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Cyclooxygenase-2 (COX-2) and presenilin (PSEN) 1 and 2 genes are regulated during development as well as in pathological conditions associated to hypoxia. In this study, we investigated their patterns of expression during the first 2 weeks of postnatal life in a rat model of moderate global perinatal asphyxia that we have previously reported to be characterized by early oxidative stress and delayed behavioral alterations. In the hippocampus, global perinatal asphyxia induced an early up-regulation COX-2 mRNA (postnatal day, pnd, 1), which preceded those of PSEN 1 and 2 genes, observed at pnd 4. At pnd 11, the expression of all three genes was decreased compared to control animals. In addition, we analyzed the expression of the scavenging enzymes catalase, copper/zinc- and manganese-superoxide dismutase. As for COX-2, the three enzymes were up-regulated in the hippocampus at pnd 1 and returned at or below baseline by pnd 4. In the cortex, only PSEN 1 and 2 showed a moderate up-regulation at pnd 1 followed by a down-regulation at pnd 11. These findings suggest that moderate perinatal hypoxic episodes are associated with a dysregulation of the several genes involved in brain development and anti-oxidant defenses, which follows a rapid and transient oxidative stress. Such alterations are particularly evident in the hippocampus and could represent an adaptive response to the hypoxic condition. The delayed down-regulation of the scavenging enzymes could set the ground for brain damage and delayed behavioral alterations and further support the potential benefit of early anti-oxidant treatments in a short therapeutic window soon after birth.

In the present study we examined the long-term effects of neonatal lesion of basal forebrain cholinergic neurons induced by intracerebroventricular injections of the immunotoxin 192 IgG saporin. Animals were then characterised behaviourally, electrophysiologically and molecularly. Cognitive effects were evaluated in the social transmission of food preferences, a non-spatial associative memory task. Electrophysiological effects were assessed by recording of cortical electroencephalographic (EEG) patterns. In addition, we measured the levels of proteins whose abnormal expression has been associated with neurodegeneration such as amyloid precursor protein (APP), presenilin 1 and 2 (PS-1, PS-2), and cyclooxygenases (COX-1 and COX-2). In animals lesioned on postnatal day 7 and tested 6 months thereafter, memory impairment in the social transmission of food preferences was evident, as well as a significant reduction of choline acetyltransferase activity in hippocampus and neocortex. Furthermore, similar to what observed in Alzheimer-like dementia, EEG cortical patterns in lesioned rats presented changes in α, β and δ activities. Levels of APP protein and mRNA were not affected by the treatment. Levels of hippocampal COX-2 protein and mRNA were significantly decreased whereas COX-1 remained unaltered. PS-1 and PS-2 transcripts were reduced in hippocampus and neocortex. These findings indicate that neonatal and permanent basal forebrain cholinergic hypofunction is sufficient to induce behavioural and neuropathological abnormalities. This animal model could represent a valid tool to evaluate the role played by abnormal cholinergic maturation in later vulnerability to neuropathological processes associated with cognitive decline and, possibly, to Alzheimer-like dementia.