Novel effects on memory observed following unilateral intracranial administration of okadaic acid, cyclosporin A, FK506 and [MeVal4]CyA.

The involvement of protein phosphatases and peptidyl-prolyl cis/trans isomerases (PPIases) in memory formation in the chick has previously been investigated using a single-trial learning task. In these studies, inhibitory agents were administered bilaterally directly to a critical area of the chick brain. These studies are now extended to investigate whether similar effects are obtained if the drugs are administered unilaterally.

Cyclosporin A, FK506 and rapamycin produce multiple, temporally distinct, effects on memory following single-trial, passive avoidance training in the chick.

Few studies have used a pharmaco-behavioural methodology to directly investigate roles for the calcium-dependent protein phosphatase calcineurin (CaN) in memory formation, due partly to the absence of specific inhibitory agents. A number of drugs with different inhibitory profiles were used to examine this issue in groups of chicks trained on a single-trial, passive-avoidance task. Bilateral intracranial administration of the immunosuppressants FK506 and cyclosporin A (CyA) led to two temporally distinct effects, distinguished by the concentration of drug required and the effective time of administration relative to training.

Apoptosis induced by inhibitors of the plasma membrane NADH-oxidase involves Bcl-2 and calcineurin.

Activation of the plasma membrane NADH-oxidoreductase (PMOR) system by addition of growth factors or extracellular electron acceptors stimulates cellular proliferation. We now show that the vanilloids capsaicin, dihydrocapsaicin, and resiniferatoxin are inhibitors of the NADH-oxidase activity of the PMOR system and that both these and two previously identified PMOR inhibitors (chloroquine and retinoic acid) induce apoptosis in human B-cell and mouse myeloid cell lines. At the optimal concentration, PMOR inhibitors can induce between 50 and 70% of apoptosis in mouse myeloid and human B-cell lines within 8-12 h, provided these cell lines do not express Bcl-2.