CONICET | Buscador de Institutos y Recursos Humanos

Far beyond its role in reproduction, progesterone exerts neuroprotective, promyelinatingand antiinflammatory effects in the nervous system [1]. These effects are maximized underpathological conditions, implying that changes of the local environment sensitize thenervous tissues to steroid treatment [2]. In this presentation, we will discuss our results ofprogesterone neuroprotection in a motoneuron neurodegeneration model and aneuroinflammation model. In the Wobbler mouse, a mutation of the Vsp54 gene leads tomotoneuron degeneration, astrogliosis and motor impairment. Motoneurons in the cervicalspinal cord of Wobblers show cytoplasmic vacuolation, decreased immunoreactivity forcholine-acetyltransferase (ChaT), decreased expression for Na,K-ATPase and brainderivedneurotrophic factor (BDNF) mRNAs, decreased axonal transport and increasedactivity of nitric oxide synthase (NOS), without the typical signs of apoptosis [3].Additionally, Wobbler mitochondrial present membrane rupture, cristolysis, increasedintramitochondrial NOS and decreased activity of respiratory chain complexes [3].Clinically, Wobblers suffer several degrees of motor impairment. Treatment withprogesterone (20 mg implant) from 3 weeks to 2 months markedly modifies spinal cordneuropathology. Thus, progesterone reverses the impaired expression of BDNF, ChAT andNa,K-ATPase, prevents oxidative damage of motoneurons and their vacuolar degeneration,attenuates mitochondrial morphological abnormalities, decreases the activity of NOS andenhances respiratory chain enzyme activities [3]. Long-term treatment with progesteronealso increases muscle strength, biceps weigth and survival. Altogether, these data showthat progesterone strongly protects Wobbler motoneurons from degeneration. To studyprogesterone effects in a neuroinflammation model resembling multiple sclerosis (MS), weinduced experimental autoimmune encephalomyelitis (EAE) in C57Bl6 mice. In EAEmice we have analyzed if progesterone effects in the inflamed spinal cord involves thedecreased transcription of local inflammatory mediators and the increased transcription ofmyelin proteins and myelin transcription factors. To this purpose, C57Bl/6 female micedivided into controls, EAE and EAE receive progesterone (100 mg implant), 7 days beforeEAE induction. This procedure produces pregnancy progesterone levels for the mouse.Tissues are collected on day 17 post-immunization [4]. Real time PCR technology hasdemonstrated that progesterone blocks the EAE-induced increase of the proinflammatorymediators tumor necrosis factor alpha (TNFα) and its receptor TNFR1, the microglialmarker CD11b and toll-like receptor 4 (TLR4) mRNAs, and increases the mRNAexpression of PLP and MBP, the myelin transcription factors NKx2.2 and Olig1 andenhances CC1+ oligodendrocyte density respect of untreated EAE mice.Immunocytochemistry has demonstrated decreased Iba1+ microglial cells. Using dobleimmunofluorescence labelling and confocal microcoscopy, we have shown that TNFαcolocalized with glial-fibrillary acidic protein+ astrocytes and OX-42 + microglial cells.Progesterone treatment also attenuates the clinical signs of EAE. Therefore, the decreasedinflammatory glial reactivity and increased myelination from EAE mice receivingprogesterone, supports that steroid neuroprotection involves the modulation oftranscriptional events in the spinal cord of EAE mice. It is hoped that experimental dataprovided by animal models of neurodegeneration and neuroinflammation open the groundfor testing the usefulness of neuroactive steroids for the prognosis and treatment of humanneurological disorders [5].