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.

The impact of age and gender on the striatal astrocytes activation in murine model of Parkinson’s disease

“…Moreover, some recent studies suggest that an interaction of estrogens with astroglial cells induce neuroprotection [30][31][32][33]. Thus, we speculate that the later astrocytes response in females may be coupled with astrogliosis involved in compensatory and survival-promoting mechanisms.…”

Gender-specific regulation of mitochondrial fusion and fission gene transcription and viability of cortical astrocytes by steroid hormones

“…Our findings suggest a pronounced sensitivity of male astroglia for apoptosis. This may serve as an explanation for the higher incidences of neurodegenerative diseases in males (Miller et al 1998, Roof & Hall 2000, van den Eeden et al 2003, Dluzen & McDermott 2004, Kenchappa et al 2004, Baba et al 2005, Marchetti et al 2005.…”

“…Astrocytes were chosen since they are the outstanding cell type in the CNS supporting neuronal viability and function. It is apparent that neurodegenerative processes and their steroid responsiveness often occur in a gender-specific way (Miller et al 1998, Roof & Hall 2000, van den Eeden et al 2003, Dluzen & McDermott 2004, Kenchappa et al 2004, Baba et al 2005, Marchetti et al 2005. Therefore, we have analyzed female and male astroglia separately.…”

Intranasal PRGF-Endoret enhances neuronal survival and attenuates NF-κB-dependent inflammation process in a mouse model of Parkinson's disease

“…Accumulation of reactive oxygen species (ROS), inflammatory-associated factors including cycloxygenase-2 (COX-2) and induciblenitric oxide synthase (iNOS)-derived NO, and proinflammatory cytokines, including tumor necrotic factor- (TNF-, interleukine-1 (IL-1 and interferon- (IFN-) in the subtantia nigra of PD patients further support that a state of chronic inflammation characterizes PD brain [10][11][12]. In fact, blocking the action of endogenous antiinflammatory molecules, such as glucocorticoid hormones in transgenic mice expressing a glucocorticoid receptor antisense RNA, sharply increases microglial activation in response to MPTP, resulting in increased dopaminergic neuron vulnerability [13,14].…”