AUTHOR=Mouihate Abdeslam 

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

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 8 - 2014

YEAR=2014

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2014.00146

DOI=10.3389/fncel.2014.00146

ISSN=1662-5102

ABSTRACT=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 17β-estradiol. However, several studies suggest that 17β-estradiol is also endowed with proinflammatory properties.  The aim of the present study is to assess the effect of hormonal replacement therapies on LPS-induced brain inflammation and its consequent effect on newly born neurons.
Bilaterally ovariectomized rats received intrastriatal injection of lipopolysaccharide (LPS, 250 ng/µl) and subsequently were given daily subcutaneous injections of either vehicle, 17β-estradiol (25 µg/kg) or 17β-estradiol and progesterone (5mg/kg). Microglial activation and newly-born neurons in the rostral migratory stream were monitored using double immunofluorescence. Nuclear factor κB (NFκB) signaling pathway and its target inflammatory proteins were assessed by either western blot (cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6)) or ELISA (Tumor Necrosis Factor-α (TNFα)).
LPS induced activation of microglia, promoted NFκB signaling pathway and enhanced production of the pro-inflammatory proteins (TNFα and COX-2). These proinflammatory responses were not attenuated by 17β-estradiol-injection. Supplementation of 17β-estradiol with progesterone significantly dampened these pro-inflammatory processes. Interestingly, LPS-induced brain inflammation dampened the number  of newly born neuron in the rostral migratory stream. Administration of combined 17β-estradiol and progesterone resulted in a significantly higher number of newly born neurons when compared to those seen in rats given either vehicle or 17β-estradiol alone. 
These data strongly suggest that combined 17β-estradiol and progesterone, and not 17β-estradiol alone, rescues neurogenesis from the deleterious effect of brain inflammation likely via the inhibition of the signaling pathways leading to the pro-inflammatory gene activation.