Upregulation of Pentose Phosphate Pathway and Preservation of Tricarboxylic Acid Cycle Flux after Experimental Brain Injury

Bartnik, Brenda L.; Sutton, Richard L.; Fukushima, Masamichi; Harris, Neil G.; Hovda, David A.; Lee, Stefan M.

doi:10.1089/neu.2005.22.1052

Cited by 107 publications

(135 citation statements)

References 86 publications

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“…In fact it was at levels comparable to those reported after stress such as traumatic brain injury in adult human and rodent brain [24,25]. Activity of the PPP was evident in neurons due to the presence of [4-C]glutamate.…”

Section: Pppsupporting

confidence: 78%

“…These needs can be met by the PPP, which produces nucleotides and NADPH. Earlier studies have shown that the pathway accounts for approximately 2-5 % [21][22][23] of the glucose metabolism in the adult brain and can be upregulated to 9-20 % in response to injury in animal and human studies [24,25]. However, little is known about the PPP in the developing brain.…”

mentioning

confidence: 99%

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Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

et al. 2013

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Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-C]glucose and [1,2-C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity during development, P7 rats received [1,2-C]glucose and were sacrificed 30 min later. Brain extracts were analysed using Hand C-NMR spectroscopy. The neonatal brain contained lower levels of glutamate, aspartate and N-acetylaspartate but similar levels of GABA and glutamine compared to adults. Metabolism of [1-C]glucose at the acetyl CoA stage was reduced much more than that of [1,2-C]acetate. The transfer of glutamate from neurons to astrocytes was greatly reduced while transfer of glutamine from astrocytes to glutamatergic neurons was relatively higher compared to adults. However, transport of glutamine from astrocytes to GABAergic neurons was lower. Using [1,2-C]glucose it could be shown that despite much lower pyruvate carboxylation, relatively more pyruvate from glycolysis was directed towards anaplerosis than pyruvate dehydrogenation in astrocytes compared to reports from the adult brain. Moreover, the ratio of PPP/glucose metabolism was higher in P7 compared to adult brain. Our findings indicate that only the part of the glutamateglutamine cycle that transfers glutamine from astrocytes to neurons is operating in the After uptake into the cell, glucose (via pyruvate from glycolysis) and acetate can be converted to the TCA cycle substrate acetyl CoA. It has been reported that glucose oxidation is lower and that the average time the metabolites stay in the TCA cycle before conversion to substances such as neurotransmitters glutamate and thereafter γ-amino butyric acid (GABA) is longer in the neonatal compared to the adult brain [7]. This is in part attributed to the low levels of enzymes for pyruvate metabolism and oxidative glucose metabolism in the postnatal period [8].Pyruvate carboxylase, the brain's exclusive anaplerotic enzyme [9], is present in astrocytes only [10], and is of major importance for glial metabolic support of neurotransmission. Pyruvate carboxylase content is low in the neonatal period and increases 15-fold up to young adult age (postnatal day 30-40) when the level reaches a plateau [8].Most of the glutamate in the brain is found in neurons and is released into the synapse after depolarisation [11]. The ability of astrocytes to take up glutamate from the synapse and convert it into glutamine by the astrocyte specific enzyme glutamine synthetase [12] is vital for normal metabolic homeostasis and as a defence mechanism against excitotoxicity [13]. The subsequent transfer of glutamine from astrocytes to neurons for deamidation to glutamate closes the glutamate-

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Section: Pppsupporting

confidence: 78%

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confidence: 99%

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

et al. 2013

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“…An appropriate comparison for our study used adult monkey brains and found PPC activity of 5.6% in the cerebral hemispheres, 5.4% in brainstem, 6.4% in hypothalamus, and 8% in cerebellum (Hostetler et al, 1970). Recent studies from our laboratory of brain tissue extracts in a rat brain injury model confirm the increase in PPC flux after TBI (Bartnik et al, 2005).…”

Section: Normal Cerebral Pentose Phosphate Flux and Increased Flux Afsupporting

confidence: 51%

Increased Pentose Phosphate Pathway Flux after Clinical Traumatic Brain Injury: A [1,2-¹³C₂]glucose Labeling Study in Humans

Dusick

Glenn

Lee

et al. 2007

J Cereb Blood Flow Metab

116

134

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Patients with traumatic brain injury (TBI) routinely exhibit cerebral glucose uptake in excess of that expected by the low levels of oxygen consumption and lactate production. This brings into question the metabolic fate of glucose. Prior studies have shown increased flux through the pentose phosphate cycle (PPC) during cellular stress. This study assessed the PPC after TBI in humans.[1,2-13 C 2 ]glucose was infused for 60 mins in six consented, severe-TBI patients (GCS < 9) and six control subjects. Arterial and jugular bulb blood sampled during infusion was analyzed for 13 C-labeled isotopomers of lactate by gas chromatography/mass spectroscopy. The product of lactate concentration and fractional abundance of isotopomers was used to determine blood concentration of each isotopomer. The difference of jugular and arterial concentrations determined cerebral contribution. The formula PPC = (m1/m2)/(3 + (m1/m2)) was used to calculate PPC flux relative to glycolysis. There was enrichment of [1,2-13 C 2 ]glucose in arterial-venous blood (enrichment averaged 16.6% in TBI subjects and 28.2% in controls) and incorporation of 13 C-label into lactate, showing metabolism of labeled substrate. The PPC was increased in TBI patients relative to controls (19.6 versus 6.9%, respectively; P = 0.002) and was excellent for distinguishing the groups (AUC = 0.944, P < 0.0001). No correlations were found between PPC and other clinical parameters, although PPC was highest in patients studied within 48 h of injury (averaging 33% versus 13% in others; P = 0.0006). This elevation in the PPC in the acute period after severe TBI likely represents a shunting of substrate into alternative biochemical pathways that may be critical for preventing secondary injury and initiating recovery.

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“…36) In previous study, the pentose phosphate pathway is increased after traumatic brain injury. 37) These suggested that increase of 6-phosphogluconolactonase may contribute to enhance of anti-oxidative stress after cerebral ischemia. Apoprotein A-I, which the major component antiatherogenic properties of high density lipoprotein (HDL) are mainly related to reverse cholesterol transport process (i.e., removing excess cholesterol from the arterial wall's foam macrophages to the liver for metabolism).…”

Section: Discussionmentioning

confidence: 99%

Withdrawal: Proteomic Profiling in the Spinal Cord and Sciatic Nerve in a Global Cerebral Ischemia-Induced Mechanical Allodynia Mouse Model

Harada

Matsuura

Takano

et al. 2016

Biological & Pharmaceutical Bulletin

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Central post-stroke pain (CPSP) is one of the complications of cerebral ischemia and neuropathic pain syndrome. At present, there are few studies of pain in regions such as the spinal cord or sciatic nerve in cerebral ischemic animal models. To identify proteomic changes in the spinal cord and sciatic nerve in global cerebral ischemic model mice, in the present study we performed an investigation using proteomic methods. In a comparison between the intensity of protein spots obtained from a sham and that from a bilateral carotid artery occulusion (BCAO) in spinal cord and sciatic nerve, the levels of 10 (spinal cord) and 7 (sciatic nerve) protein spots were altered. The protein levels in the spinal cord were significantly increased in N G ,N Gdimethylarginine dimethylaminohydrolase 1 (DDAH1), 6-phosphogluconolactonase isoform 1, and precursor apoprotein A-I and decreased in dihydropyrimidinase-related protein 2 (CRMP-2), enolase 1B, rab guanosine 5′-diphosphate (GDP) dissociation inhibitor beta, septin-2 isoform a, isocitrate dehydrogenase subunit alpha, cytosolic malate dehydrogenase, and adenosine triphosphate synthase. The protein levels in the sciatic nerve were significantly increased in a mimecan precursor, myosin light chain 1/3, and myosin regulatory light chain 2 (MLC2), and decreased in dihydropyrimidinase-related protein 3 (CRMP-4), protein disulfideisomerase A3, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1, and B-type creatine kinase. In addition, CRMP-2 and CRMP-4 protein levels were decreased, and DDAH1 and MLC2 protein levels were increased on day 1 after BCAO using Western blotting. These results suggested that changes in these proteins may be involved in the regulation of CPSP.Key words global ischemia; pain; spinal cord; sciatic nerve; proteome Cerebral stroke remains one of the leading causes of death and disability worldwide.1) Recent insights into the basic mechanism involved in ischemic stroke indicate that endothelial dysfunctions along with oxidative stress and neuroinflammation are key elements in the occurrence and development of ischemic brain damage that results in cell damage and death.2,3) Many clinical symptoms can manifest after strokes, including motor deficits, cognitive dysfunction, language problems, emotional disturbances, social maladjustment, somatosensory dysfunction, and central pain. 4,5) Cerebral stroke occasionally induces central post-stroke pain (CPSP) that manifests as burning pain, throbbing pain, aching pain, slashing pain, allodynia, and hyperalgesia, either continuously or intermittently on the affected side.6,7) CPSP is known to be one of the neuropathic pain.8) Neuropathic pain is defined as "pain initiated or caused by a primary lesion or dysfunction of the nervous system." It can be a debilitating and difficult condition to treat and is often resistant to simple analgesics, requiring additional analgesic treatment. 9)Some hypotheses of the pathophysiological mechanisms of somatosensory dysfunction have been proposed to explain CPSP symptoms, such as the ...

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Upregulation of Pentose Phosphate Pathway and Preservation of Tricarboxylic Acid Cycle Flux after Experimental Brain Injury

Cited by 107 publications

References 86 publications

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

Increased Pentose Phosphate Pathway Flux after Clinical Traumatic Brain Injury: A [1,2-¹³C₂]glucose Labeling Study in Humans

Withdrawal: Proteomic Profiling in the Spinal Cord and Sciatic Nerve in a Global Cerebral Ischemia-Induced Mechanical Allodynia Mouse Model

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Upregulation of Pentose Phosphate Pathway and Preservation of Tricarboxylic Acid Cycle Flux after Experimental Brain Injury

Cited by 107 publications

References 86 publications

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

Increased Pentose Phosphate Pathway Flux after Clinical Traumatic Brain Injury: A [1,2-13C2]glucose Labeling Study in Humans

Withdrawal: Proteomic Profiling in the Spinal Cord and Sciatic Nerve in a Global Cerebral Ischemia-Induced Mechanical Allodynia Mouse Model

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Increased Pentose Phosphate Pathway Flux after Clinical Traumatic Brain Injury: A [1,2-¹³C₂]glucose Labeling Study in Humans