NEURONAL PLASTICITY AND NEUROPROTECTION: ROLE OF HORMONES AND NEUROSTEROIDS

Our understanding of the role of gonadal steroids is actually undergoing a major reassessment. Experimental data indicate that apart from being neuroendocrine regulators, these hormones exert a variety of morphogenetic and organizing effects in the nervous system. They influence the development of certain brain regions and also affect the differentiation of specific neuronal and glial populations and the establishment of synaptic connectivity. Moreover, it has been discovered that these hormones can be produced in the central nervous system as well and they act locally, resulting in well-defined structural and functional changes. These data have led to the birth of two categories: neurosteroids, i. e. brain-derived steroids and neuroactive steroids, i.e. steroids acting on the brain but produced in the gonads.

The research interest of the Group is focused on the role of gonadal steroids in neuro-glial plasticity, more specifically on the mechanism of neurodegeneration and neuroprotection. Our aim is to perform basic research to study the cellular and molecular mechanisms responsible for the neuroprotective effects of certain neurosteroids, namely estrogen and one of its precursors, dehydroepiandrosterone (DHEA). At this phase of research the aim is not the development of new drugs, but on the long run we focus on the possible therapeutic use of neuroactive steroids and neurosteroids. According to our opinion the detailed knowledge of hormonal action may provide new pieces of evidence for the understanding of the regenerative capacity of the central nervous system. On the basis of our results we may work out a model system to study the neuroprotective effect of new synthetic steroids. Any knowledge in this field will be especially useful for the elder generation, because at the time of approaching senescence there is a significant decrease in the plasma concentrations of DHEA, IGF-I and estradiol (and its precursor testosterone) both in women and men, consequently the neuroprotective effect of these molecules is also diminished.

Classical studies supported the idea of extensive neuronal loss even in normal ageing, and neuronal degeneration in the hippocampus and cerebral cortex was thought to contribute directly to age-related cognitive deficits. It is now recognised that biological changes in the healthy ageing brain are more subtle than it was previously thought and mainly involve shrinkage of neuronal cell bodies and a decrease in the density of neurones and synapses. This is encouraging news, because it means that treating normal age-related dysfunctions of the nervous system such as memory loss will be possible.

Research carried out in different laboratories has demonstrated that the ageing nervous system retains its capacity for regeneration and that age-dependent biological changes such as memory impairment and myelin abnormalities can be reversed by the administration of estrogen and other neurosteroids. Their findings also show that the reduction in neurosteroid levels during ageing renders the nervous system more susceptible to degeneration.

Our working hypothesis is that the beneficial effect of these compounds is not limited to the protection of neurons, but may affect preserving and/or remodelling synaptic connections as well. Such hormonally driven synaptic plasticity can explain memory improvement and the functional recovery observed after neuronal injury.