IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Progesterone effects in neuroinflammation and neurodegeneration
Autor/es:
DE NICOLA A.F.
Lugar:
Torino
Reunión:
Congreso; 7th International meeting Steroids and Nervous System; 2013
Institución organizadora:
Fondazione Cavalieri Ottolenghi
Resumen:
Far beyond its role in reproduction, progesterone exerts neuroprotective, promyelinating and antiinflammatory effects in the nervous system [1]. These effects are maximized under pathological conditions, implying that changes of the local environment sensitize the nervous tissues to steroid treatment [2]. In this presentation, we will discuss our results of progesterone neuroprotection in a motoneuron neurodegeneration model and a neuroinflammation model. In the Wobbler mouse, a mutation of the Vsp54 gene leads to motoneuron degeneration, astrogliosis and motor impairment. Motoneurons in the cervical spinal cord of Wobblers show cytoplasmic vacuolation, decreased immunoreactivity for choline-acetyltransferase (ChaT), decreased expression for Na,K-ATPase and brain-derived neurotrophic factor (BDNF) mRNAs, decreased axonal transport and increased activity of nitric oxide synthase (NOS), without the typical signs of apoptosis [3]. Additionally, Wobbler mitochondrial present membrane rupture, cristolysis, increased intramitochondrial NOS and decreased activity of respiratory chain complexes [3]. Clinically, Wobblers suffer several degrees of motor impairment. Treatment with progesterone (20 mg implant) from 3 weeks to 2 months markedly modifies spinal cord neuropathology. Thus, progesterone reverses the impaired expression of BDNF, ChAT and Na,K-ATPase, prevents oxidative damage of motoneurons and their vacuolar degeneration, attenuates mitochondrial morphological abnormalities, decreases the activity of NOS and enhances respiratory chain enzyme activities [3]. Long-term treatment with progesterone also increases muscle strength, biceps weigth and survival. Altogether, these data show that progesterone strongly protects Wobbler motoneurons from degeneration. To study progesterone effects in a neuroinflammation model resembling multiple sclerosis (MS), we induced experimental autoimmune encephalomyelitis (EAE) in C57Bl6 mice.  In EAE mice we have analyzed if progesterone effects in the inflamed spinal cord involves the decreased transcription of local inflammatory mediators and the increased transcription of myelin proteins and myelin transcription factors. To this purpose, C57Bl/6 female mice divided into controls, EAE and EAE receive progesterone (100 mg implant), 7 days before EAE induction. This procedure produces pregnancy progesterone levels for the mouse. Tissues are collected on day 17 post-immunization [4]. Real time PCR technology has demonstrated that progesterone blocks the EAE-induced increase of the proinflammatory mediators tumor necrosis factor alpha (TNFa) and its receptor TNFR1, the microglial marker CD11b and toll-like receptor 4 (TLR4) mRNAs, and increases the mRNA expression of PLP and MBP, the myelin transcription factors NKx2.2 and Olig1 and enhances CC1+ oligodendrocyte density respect of untreated EAE mice. Immunocytochemistry has demonstrated decreased Iba1+ microglial cells. Using doble immunofluorescence labelling and confocal microcoscopy, we have shown that TNFa colocalized with glial-fibrillary acidic protein+ astrocytes and OX-42 + microglial cells. Progesterone treatment also attenuates the clinical signs of EAE. Therefore, the decreased inflammatory glial reactivity and increased myelination from EAE mice receiving progesterone, supports that steroid neuroprotection involves the modulation of transcriptional events in the spinal cord of EAE mice. It is hoped that experimental data provided by animal models of neurodegeneration and neuroinflammation open the ground for testing the usefulness of neuroactive steroids for the prognosis and treatment of human neurological disorders [5].   Reference list   [1] Schumacher M, Sitruk-Ware R, De Nicola AF. Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol. 2008;8 :740-746.   [2] De Nicola AF, Labombarda F, Deniselle MC, Gonzalez SL, Garay L, Meyer M, Gargiulo G, Guennoun R, Schumacher M. Progesterone neuroprotection in traumatic CNS injury and motoneuron degeneration. Front Neuroendocrinol. 2009 ;30:173-187.   [3] Gonzalez Deniselle MC, Carreras MC, Garay L, Gargiulo-Monachelli G, Meyer M, Poderoso JJ, De Nicola AF. Progesterone prevents mitochondrial dysfunction in the spinal cord of wobbler mice. J Neurochem. 2012;122 :185-195.   [4] Garay LI, González Deniselle MC, Brocca ME, Lima A, Roig P, De Nicola AF. Progesterone down-regulates spinal cord inflammatory mediators and increases myelination in experimental autoimmune encephalomyelitis. Neuroscience 2012 (in press).   [5] Gargiulo Monachelli G, Meyer M, Rodríguez GE, Garay LI, Sica RE, De Nicola AF, González Deniselle MC. Endogenous progesterone is associated to amyotrophic lateral sclerosis prognostic factors. Acta Neurol Scand. 2011;123 :60-67.