Vasile Hefco

Memory deficits and increased emotionality induced by β-amyloid (25–35) are correlated with the reduced acetylcholine release and altered phorbol dibutyrate binding in the hippocampus

Summary. In the present study we found that chronic infusion of β-amyloid fragment (25–35) at nanomolar concentration into rat cerebral ventricle impairs learning and memory. At a concentration of 3 nmol/day but not 0.3 nmol/day, β-amyloid significantly reduced the spontaneous alternation behavior and the memory performance in the water maze and multiple passive avoidance tests. A significant increase in anxiety was also found in the animals infused with 3 nmol/day β-amyloid fragment. Memory deficits and the increased emotionality were correlated with a decreased nicotine-evoked acetylcholine release from the frontal cortex/hippocampus, as assessed by microdialysis, in freely moving rats. The amyloid fragment infused either at pico- or nanomolar concentrations reduced the affinity of [3H] phorbol dibutyrate binding, an index of activated protein kinase C (PKC), and increased the total number of binding sites in the hippocampal particulate fraction. Our results suggest that the amnesic and anxiogenic effects of chronic infusion of β-amyloid (25–35) are related to the decreased acetylcholine release and reduced PKC activation.

Memory impairment induced by chronic intracerebroventricular infusion of beta-amyloid (1–40) involves downregulation of protein kinase C

Signaling pathways underlying the cognitive deficit of the Alzheimers disease (AD) are not completely understood. Protein kinase C (PKC), a major neuronal protein plays a critical role in cellular signal transduction and it is known to be subjected to modulation in AD. We showed previously that, chronic infusion of beta-amyloid (1-40) into rat cerebroventricle leads to deficit in spatial and non-spatial memory formation. As an attempt to identify the cellular correlates of the memory deficit, in the present study we investigated the PKC activation in different brain areas. Chronic infusion of beta-amyloid (1-40) for 14 days into the rat cerebroventricle decreased the activity of soluble protein kinase C (PKC) in the hippocampus. Subcellular translocation of PKC to membrane fraction in hippocampal slices of rats treated with beta-amyloid (1-40) was completely abolished under acute stimulation with 0.5 microM phorbol-dibutyrate (PDBu). We also reported a decreased affinity (k(D)) for PDBu binding in the hippocampus, cerebral cortex and striatum. The total number of binding sites for PDBu (B(max)) was increased, in the three brain areas analyzed on the day 14, but the changes were not statistically significant. Our data indicate that chronic accumulation of beta-amyloid (1-40) into the rat brain reduced activation of PKC, effect that would substantially contribute to the memory deficit found in these animals.

Effects of nicotine on memory impairment induced by blockade of muscarinic, nicotinic and dopamine D2 receptors in rats

Scopolamine dose-dependently inhibits passive avoidance latency and decreases spontaneous alternation in the Y-maze, suggesting effects on long-term and short-term memory, respectively. Chlorisondamine (10 mg/kg), a compound which produces a long-lasting central nicotinic receptor blockade, did not affect short-term and long-term memory performance. In normal rats, nicotine at the doses of 0.3, 1.0, and 3.0 mg/kg administered once had a facilitating effect on short-term memory; a higher dose (3.0 mg/kg) did not show a more pronounced effect than a lower one (0.3 mg/kg). Nicotine, by activating the nicotinic acetylcholine receptors, attenuated the impairment of short-term memory induced by muscarinic or dopamine D2 receptor blockade. On long-term memory, a single dose of nicotine (0.3, 1.0, 3.0 mg/kg) did not affect memory performance, but improved it after chronic (10 consecutive days, 0.3 mg/kg) administration. The antiamnesic effect of nicotine administered once was observed in scopolamine-, scopolamine+chlorisondamine- or sulpiride-treated rats. These results suggest that the antiamnesic effect of nicotine can result from an action at nicotinic receptors subtypes not blocked by chlorisondamine or at nonnicotinic receptors.

The modulator role of the hypothalamic paraventricular nucleus on immune responsiveness

Role of the paraventricular nucleus of the hypothalamus (PVH) upon immune modulation was studied by either mechanically destroying the PVH (PVHL) or by isolating the PVH (PVHI) with a knife-cut. PVHL or PVHI manipulations induced significant leukopenia characterized by a decrease in the number of neutrophils and lymphocytes two weeks post surgery. The numbers of circulating monocytes and eosinophils were not affected by PVH interventions. In addition, PVHL and PVHI were also associated with a reduction, relative to controls, in the phagocytosis by neutrophils and an increase in blastic transformation of T lymphocytes induced by phytohemagglutinin-M (PHA-M). Antibody titers rose against sheep red blood cells (SRBC) after either PVHL or PVHI were reduced. The magnitude of the SRBC antibody reduction after PVH manipulations was similar to that observed in rats that received a peripheral chemical sympathectomy two hrs prior immunization. Comparison of thyroid hormones blood levels two weeks after PVHL or PVHI revealed significant reductions in comparison with sham-operated group (SO), whereas blood corticosterone was not significantly altered. In summary, we provide evidence that lesion or isolation of the PVH selectively reduces circulating white blood cells and the primary immune response, while it enhances the cell-mediated immune function. Taken together our data showed that PVH modulates immune functions by altering both the peripheral sympathetic tone and thyroid hormone secretion.