Neuroprotective effects of estradiol in the adult rat hippocampus: Interaction with insulin-like growth factor-I signalling

We have previously shown that 17-beta-estradiol protects neurons in the den tate gyrus from kainic acid-induced death in vivo. To analyse whether this effect is mediated through estrogen receptors and through cross-talk betwee n steroid and insulin-like growth factor (IGF) systems, we have concomitant ly administered antagonists of estrogen receptor (ICI 182,780) or the IGF-I receptor (JB1) with estradiol, In addition, we have also administered IGF- I with or without the estrogen receptor antagonist, JB1 (20 mu g/ml), ICI 1 82,780 (10(-7) M), and IGF-I (100 mu g/ml) were delivered into the left lat eral ventricle of young ovariectomized rats via an Alzet osmotic minipump ( 0.5 mu l/hr) for 2 weeks. All rats received kainic acid (7 mg/Kg b.w.) or v ehicle i.p. injections at day 7 after minipump implant, Also on day 7, rats treated i.c. v.with only ICI 182,780 or JB1 received a single i.p. injecti on of 17-beta-estradiol (150 mu g/rat) or vehicle. On day 14 after minipump implant, the rats were killed, brains processed, and the number of survivi ng hilar neurons estimated by the optical disector technique. Both IGF-I an d estradiol treatments resulted in over 90% survival of hilar neurons, The neuroprotective action of estradiol was blocked by ICI 182,780 and by JB1, Furthermore, IGF-I enhancement of neuronal survival was significantly reduc ed by ICI 182,780, These results indicate that in this model of hippocampal lesion, the neuroprotective effect of estradiol depends both on estrogen r eceptors and IGF-I receptors, while the protection exerted by IGF-I depends also on estrogen receptors, In conclusion, an interaction of estrogen rece ptor and IGF-I receptor signalling may mediate neuroprotection in the adult rat hippocampus, J. Neurosci, Res. 58:815-822, 1999, (C) 1999 Wiley-Liss, Inc.