Cellular and molecular basis of progesterone-induced neuroprotection

Progesterone exerts several effects in the central nervous system not directly involved in reproduction or sex behavior. Non-reproductive effects are better observed under pathological conditions, and include stimulation of myelin formation, neurogenesis and neurosteroidogenesis, preserved mitochondrial function, neuroprotection, anti-inflammatory effects, decreased glutamate excitotoxicity, and regulation of mood, memory and cognition. In addition, the progesterone reduced derivative allopregnanolone shows anxiolytic, sedative and anesthetic properties after binding to GABAa receptors. In the present report we provide examples of [1] progesterone effects on the local synthesis of steroids (“neurosteroids”) in a demyelination model, [2] the requirement of the classical progesterone receptor for the antiinflammatory effects in mice with spinal cord injury, and [3] the protective role of progesterone and allopregnanolone in a mouse model of neurodegeneration. In conclusion, the beneficial effects observed in different experimental paradigms support the versatile properties of progesterone in animal models of central nervous system disorders.La progesterona produce varios efectos en el sistema nervioso central no relacionados a la reproducción o comportamiento sexual. Estos efectos adicionales se observan preferentemente bajo condiciones patológicas, e incluyen la estimulación de la formación de mielina, la neurogenesis y neuroesteroidogenesis, el mantenimiento de la función mitocondrial, efectos anti-inflamatorios, disminución de la excitotoxicidad del glutamato y regulación del humor, memoria y conocimiento. En agregado, el derivado reducido de progesterona – alopregnanolona – muestra propiedades ansiolíticas, sedantes y anestésicas luego de su unión al receptor GABAa. Este Minireview detalla los efectos de progesterona sobre [1] la síntesis local de esteroides (“neuroesteroides”), en un modelo de desmielinizacion, [2] ejemplifica el requerimiento del receptor clásico de progesterona para los efectos anti-inflamatorios en un modelo de injuria espinal en ratón, y finalmente [3] discute el rol protector de la progesterona y de la alopregnanolona en un modelo murino de degeneración de motoneurona. Como conclusión, los efectos beneficiosos mostrados en diferentes paradigmas experimentales apoyan las propiedades versátiles de la progesterona en modelos de patologías del sistema nervioso central.Sociedad Argentina de Fisiologí

Progesterone treatment modulates mRNA of neurosteroidogenic enzymes in a murine model of multiple sclerosis.

Previous studies of experimental autoimmune encephalomyelitis (EAE) have shown that progesterone decreases inflammatory cell infiltration and proinflammatory factors, increases myelination and attenuates clinical grade of EAE mice. To elucidate potential mediators of these effects, we analyzed the mRNA expression of neurosteroidogenic enzymes in the spinal cord, in view of the protective role of steroids in EAE. We also analyzed mitochondrial morphology and dynamics (fusion and fission proteins), considering the role of mitochondria in neurosteroidogenesis. EAE was induced in C57Bl6 mice using MOG40-54 and killed on day 16 after induction. Using qPCR, we found in steroid-untreated EAE mice decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), P450scc (cholesterol side-chain cleavage), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSD) and aromatase, whereas levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) showed a large intra-group variance. We also found increased mRNA expression of 18Kd translocator protein (TSPO), which likely resulted from the reactive microgliosis in this model. EAE mice also showed pathological mitochondrial morphology and reduced expression of fission and fusion protein mRNAs. Most importantly, pretreatment with progesterone a week before EAE induction increased Star,VDAC, P450scc, 5α-reductase type I, 3α-HSD and aromatase mRNAs and did not modify 3β-HSD. TSPO mRNA was decreased, consequent with the inhibition of microgliosis. Mitochondrial morphology was improved and fission/fusion protein mRNAs were enhanced by progesterone treatment. Furthermore, progesterone protective effects on mitochondrial and endoplasmic reticulum may allow the recovery of neurosteroidogenesis. In this way, endogenously synthesized neurosteroids may reinforce the beneficial effects of exogenous progesterone previously shown in MS mice.Fil: Garay, Laura Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: González Giqueaux, Paula Anahí. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Guennoun, Rachida. Inserm; FranciaFil: Schumacher, Michael. Inserm; FranciaFil: Gonzalez Deniselle, Maria Claudia. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis

OBJECTIVES: Mitochondrial dysfunction has been reported in the central nervous system, hepatocytes and peripheral blood lymphocytes from patients with sporadic amyotrophic lateral sclerosis (SALS). However, the status of skin mitochondria has not been reported, in spite of the fact that SALS patients present skin abnormalities. The objective of the present study was to compare mitochondrial ultrastructural parameters in keratinocytes from patients with SALS and healthy controls. METHODS: Our study was based on the analysis of 112 skin mitochondria from 5 SALS patients and 99 organelles from 4 control subjects by electron microscopy. RESULTS: Computerized image analysis showed that mitochondrial major axis length, area and perimeter of the organelle were significantly smaller in SALS respect of healthy control subjects. Morphologically, SALS mitochondria presented cristolysis and breakage of the outer membrane. CONCLUSIONS: Mitochondrial dysfunction in the skin may possibly reflect changes occurring in mitochondria of the central nervous system. The analysis of mitochondrial morphology in this tissue may be of value to follow disease progression and, eventually, the effectiveness of current therapies for SALS