Postnatal age influences hypoglycemia-induced neuronal injury in the rat brain

Ennis, Kathleen; Tran, Phu V.; Seaquist, Elizabeth R.; Rao, Raghavendra

doi:10.1016/j.brainres.2008.06.003

Cited by 48 publications

(101 citation statements)

References 44 publications

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“…According to the present data, noncoma hypoglycemia leads to cell death in the parietal and frontal cortices, showing the parietal cortex the highest number of degenerating neurons. In contrast to previous studies, 28,29 we were unable to detect a significant number of FJB-positive neurons in the piriform cortex. This discrepancy, might be possibly attributed to some variations in the experimental protocols or to differences in strain vulnerability to hypoglycemic neuronal damage.…”

Section: Discussioncontrasting

confidence: 99%

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

Julio-Amilpas

Montiel

Soto‐Tinoco

et al. 2015

J Cereb Blood Flow Metab

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Glucose is the main energy substrate in brain but in certain circumstances such as prolonged fasting and the suckling period alternative substrates can be used such as the ketone bodies (KB), beta-hydroxybutyrate (BHB), and acetoacetate. It has been shown that KB prevent neuronal death induced during energy limiting conditions and excitotoxicity. The protective effect of KB has been mainly attributed to the improvement of mitochondrial function. In the present study, we have investigated the protective effect of D-BHB against neuronal death induced by severe noncoma hypoglycemia in the rat in vivo and by glucose deprivation (GD) in cortical cultures. Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury. INTRODUCTIONGlucose is the main energy source in brain. However, under certain conditions other energy substrates such as the ketone bodies (KB), acetoacetate (AcAc), and β-hydroxybutyrate (BHB) can be used by brain, including the suckling period, 1,2 prolonged fasting, 3 and the ketogenic diet; 4 all these situations are associated with increased KB levels in blood. Several studies have shown that KB can protect the brain against damage associated with diverse neurotoxic insults such as hypoxia, 5 ischemia, 6-8 hypoglycemia, 9,10 and excitotoxicity. 11,12 In addition, the ketogenic diet has been used for a long time for the treatment of refractory epilepsy. 4,13,14 The protective effect of KB has been mostly attributed to their conversion to AcetylCoA improving mitochondrial metabolism and preserving energy levels. [15][16][17] However, studies suggest that besides providing energy to neurons, KB reduce the production of reactive oxygen species (ROS) contributing to their protective effect. It has been observed in vitro that AcAc reduces ROS levels induced by glutamate exposure and glycolysis inhibition in cultured neurons, 12,16 and previous in vivo studies have shown that BHB decreases hypoglycemia and glutamate-mediated lipoperoxidation in the rat brain. 10,18 The mechanism underlying the reduction of ROS by BHB has not been elucidated but we have previously reported that KB display a scavenging action of ROS, in particular of the hydoxyl radical ( • OH). 10 The physiologic and the

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Section: Discussioncontrasting

confidence: 99%

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

Julio-Amilpas

Montiel

Soto‐Tinoco

et al. 2015

J Cereb Blood Flow Metab

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“…Similar to previous studies (4,5,16,26), neuronal injury was primarily seen in the anterior regions of the cerebral cortex, confirming the vulnerability of this brain region during moderate hypoglycemia. Contrary to our expectation, hyperglycemia accentuated the severity of injury, likely via glucose reperfusion and PARP-1 overactivation.…”

Section: Discussionsupporting

confidence: 76%

“…β-hydroxybutyrate was administered in the ketone group, beginning at 120 min after the insulin administration, while the dextrose group was maintained without additional treatment until hypoglycemia was terminated 240 min after the insulin administration in both groups using 10% dextrose. The timing of β-hydroxybutyrate administration was based on the occurrence of neuronal injury after 120 min of hypoglycemia in P28 rats (4). The blood glucose concentration during the 210 min of hypoglycemia was comparable in the two groups (dextrose-group, 31.3 ± 4.3 mg/dl; ketone-group, 32.7 ± 2.3 mg/dl, P = NS).…”

Section: Experiments 2: Effect Of Ketonemia On Hypoglycemia-induced Nementioning

confidence: 99%

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Hyperglycemia accentuates and ketonemia attenuates hypoglycemia-induced neuronal injury in the developing rat brain

et al. 2014

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Background: Prolonged hypoglycemia leads to brain injury, despite treatment with 10% dextrose. Whether induction of hyperglycemia or ketonemia achieves better neuroprotection is unknown. Hyperglycemia is neuroprotective in other brain injuries during development; however, it worsens hypoglycemia-induced injury in the adult brain via poly(ADPribose)polymerase-1 (PARP-1) overactivation. Methods: Three-week-old rats were subjected to insulininduced hypoglycemia and treated with 10% dextrose or 50% dextrose. Neuronal injury, PARP-1, and brain-derived neurotrophic factor (BDNF) III/TrkB/p75 NTR expressions were determined. In the second experiment, ketonemia was induced by administering β-hydroxybutyrate during hypoglycemia and its effect on neuronal injury was compared with those conventionally treated using 10% dextrose. results: Both 10 and 50% dextrose administration led to hyperglycemia (50% dextrose > 10% dextrose). Compared with the 10% dextrose group, neuronal injury was greater in the 50% dextrose group and was accompanied by PARP-1 overactivation. BDNF III and p75 NTR , but not TrkB FL , mRNA expressions were upregulated. Neuronal injury was less severe in the rats subjected to ketonemia, compared with those conventionally treated using 10% dextrose. conclusion: Hyperglycemia accentuated hypoglycemiainduced neuronal injury, likely via PARP-1 overactivation. Although BDNF was upregulated, it was not neuroprotective and potentially exaggerated injury by binding to p75 NTR receptor. Conversely, ketonemia during hypoglycemia attenuated neuronal injury.

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“…10 This finding supports the concept that the hippocampus may be differentially vulnerable depending on the developmental stage at which hypoglycemia occurs. This possibility is also supported by the finding that adult rats show more hypoglycemic cell death in the hippocampus than the young, 65 but in young rats, long-term potentiation (a presumed mechanism of learning and memory) is severely decreased in the hippocampus with hypoglycemia.…”

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confidence: 84%

Hippocampal Volume in Type 1 Diabetes

Murray¹,

Stanley²,

Lugar³

et al. 2014

US Neurology

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The hippocampus plays an important role in human learning and memory and is known to be vulnerable to the effects of stress and disease. 1 Within animal models of type 1 diabetes, 2 significant hyperglycemia and hypoglycemia exposure has been shown to cause complex molecular and structural changes in the hippocampus. 2,3 Within humans with type 1 diabetes, exposure to both extremes of the glycemic spectrum have been inconsistently associated with alterations in hippocampal structure [4][5][6][7][8][9] and worse memory function, [8][9][10][11] but it is unclear whether these two findings relate to each other. Given that the diagnosis of type 1 diabetes and exposure to glycemic extremes often occur at a time of dynamic neurodevelopment, it has been hypothesized that exposure at early ages may have different effects on the brain than exposure in adulthood, which could explain some of these inconsistent findings. However, data addressing this concept are limited. In this article, we review the existing literature on the effects of hyperglycemia and hypoglycemia in type 1 diabetes, with focus on the structure and function of the hippocampus during both development and adulthood. Hippocampal Structure, Volume, and FunctionThe hippocampus is a subcortical, primarily gray matter structure residing bilaterally within the medial temporal lobes. It consists of several regions, including the cornu ammonis (CA) and its subregions (CA1-CA4), the dentate gyrus (DG), and the subiculum, which connects the hippocampus to the parahippocampal gyrus. 1 These regions contain intra-and interhippocampal connections through multiple synaptic pathways 12 and have been ascribed specialized roles in the processing of information. 13-16Overall, the hippocampus appears to play an important role in laying down and consciously retrieving explicitly learned, novel information. 17 Within this complex process, the CA1 has been selectively associated with long-term and autobiographical memory, 15,18 the CA2 and CA3 with encoding processes, and the DG with early retrieval and episodic memory formation. 15,19The hippocampus develops heterogeneously and nonlinearly up to age 25 20,21 and is a site of sustained neurogenesis throughout the lifespan. 20-22Hippocampal volume is developmentally dynamic, with the posterior and anterior portions increasing and decreasing respectively with age. 20The total volume steeply increases until approximately age 4, followed by a gradual increase and reaching a peak in volume around age 10. 21Hippocampal volume remains fairly stable until age 50 in healthy adults, followed by a variable level of decline and a significant decrease in volume by age 80. 23 The relationship between developmental changes in hippocampal volume and memory function is complex and still unclear. A meta-analysis of the literature examining hippocampal volume and memory performance in healthy children, adolescents, and young adults revealed that smaller hippocampal volume was associated with better memory performance and that this effect could ...

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Postnatal age influences hypoglycemia-induced neuronal injury in the rat brain

Cited by 48 publications

References 44 publications

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

Hyperglycemia accentuates and ketonemia attenuates hypoglycemia-induced neuronal injury in the developing rat brain

Hippocampal Volume in Type 1 Diabetes

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