Endocrine Abstracts

Estrogens, in particular 17β-estradiol (E₂), orchestrate cellular mechanisms involved in the development and differentiation of various neuron populations, modulation of synaptic plasticity, induction of neuronal survival, and neurogenesis. Beneficial effects of E₂ have been widely reported against a variety of insults, including H₂O₂ injury, serum deprivation, and glutamate excitotoxicity. Recently, we identified E₂ as an endogenous modulator of a new neuroprotectant protein, neuroglobin (Ngb). Here, our principal aim is to identify the role played by E₂-induced Ngb up-regulation in neuroprotective signaling pathways. In neuroblastoma SK-N-BE cells Ngb is expressed in the nucleus, mitochondria and is scattered in the cytoplasm. Upon E₂ stimulation, Ngb reallocates mainly into mitochondria where the physical association with the mitochondrial cytochrome c occurs. E₂ pretreatment before H₂O₂ addition strongly enhances Ngb:cytochrome c association reducing its release into the cytosol. As a consequence, a decrease of caspase-3 activation and, in turn, of the apoptotic cascade activation takes place. E₂ induces Ngb level regulation also in astrocytes, where this globin is required for E₂ effects in preventing lipopolysaccharide (LPS)-induced cytochine release. All these effects are mediated by estrogen receptor β (ERβ) via genomic and extranuclear signals involving p38/MAPK pathway. As a whole, the well known neuroprotective effects elicited by E₂ may, at least in part, be explained by an enhanced Ngb expression in neurons and astrocytes. The principal role played by Ngb in the brain could be related to the reduction of neuronal death by resetting the trigger level of apoptosis and inhibition of pro-inflammatory cytokines expression, leading to the onset of physiological response to stress. E₂ acts to accelerate Ngb neuroprotective effect rapidly enhancing its levels in both neurons and astrocytes.