The aim of the present study was to investigate the effect of aging and ovariectomy on neuro- inflammation in dentate gyrus of the hippocampus obtained from old female rats and the influence of chronic exogenous administration of estrogens (Eos) and melatonin (Mel) on these. Thirty-six female Wistar rats of 22 months of age were used. Twelve of them remained intact, and the other 24 were ovariectomized at 12 months of age. Ovariectomized animals were divided into 3 groups and treated for 10 weeks with Eos, Mel or saline. All rats were killed by decapitation at 24 months of age and dentate gyri were collected. A group of 2 month old intact female rats was used as young control. The levels of TNFα, IL1β and IL6 were analysed by ELISA. The expression of TNFα, IL1β, GFAP, nNOS, iNOS, HO-1 and NFkB genes were detected by RT-PCR. The levels of IL1β and IL6 were significantly elevated in the dentate gyrus of old rats as compared to young ones, and this effect was more evident in ovariectomized animals. The mRNA expression of IL1β was also increase in old intact and ovariectomized females as compared to young. No statistically significant differences were observed between TNFα levels of intact and castrated old female rats. However, a significant increase in mRNA expression of TNFα of ovariectomized versus the old intact group was observed. Administration of Eos and Mel to the ovariectomized females significantly decreased both levels and gene expression of pro-inflammatory cytokines. Aging significantly increased mRNA expression of iNOS, HO-1 and NFkB and these changes were more marked in ovariectomized animals. The expressions of these genes were significantly attenuated after Eos and Mel replacement in the group of castrated females. The dentate gyrus of aged rats showed a highly significant increase in mRNA expression of GFAP and ovariectomized rats showed an additional increase. Administration of Eos to the ovariectomized females significantly decreased this parameter, but this was not the case in those treated with Mel. The results revealed that chronic administrations of Eos and Mel were able to prevent the ovariectomy-induced increase in the levels of pro-inflammatory cytokines and also in the up-regulation of GFAP and NFkB in the dentate gyrus as observed in intact rats.