Sex‐ and brain region‐specific role of cytochrome c oxidase in 1‐methyl‐4‐phenylpyridinium‐mediated astrocyte vulnerability

Abstract

Parkinson's disease is a neurodegenerative disorder characterized by a sex and brain region specificity, showing a higher incidence in men than in women, which is caused by cell death of mainly dopaminergic neurons in the mesencephalon. Mitochondrial toxins are often used to trigger and mimic neurodegenerative processes. Thus, systemic application of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinsonian symptoms, indicating a causative or consequent involvement of mitochondria. Therefore, mitochondria of neural cells may demonstrate a sex and brain region specificity with respect to structural and functional characteristics of these organelles during toxic and degenerative processes. The application of MPTP in vivo and its toxic derivative 1-methyl-4-phenylpyridinium (MPP 1 ) in vitro represent a well-accepted experimental model of Parkinson's disease. Aside from the known effects of MPP 1 on mitochondria and neural cell survivability and with respect to the supportive role of astrocytes for neuronal function, we aimed to demonstrate the involvement of cytochrome c oxidase subunit IV isoform expression in energy and reactive oxygen species production taking part in an impairment of astrocyte survival. MPP 1 caused a specific increase of COX IV-2 transcript and protein levels in male mesencephalic astrocytes, accompanied by decreased ATP and increased reactive oxygen species levels and elevated apoptotic cell death, which were more pronounced in mesencephalic than in cortical astrocytes from male than from female mice. Our data suggest that MPP 1 acts on astrocytes in a sex-and brain region-specific manner involving cytochrome c oxidase isoform expression in an impairment of energy production and elevated oxidative stress levels, which represent hallmarks of neurodegenerative diseases. V V C 2011 Wiley-Liss, Inc.

Glia Maturation Factor Deficiency Suppresses 1-Methyl-4-Phenylpyridinium-Induced Oxidative Stress in Astrocytes

“…In the present study, MPP + treatment with different concentrations at three different time points to astrocytes caused an overproduction of free radicals which, in turn, caused oxidative damages to membrane lipid and protein levels, and ultimately led to a decrease in GSH content. Our results suggest that GMF could protect astrocytes from oxidative stress generated by MPP + which is consistent with previous reports where MPP + -induced toxicity leads to oxidative damage (Sundar Boyalla et al 2011; Xiao et al 2011). …”

Sex differences in mitochondrial (dys)function: Implications for neuroprotection

“…XX neurons (Misiak and Beyer 2010). Similar ROS and mitochondrial changes are observed in sex-dependent vulnerability of cultured astrocytes in the 1-methyl-4-phenylpyridinium (MPTP) model of PD (Sundar et al 2011). These molecular mechanisms of ROS/RNS production and antioxidant detoxification may underlie the higher incidence of early onset (age 50–59) PD in human males (Pringsheim et al 2014) and contribute to their poorer quality of life due to increased burden of symptoms vs .…”

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…Sex also influences the response of astrocytes to harmful stimuli such as prenatal or neonatal stress (Garcia-Caceres et al, 2010;Llorente et al, 2009Llorente et al, , 2008Lopez-Gallardo et al, 2012), exposure to toxins (Santos-Galindo et al, 2011) and to environmental contaminants (Astiz et al, 2014;Miller et al, 2010;Sundar Boyalla et al, 2011) or deprivation of oxygen and glucose (Liu et al, 2008(Liu et al, , 2007 (Figure 1). …”