TLR4-mediated brain inflammation halts neurogenesis: impact of hormonal replacement therapy

Experimental and epidemiological data show that the severity and the duration of brain inflammation are attenuated in females compared to males. This attenuated brain inflammation is ascribed to 1713-estradiol. However, several studies suggest that 1713estradiol is also endowed with proinflammatory properties. The aim of the present study is to assess the effect of hormonal replacement therapies on lipopolysaccharide (LPS)-induced brain inflammation and its consequent effect on newly born neurons. Bilaterally ovariectomized rats received intrastriatal injection of LPS (2 50 ng/p,I) and were subsequently given daily subcutaneous injections of either vehicle, 1713-estradiol (2 5 kg/kg) or 1713-estradiol and progesterone (5 mg/kg). Microglial activation and newly born neurons in the rostral migratory stream were monitored using double immunofluorescence. Nuclear factor KB (NFKB) signaling pathway and its target inflammatory proteins were assessed by either western blot [cyclooxygenase-2 (COX-2) and interleukin-6 (1156)1 or enzymelinked immunosorbent assay [tumor necrosis factor-a (INF-a)]. LPS-induced activation of microglia, promoted NFKB signaling pathway and enhanced the production of proinflammatory proteins (INF-a and COX-2). These proinflammatory responses were not attenuated by 1713-estradiol injection. Supplementation of 1713-estradiol with progesterone significantly dampened these proinflammatory processes. Interestingly, LPS-induced brain inflammation dampened the number of newly born neurons in the rostral migratory stream. Administration of combined 1713-estradiol and progesterone resulted in a significantly higher number of newly born neurons when compared to those seen in rats given either vehicle or 1713-estradiol alone. These data strongly suggest that combined 1713-estradiol and progesterone, and not 1713-estradiol alone, rescues neurogenesis from the deleterious effect of brain inflammation likely via the inhibition of the signaling pathways leading to the activation of proinflammatory genes.