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 pyrrolopyrimidines, have been found to act as neuroprotective drugs against lipid peroxidation in the injured CNS. Like glucocorticoids at high doses they are assumed to produce their effects at least in part by direct membrane stabilizing effects. In order to prove this hypothesis, we have investigated in this 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 processes of ATP turnover. We compared the in vitro effects of (i) the 21-aminosteroid 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-stimulated respiration rate and sodium cycling across the plasma membrane. The effect of methylprednisolone is similar indicating corresponding cellular mechanisms. However, unlike methylprednisolone, tirilazad produced no significant effect on calcium cycling across the plasma membrane. PNU-101033E in our test system caused cytotoxic effects on PBMC that did not allow us to quantify cellular actions on energy metabolism. Our results underline the view that tirilazad, first, is mimicking the high-dose immunosuppressive pharmacology of glucocorticoids such as methylprednisolone and, second, is likely to produce its therapeutic effects by direct physicochemical interactions with cellular membranes.
Schmid
D
D
Department of Medicine (Rheumatology), Charité University Hospital, Humboldt University, Berlin, Germany.
Burmester
G R
GR
Tripmacher
R
R
Fici
G
G
von Voigtlander
P
P
Buttgereit
F
F
D000255:Adenosine Triphosphate / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D003208:Concanavalin A / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D008775:Methylprednisolone / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011281:Pregnatrienes / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C112281:PNU 101033E; D011281:Pregnatrienes; D011506:Proteins; D011743:Pyrimidines; D011758:Pyrroles; D003208:Concanavalin A; D000255:Adenosine Triphosphate; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D008775:Methylprednisolone; C053355:tirilazad