INTERLEUKIN-1 MEDIATES INDUCTION OF TOLERANCE TO GLOBAL-ISCHEMIA IN GERBIL HIPPOCAMPAL CA1 NEURONS

A series of experiments was performed to determine the role of interle ukin (IL)-1 in the induction of tolerance to global ischemia in Mongol ian gerbils. In Group I, a 2-min ''preconditioning'' ischemia protecte d CA1 hippocampal neurons in gerbils subjected to 3.5 min ischemia 3 d ays later. CA1 neuronal density was: sham, 171 +/- 3/mm; 3.5 min ische mia, 30 +/- 30/mm; 2 and 3.5 min ischemia 162 +/- 6/mm. Experiments in Group II addressed the role of IL-1 in the induction of tolerance by sublethal ischemia. Arterial IL-1 alpha and IL-1 beta became elevated between 1 and 3 days after a 2-min ischemic exposure. IL-1 alpha was: sham, 6.4 +/- 0.6 ng/ml; and 2-day, 10.2 +/- 1.2 ng/ml. IL-1 beta was: sham, 6.4 +/- 0.5 ng/ml; and 2-day, 17.3 +/- 2 ng/ml. Recombinant hum an IL-1 receptor antagonist (IL-1ra) i.p. blocked ischemic tolerance i nduction by 2-min preconditioning ischemia: 2-min ischemia + vehicle, 162 +/- 6/mm; and 2-min ischemia + IL-1ra, 67 +/- 17/mm. Experiments i n Group III assessed the capacity of IL-1 to induce tolerance to brain ischemia. IL-1 alpha i.p. (0, 10, 20 mu g/kg) for 3 days prior to 3.5 -min forebrain ischemia provided significant CA1 neuroprotection in a dose-dependent manner: 2 +/- 2, 68 +/- 83, and 129 +/- 42/mm, respecti vely. IL-1 beta (15 mu g/kg) in combination with either IL-1ra (100 mg /kg) or IL-1ra vehicle i.p. on the same schedule demonstrated a signif icant CA1 neuroprotection that could be nullified by IL-1ra: IL-1 beta + IL-1ra vehicle, 153 +/- 16/mm; and IL-1 beta +/- IL-1ra, 67 +/- 36/ mm. Recognition that tolerance arises from stimulation of a known rece ptor (IL-1RI) permits molecular analysis of the intracellular signalin g that is critical for production of that state.