title: Hormones are key actors in gene x environment interactions programming the vulnerability to Parkinson's disease: glia as a common final pathway.
abstract: Alterations in developmental programming of neuroendocrine and immune system function may critically modulate vulnerability to various diseases. In particular, genetic factors, including gender, may interact with early life events such as exposure to hormones, endotoxins, or neurotoxins, thereby influencing disease predisposition and/or severity, but little is known about the role of the astroglial cell compartment and its mediators in this phenomenon. Indeed, in the context of innate inflammatory mechanisms, a dysfunction of the astroglial cell compartment is believed to contribute to the selective degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta in Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Hence, in response to brain injury the roles of astrocytes and microglia are very dynamic and cell type-dependent, in that they may exert the known proinflammatory (harmful) effects, but in certain circumstances they can turn into highly protective cells and exert anti-inflammatory (beneficial) functions, thereby facilitating neuronal recovery and repair. Here, we summarize our work suggesting a chief role of hormonal programming of glial response to inflammation and oxidative stress in MPTP-induced loss of DA neuron functionality and demonstrate that endogenous glucocorticoids and the female hormone estrogen (E(2)) inhibit the aberrant neuroinflammatory cascade, protect astrocytes and microglia from programmed cell death, and stimulate recovery of DA neuron functionality, thereby triggering the repair process. The overall results highlight glia as a final common pathway directing neuroprotection versus neurodegeneration. Such recognition of endogenous glial protective pathways may provide a new insight and may contribute to the development of novel therapeutic treatment strategies for PD and possibly other neurodegenerative disorders.
authors.affiliation: OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS), Neuropharmacology Section, Via Conte Ruggero 73, 94018 Troina (EN), Italy. bianca.marchetti@oasi.en.it
authors.forename: Bianca
authors.initials: B
authors.lastname: Marchetti
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Serra
authors.forename: Francesca
authors.initials: F
authors.lastname: L'Episcopo
authors.forename: Cataldo
authors.initials: C
authors.lastname: Tirolo
authors.forename: Salvo
authors.initials: S
authors.lastname: Caniglia
authors.forename: Nuccio
authors.initials: N
authors.lastname: Testa
authors.forename: Serena
authors.initials: S
authors.lastname: Cioni
authors.forename: Florinda
authors.initials: F
authors.lastname: Gennuso
authors.forename: Gaia
authors.initials: G
authors.lastname: Rocchitta
authors.forename: Maria Speranza
authors.initials: MS
authors.lastname: Desole
authors.forename: Maria Clorinda
authors.initials: MC
authors.lastname: Mazzarino
authors.forename: Egidio
authors.initials: E
authors.lastname: Miele
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Morale
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D004777:Environment; D004967:Estrogens / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005938:Glucocorticoids / Q000378:metabolism; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009498:Neurotoxins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D004967:Estrogens; D005938:Glucocorticoids; D006728:Hormones; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D052247:Nitric Oxide Synthase Type II; D004298:Dopamine