Acidosis, energy depletion, overstimulation by excitatory amino acids, and free radical-mediated reactions are the major current concepts for the explanation of damage and death resulting from asphyxia. Impaired phosphorylation by protein kinase C (PKC) represents another mechanism incriminated for cell death. We used an unsophisticated perinatal asphyxia model to study heart protein kinases PKC and cyclin dependent kinase (CDK). Tissue pH, ATP, the antioxidant enzymes superoxide dismutase, catalase, and glutathion peroxidase, lipid peroxidation products, carbonyls, and aromatic hydroxylation were also tested. Electron spin resonance was applied to demonstrate the possible presence of radical adducts. An ELISA method was used to determine cell death. PKC activity and mRNA decreased with the length of the asphyctic periods and were paralleled by CDK and pH, whereas cell death gradually increased. No evidence was found for the involvement of active oxygen species or a radical adduct, and no energy depletion was observed. We conclude that impaired protein phosphorylation and/or acidosis may play a role in the pathobiochemistry of death from perinatal asphyxia in the rat.

Our findings indicate that homocysteine specifically stimulates aortic cyclin-dependent kinase at the transcriptional level, with the possible consequence of proliferation of aortic cells as revealed by incorporation of bromodeoxyuridine in the aortic wall.

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No information is available on transcription factors (TF), the main regulators of gene expression, in perinatal asphyxia (PA), and as pathomechanisms in PA are different, data on TFs from ischemia or hypoxia cannot be simply extrapolated to PA, and no studies have been reported to show an expressional pattern or the concerted action of TFs. We, therefore, used a gene-hunting technique, subtractive hybridization, to show sequences different in brains of normoxic and perinatally asphyxiated (10 and 20 min of asphyxia) rats. These subtracted sequences were identified by gene bank and assigned to individual genes. At 10 min of PA the TFs NFI/CAAT-binding protein, NF-kappa-B p65, N-myc, basic helix loop helix protein D82868, and c-myc intron binding protein were upregulated. At 20 min of PA the TFs SOX4 and neuronal death factor were upregulated, whereas the TFs c-maf, PEBP major transcription factor, brn-2, homeodomain protein Af004431, and zinc finger transcriptional factor M65008 were downregulated. The biological meaning of our findings is the demonstration of a pathophysiological pattern of TFs including POU, zinc finger, homeodomain, and basic helix-loop helix motifs in PA, proposing pathomechanisms for brain damage from PA, explaining transcriptional changes in general (as, e.g., NF-kappa-B p65, etc.) or in specific terms (as, e.g., neuronal death factor).

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