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 lipopolysaccharide (LPS)-induced brain inflammation and its consequent effect on newly born neurons. Bilaterally ovariectomized rats received intrastriatal injection of LPS (250 ng/μl) and were subsequently given daily subcutaneous injections of either vehicle, 17β-estradiol (25 μg/kg) or 17β-estradiol and progesterone (5 mg/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 enzyme-linked immunosorbent assay [tumor necrosis factor-α (TNF-α)]. LPS-induced activation of microglia, promoted NFκB signaling pathway and enhanced the production of proinflammatory proteins (TNF-α and COX-2). These proinflammatory responses were not attenuated by 17β-estradiol injection. Supplementation of 17β-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 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 activation of proinflammatory genes.
Highlights
The phosphorylation of IκB results in the release of a nuclear transcription factor: nuclear factor κB (NFκB; Rivest, 2003; Dev et al, 2011), which translocates into the nucleus and induces the transcription of inflammatory genes, such as cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) (Libermann and Baltimore, 1990; Cao et al, 1997; Rivest, 2003; Krakauer, 2004; Chew et al, 2006; Brasier, 2010)
Because brain inflammation dampens neurogenesis and that the striatal inflammatory response spreads to the rostral migratory stream (RMS), a route of newly born neurons migrating toward the olfactory bulb (Lepousez et al, 2013), we explored whether the hormonal replacement therapy (HRT) impact on brain inflammation is associated with survival of newly born neurons in the RMS
In the present paper, we have made several important and novel observations, (1) E + Pr but not E only based HRT significantly reduced LPS-induced microglial activation during brain inflammation in OVX rats, (2) the dampening of microglial activation operates likely by an inhibitory effect of E + Pr on the LPS-activated NFκB signaling pathway and the product of its target genes; TNF-α and COX-2, (3) toll like receptor 4 (TLR4)-mediated brain inflammation reduced the survival of newly born neurons which were migrating through the RMS, (4) this reduction in the survival of newly born neurons was partially reverted by an HRT regimen containing both E and Pr
Summary
Brain inflammation is a common symptom that develops as a result of many infectious diseases (e.g., E. coli meningitis, HIV encephalopathy, West Nile virus induced dementia; Nau and Bruck, 2002; Gendelman and Persidsky, 2005; Hayes et al, 2005), neurological diseases (Eikelenboom et al, 2002; Streit, 2004; Nagatsu and Sawada, 2005; Stys et al, 2012), stroke and brain trauma (Spencer et al, 2008; Lambertsen et al, 2012). A well-established model of brain inflammation consists of the local application of lipopolysaccharide (LPS; the outer coat of Gram negative bacteria) within the brain parenchyma, at the level of the striatum (Nadeau and Rivest, 2002; Cunningham et al, 2005; Soucy et al, 2005; Glezer et al, 2007; Hunter et al, 2007). LPS binds to a specific receptor called toll like receptor 4 (TLR4) expressed largely on microglia; the immune competent cells within the brain (Laflamme and Rivest, 2001; Lehnardt et al, 2002, 2003). TLR4 activation results in the phosphorylation of a series of intracellular kinases culminating in the phosphorylation of an inhibitory factor called IκB. The phosphorylation of IκB results in the release of a nuclear transcription factor: nuclear factor κB (NFκB; Rivest, 2003; Dev et al, 2011), which translocates into the nucleus and induces the transcription of inflammatory genes, such as cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) (Libermann and Baltimore, 1990; Cao et al, 1997; Rivest, 2003; Krakauer, 2004; Chew et al, 2006; Brasier, 2010)
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