Effect of Progesterone on myelin and inflammation in acute experimental autoimmune encephalomyelitis

GARAY LAURA; GONZALEZ DENISELLE, MARIA CLAUDIA; ANALIA LIMA; PAULINA ROIG; ALEJANDRO DE NICOLA

Torino-Orbassano

Congreso; 7th International Meeting Steroids and Nervous System; 2013

A common model to study Multiple Sclerosis (MS) is experimental autoimmune encephalomyelitis (EAE) in rodents. Both share histopathological characteristics such as demyelination, cell infiltration and neurodegeneration [1] . Previous work from our laboratory demonstrated that pretreatment with progesterone improves clinical signs in EAE mice and decreases the loss of myelin basic protein (MBP) and proteolipid protein (PLP) measured in the acute phase by immunohistochemistry and in situ hybridization [2]. The aim of the present study was to analyze if progesterone protective effects in the spinal cord of C57Bl/6 female EAE mice during the acute phase of the disease, involved the decreased transcription of local inflammatory mediators and the increased transcription of myelin proteins and myelin transcription factors. Real time PCR technology demonstrated that progesterone blocked the EAE-induced increase of the proinflammatory mediator tumor necrosis factor alpha (TNFa), which plays a detrimental role in MS and EAE, and its receptor TNFR1. Progesterone treatment also attenuated the microglial/macrophage marker CD11b and toll-like receptor 4 (TLR4) mRNAs. Conversely, progesterone increased the mRNA expression of PLP and MBP, the myelin transcription factors NKx2.2 and Olig1 and enhanced CC1+ oligodendrocyte density respect of untreated EAE mice. Additionally, immunocytochemistry demonstrated decreased microgliosis, demonstrated by the significantly decreased number of Iba1+ cells in gray and white matter of animals receiving the steroid. Double fluorescence immunostaining with specific markers demonstrated the colocalization of TNFa with glial-fibrillary acidic protein+ astrocytes and OX-42 + microglial cells. Therefore, progesterone treatment improved the clinical signs of EAE, decreased inflammatory reactivity of microglia and astrocytes and increased myelination. These data suggest that progesterone neuroprotection involves the modulation of several transcriptional events in the spinal cord of mice with acute EAE. This work contributes to strengthen the potential therapeutic use of neuroactive steroids in MS