Hypoxia in human NT2-N neurons : The role of acidosis, mitochondria and inflammation
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AbstractApproximately 4 million infants out of 130 million worldwide annual births suffer from birth asphyxia. Of these, approximately 25% die and 25% develop some kind of neurological sequelae (UNICEF 2003). In the western part of the world, 2-6/1000 of all newborn are diagnosed with HIE, hypoxic ischemic encephalopathy, during the first days of life, due to reduced gas exchange through placenta or lungs.
The overall aim for this thesis in pediatric neurology was to understand more about the mechanisms behind hypoxic-ischemic brain damage, so that treatment for this important condition hopefully can be improved. We focused our research on acidosis, mitochondrial function and inflammation, all important but not fully understood phenomena in hypoxic-ischemic brain damage and all possibly amendable to interventional treatment.
Hypoxia studies were done in NT2-N neurons, a human cell line consisting of postmitotic, differentiated fenotypic neurons. Analyses were done for cell death, energy level, mitochondrial function and different mediators of inflammation. Acidosis was confirmed to have a protective effect during hypoxia and a detrimental effect early during reoxygenation. Further, an early decline in mitochondrial function was found. Inflammation played a role during hypoxic-ischemic brain damage. Finally, the results showed neuronal damage to occur several hours after the insult. This “delayed” cell death gives the possibility of beneficial intervention during this “therapeutic time window”.
Papers included in the thesis
I Frøyland E, Wibrand F, Almaas R, Dalen I, Lindstad JK, Rootwelt T. Acidosis during reoxygenation has an early detrimental effect on neuronal metabolic activity. Pediatr.Res. 2005 57(4):488-493.
II Frøyland E, Pedersen ED, Kvissel AK, Almaas R, Pharo AM, Skålhegg BS, Mollnes TE, Rootwelt T. Effect of acidosis on IL-8 and MCP-1 during hypoxia and reoxygenation in human NT2-N neurons. Brain Research 2006 1113(1):64-73.
III Frøyland E, Skjæret C, Wright M, Dalen ML, Cvancarova M, Kasi C Rootwelt T. Inflammatory receptors and pathways in human NT2-N neurons during hypoxia and reoxygenation. Impact of acidosis. Accepted for publication in Brain Research (2008). Brain Res. 2008 1217C:37-49.2008.
IV Pedersen ED, Frøyland E, Kvissel AK, Pharo AM, Skålhegg BS, Rootwelt T, Mollnes TE. Expression of complement regulators and receptors on human NT2-N neurons - effect of hypoxia and reoxygenation. Mol. Immunol. 2007 44(9):2459-68.