The work in Dr. Pastuszko's laboratory is focused on determining the mechanisms by which the monoamine and excitatory neurotransmitters contribute to metabolic stress and dysfunction induced by hypoxia-ischemia in the young brain.

The newborn brain is often subject to hypoxic/ischemic insult due to perinatal asphyxia, such as apnea or cardiopulmonary dysfunction. These insults result in metabolic alterations which can lead to a wide range of disturbances of neuronal function, from outright cell death to long term developmental disorders. Identifying and quantitating the factors which exacerbate the metabolic disturbances during controlled, graded hypoxia-ischemia and reperfusion, will allow us to infer their relative contributions to brain pathology.

The work in Dr. Pastuszko's laboratory is focused on determining the mechanisms by which the monoamine and excitatory neurotransmitters contribute to metabolic stress and dysfunction induced by hypoxia-ischemia in the young brain. Experimental models include brain hypoxia induced by arterial hypoxia, hemorrhagic hypotension with bilateral carotid occlusion, cardiopulmonary bypass, and stroke. The level and duration of hypoxic/ischemic insult is controlled and quantitated by measuring cortical oxygen pressure using oxygen dependent quenching of phosphorescence. Neurotransmitter levels are continuously monitored by in vivo microdialysis. Metabolic stress and cellular dysfunction are evaluated by the extracellular levels of dopamine, glutamate and hydroxyl radicals, expression of the hsp-72 mRNA, induction of apoptosis, etc.

One finding is that, particularly in mild hypoxia, the extracellular level of dopamine depends primary on the oxygen concentration in the tissue with minimal influence of blood flow and pH. There is no "oxygen reserve" in the brain and the extracellular levels of dopamine increase almost linearly with decrease in oxygen pressure, with even small decreases in oxygen pressure resulting in increased dopamine levels (see figure). A variety of mechanisms by which dopamine, in particular extracellular dopamine, can contribute to cellular injury in the brain are being investigated.

RECENT REPRESENTATIVE PUBLICATIONS

1. Kuo, M.F., D. Song, S. Murphy, M. Papadopoulos, D.F. Wilson and A. Pastuszko (1998) Excitatory amino acid receptor antagonists decrease hypoxia induced increase in extracellular dopamine in striatum of newborn piglets. Neurochem. Internatl. 32:281-289.
2. Tammela, O., D. Song, M. Olano, M. Delivoria-Papadopoulos, D.F. Wilson and A. Pastuszko (1997) Response of cortical oxygen pressure and striatal extracellular dopamine to metabolic acidosis in newborn piglets. Adv. Exptl. Med. Biol. 389:103-112.
   
3. Murphy, S., D. Song, F.A. Welsh, D.F. Wilson and A. Pastuszko (1996) The effect of catecholamines on regional expression of heat shock protein-72 mRNA in neonatal piglet brain during hypoxia and posthypoxic reoxygenation. Brain Res. 727:145-152.
4. Olano, M., D. Song, S. Murphy, D.F. Wilson and A. Pastuszko (1995) Relationships of dopamine, cortical oxygen pressure, and hydroxyl radicals in brain of newborn piglets during hypoxia and posthypoxic recovery. J. Neurochem. 65:1205-1212.
5. Yonetani, M., Ch-Ch. Huang, N. Lajevardi, A. Pastuszko, M. Delivoria-Papadopoulos and D.F. Wilson. (1994) Effect of hemorrhagic hypotension on extracellular level of dopamine, cortical oxygen pressure and blood flow in brain of newborn piglets. Neurosci. Lett. 180:247-252.
   
6. Pastuszko, A. (1994) Metabolic response of dopaminergic system during hypoxia-ischemia and reoxygenation in the immature brain. Biochem. Med. Metabol. Biol. 51:1-15.