INVESTIGADORES
CAPANI Francisco
congresos y reuniones científicas
Título:
CHRONIC CEREBELLAR ALTERATIONS CAUSED BY PERINATAL ASPHYXIA. ESTRADIOL AS A POSSIBLY NEUROPROTECTIVE THERAPY
Autor/es:
VERÓNICA CAMPANILLE, G. EZEQUIEL. SARACENO, STÉPHANIE RIVIÈRE, TAMARA LOGICA, RODOLFO KÖLLIKER, FRANCISCO CAPANI AND ROCÍO CASTILLA
Reunión:
Congreso; CIASEM; 2015
Institución organizadora:
CIASEM
Resumen:
Perinatal asphyxia (PA)-induced brain injury is one of the most frequent causes of morbidity and mortality in term and preterm neonates, accounting for 23% of neonatal deaths globally. Following PA, approximately 45% of newborns die and 25% have permanent neurological deficits including cerebral palsy, mental retardation and developmental delay, learning disabilities, eyesight and hearing problems and an impairment in school readiness. The developing brain may be particularly vulnerable to injury before, at and after birth. The type and distribution of human brain lesions differ markedly between premature and term babies, likely as a consequence of the stage of brain maturation and subsequent regional vulnerability. The cerebellar circuitry appears to be particularly susceptible, as the cellular makeup and the quantity of inputs change quickly during days and weeks following birth (1). Although different strategies have been used to treat the consequences of PA, only hypothermia is recommended as a routine in clinical practice (2). In the last few years, 17-estradiol has emerged as a potential neuroprotective agent against several neuropathological diseases including Parkinson?s, Alzheimer?s, multiple sclerosis and stroke. In recent work, we have shown the repair of chronic neurodegenerative hippocampal modifications in four-month-old male Sprague-Dawley rats submitted to severe global PA at the time of birth and injected 17-estradiol for 3 consecutive days (3). Short-term cerebellar alterations within this PA model have been previously reported but whether such alterations remain in adulthood has not been conclusively determined yet. For this reason, and given the crucial cerebellar role in determining connectivity patterns in the brain, the aim of our work was to unveil long-term cerebellum histomorphology following a PA insult and to evaluate the effectiveness of 17-estradiol as treatment. Morphological and cytological neuronal changes and glial reaction in the cerebellar cortex were analyzed at postnatal day 120 following injury performed at birth. As compared to control, PA animals exhibited: 1) an increase in molecular and granular thickness, both layers presenting lower cellular density, with no modifications in the total number of cells, 2) a disarrayed Purkinje cell layer presenting a higher number of anomalous calbindin-stained cells (Fig 1 A and B) and a reduction in calbindin expression as evaluated by Western blot, 3) focal swelling and marked fragmentation of microtubule-associated protein 2 (MAP-2) in Purkinje cell dendrites and, 4) an increase in glial fibrillary acidic protein (GFAP) expression evaluated by Western blot and a higher percentage of GFAP-positive reactive area in Bergmann cells and the granular layer. The 17-estradiol treatment administered three consecutive days before euthanasia was unable to reverse the morphological or cytological changes produced by PA (Fig 1 C and D). However, 17-estradiol increased the Bcl2/Bax ratio and calbindin expression, both associated to cell survival and possibly effective in longer treatments. In conclusion, we demonstrate that PA produces long-term damage in cellular histomorphology in rat cerebellar cortex which could be involved in the pathogenesis of cognitive deficits observed in both animals and humans. In addition, we prove that late administration of 17-estradiol is ineffective in the treatment of cerebellar alterations produced by PA at the times analyzed