Short-term effects of the 21-aminosteroid lazaroid tirilazad mesylate (PNU-74006F) and the pyrrolopyrimidine lazaroid PNU-101033E on energy metabolism of human peripheral blood mononuclear cells

Two groups of antioxidant compounds, the 21-aminosteroids and the pyrrolopy rimidines, have been found to act as neuroprotective drugs against lipid pe roxidation in the injured CNS. Like glucocorticoids at high doses they are assumed to produce their effects at least in part by direct membrane stabil izing effects. In order to prove this hypothesis, we have investigated in t his study the effects of these drugs on the energy metabolism of activated human peripheral blood mononuclear cells (PBMC) since these cells have been shown to serve as a suitable test system for substances affecting processe s of ATP turnover. We compared the in vitro effects of (i) the 21-aminoster oid lazaroid tirilazad, (ii) the pyrrolopyrimidine lazaroid PNU-101033E and (iii) the glucocorticoid methylprednisolone on mitogen-induced respiration rate and ATP-consumption. We show that tirilazad inhibits concanavalin A-s timulated respiration rate and sodium cycling across the plasma membrane. T he effect of methylprednisolone is similar indicating corresponding cellula r mechanisms. However, unlike methylprednisolone, tirilazad produced no sig nificant effect on calcium cycling across the plasma membrane. PNU-101033E in our test system caused cytotoxic effects on PBMC that did not allow us t o quantify cellular actions on energy metabolism. Our results underline the view that tirilazad, first, is mimicking the high-dose immunosuppressive p harmacology of glucocorticoids such as methylprednisolone and, second, is l ikely to produce its therapeutic effects by direct physicochemical interact ions with cellular membranes.