IL-1 Effects in Brain.
Final rept. 1 Jun 91-31 Dec 96,
TUFTS UNIV BOSTON MA SCHOOL OF MEDICINE
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This research explored the effect of cytokines and neurosteroids on the GABAergic and I glutamatergic neurotransmitter systems in the CNS. lnterleukin-1 IL-1 augmented GABAA receptor function in behavioral, neurochemical and electrophysiological paradigms both in vivo and in vitro. These effects of IL-1 were inhibited by the IL-1 receptor antagonist suggesting an indirect effect of IL-1 at its own receptor in the modulation of the GABAA receptor. Subsequent experiments demonstrated a negative modulatory role of IL-1 on NMDA receptor-mediated intracellular calcium increases which was unique to both IL-1 and to the NMDA receptor. These results provided the first direct evidence of a functional interaction of IL-1 with the NMDA receptor and implies a beneficial role of this cytokine in neurodegenerative processes. Additional work in our laboratory confirmed that pregnenolone sulfate PS potentiated the NMDA receptor-mediated increases in calcium flux, most likely acting at a unique steroid recognition site on the NMDA receptor. Further studies demonstrated a neurotoxic effect of PS on these cortical neurons in vitro. This study also demonstrated a synergistic toxic effect of PS and NMDAglycine, providing additional evidence of the possible involvement of PS in the excitotoxic damage.
- Anatomy and Physiology