduced by the NADPH oxidase inhibitor, apocynin. CONCLUSION The present study suggests that oxidative injury of the hippocampal CA1 dendritic region by R/M hypoglycemia is associated with chronic cognitive impairment in diabetic patients. The present study further suggests that NADPH oxidase inhibition may prevent R/M hypoglycemia-induced hippocampal dendritic injury.
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Affiliation(s)
- Seok Joon Won
- Department of Neurology, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, CA, USA
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Won SJ, Jang BG, Yoo BH, Sohn M, Lee MW, Choi BY, Kim JH, Song HK, Suh SW. Prevention of acute/severe hypoglycemia-induced neuron death by lactate administration. J Cereb Blood Flow Metab 2012; 32:1086-96. [PMID: 22453629 PMCID: PMC3367225 DOI: 10.1038/jcbfm.2012.30] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Hypoglycemia-induced cerebral neuropathy can occur in patients with diabetes who attempt tight control of blood glucose and may lead to cognitive dysfunction. Accumulating evidence from animal models suggests that hypoglycemia-induced neuronal death is not a simple result of glucose deprivation, but is instead the end result of a multifactorial process. In particular, the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) consumes cytosolic nicotinamide adenine dinucleotide (NAD(+)), resulting in energy failure. In this study, we investigate whether lactate administration in the absence of cytosolic NAD(+) affords neuroprotection against hypoglycemia-induced neuronal death. Intraperitoneal injection of sodium L-lactate corrected arterial blood pH and blood lactate concentration after hypoglycemia. Lactate administered without glucose was not sufficient to promote electroencephalogram recovery from an isoelectric state during hypoglycemia. However, supplementation of glucose with lactate reduced neuronal death by ∼80% in the hippocampus. Hypoglycemia-induced superoxide production and microglia activation was also substantially reduced by administration of lactate. Taken together, these results suggest an intriguing possibility: that increasing brain lactate following hypoglycemia offsets the decrease in NAD(+) due to overactivation of PARP-1 by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels.
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Affiliation(s)
- Seok Joon Won
- Department of Neurology, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, CA, USA
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Armogida M, Spalloni A, Amantea D, Nutini M, Petrelli F, Longone P, Bagetta G, Nisticò R, Mercuri NB. The protective role of catalase against cerebral ischemia in vitro and in vivo. Int J Immunopathol Pharmacol 2011; 24:735-47. [PMID: 21978706 DOI: 10.1177/039463201102400320] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The present study aims to assess the protective role of the antioxidant enzyme catalase (CAT) with relation to hydrogen peroxide (H(2)O(2)) degradation in oxygen plus water on electrophysiological and fluorescence changes induced by in vitro ischemia and on brain damage produced by transient in vivo ischemia. Neuroprotective effects of CAT were determined by means of electrophysiological recordings and confocal fluorescence microscopy in the hippocampal slice preparation. Ischemia was simulated in vitro by oxygen/glucose deprivation (OGD). In vivo ischemia was produced by transient middle cerebral artery occlusion (MCAo). A protection of the rat CA1 field excitatory postsynaptic potential (fEPSP) loss caused by a prolonged OGD (40 min) was observed after exogenous CAT (500 U/mL) bath-applied before a combined exposure to OGD and H(2)O(2) (3 mM). Of note, neither H(2)O(2) nor exogenous CAT alone had a protective action when OGD lasted for 40 min. The CAT-induced neuroprotection was confirmed in a transgenic mouse model over-expressing human CAT [Tg(CAT)]. In the presence of H(2)O(2), the hippocampus of Tg(CAT) showed an increased resistance against OGD compared to that of wild-type (WT) animals. Moreover, CAT treatment reduced for about 50 min fEPSP depression evoked by repeated applications of H(2)O(2) in normoxia. A lower sensitivity to H(2)O(2)-induced depression of fEPSPs was also indicated by the rightward shift of concentration-response curve in Tg(CAT) compared to WT mice. Noteworthy, Tg(CAT) mice had a reduced infarct size after MCAo. Our data suggest new strategies to reduce neuronal damage produced by transient brain ischemia through the manipulation of CAT enzyme.
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Affiliation(s)
- M Armogida
- Laboratory of Experimental Neurology, Fondazione Santa Lucia IRCCS, Rome
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