Purpose: To assess the long-term neuroprotective effects of progesterone (P $_{4}$ ) and allopregnanolone (ALLO) on functional and morphological parameters of the integrity of the hippocampus, after global cerebral ischemia.

Methods: Adult male Sprague-Dawley rats were subjected to a transient severe (20 min) forebrain ischemia (Isch) episode and treated with P $_4$ or ALLO (8 mg/kg i.v.) or its vehicle, at 20 min, 2, 6, 24, 48 and 72 h after ischemia. Rats subjected to Sham procedures, and intact rats were included as non-ischemic controls. Three months after ischemia, both the functional (spatial learning and memory, and reference and working memory), and the morphological integrity (dimensions of the hippocampal formation, thickness of the CA1 subfield, and pyramidal neuron population) of the hippocampus and the medial prefrontal cortex (mPFC) were determined.

Results: Treatment with P $_4$ or ALLO significantly reduced the impairment in spatial learning and memory, as well as in reference and working memory, and prevented the narrowing of the hippocampus, otherwise induced by ischemia. This better performance of P $_4$ - and ALLO-treated rats than vehicle (Veh) -treated rats, occurred in spite of a loss of pyramidal neurons in the CA1, CA2, CA3 and hilus subfields of the Ammon's horn (remaining neurons: Isch+Veh: 21.0, 35.6, 44.1, and 40.3%; Isch+P $_4$ : 19.9, 32.2, 41.1, and 32.5%; Isch+ALLO: 25.5, 62.0, 73.7, and 56.7%), and non-significant changes in the mPFC, as compared to the Intact group (100%).

Conclusions: Performance of P $_4$ - or ALLO-treated rats in learning and memory tests suggests that these steroids promoted neural conditions accounting for adequate functioning long after ischemia, in spite of the loss of hippocampal pyramidal neurons.