Postnatal hypoxic-ischemic brain injury alters mechanisms mediating neuronal glucose transport.
We examined the effect of hypoxic ischemia and hypoxia vs. normoxia on postnatal murine brain substrate transporter concentrations and function. We detected a transient increase in the neuronal brain glucose transporter isoform (GLUT-3) in response to hypoxic ischemia after 4 h of reoxygenation. This increase was associated with no change in GLUT-1 (blood-brain barrier/glial isoform), monocarboxylate transporter isoforms 1 and 2, synapsin I (neuronal marker), or Bax (proapoptotic protein) but with a modest increase in Bcl-2 (antiapoptotic mitochondrial protein) protein concentrations. At 24 h of reoxygenation, the increase in GLUT-3 disappeared but was associated with a decline in Bcl-2 protein concentrations and the Bcl2:Bax ratio, an increase in caspase-3 enzyme activity (apoptotic effector enzyme), and extensive DNA fragmentation, which persisted later in time (48 h) only in the hippocampus. Hypoxia alone in the absence of ischemia was associated with a transient but modest increase in GLUT-3 and synapsin I protein concentrations, which did not cause significant apoptosis and/or necrosis. Assessment of glucose transporter function by 2-deoxyglucose (2-DG) uptake using two distinct techniques, namely positron emission tomography (PET) and the modified Sokoloff method, revealed a discrepancy due to glucose uptake by extracranial Harderian glands that masked the accurate detection of intracranial brain glucose uptake by PET scanning. The modified Sokoloff method assessing 2-DG uptake revealed that the transient increase in GLUT-3 was critical in protecting against a decline in brain glucose uptake. We conclude that hypoxic-ischemic brain injury is associated with transient compensatory changes targeted at protecting glucose delivery to fuel cellular energy metabolism, which then may delay the processes of apoptosis and cell necrosis.
Zovein
Ann
A
Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, Los Angeles, CA, USA.
Flowers-Ziegler
Judy
J
Thamotharan
Shanthie
S
Shin
Don
D
Sankar
Raman
R
Nguyen
Khoi
K
Gambhir
Sanjiv
S
Devaskar
Sherin U
SU
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D003847:Deoxyglucose / Q000493:pharmacokinetics; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology; D051274:Glucose Transporter Type 3; D006243:Harderian Gland / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013997:Time Factors; D014055:Tomography, Emission-Computed
D051274:Glucose Transporter Type 3; D009004:Monosaccharide Transport Proteins; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; C495689:Slc2a3 protein, mouse; D019788:Fluorodeoxyglucose F18; D003847:Deoxyglucose; D010100:Oxygen