Evaluation of the protective effect of oestradiol against toxicity induced by 6‐hydroxydopamine and 1‐methyl‐4‐phenylpyridinium ion (MPP⁺) towards dopaminergic mesencephalic neurones in primary culture

Abstract

Recent findings suggest that gonadal steroid hormones are neuroprotective and may provide clinical benefits in delaying the development of Parkinson's disease. In this report we investigated the ability of oestradiol to protect mesencephalic dopaminergic neurones cultured in serum-free or serumsupplemented medium from toxicity induced by 6-hydroxydopamine or 1-methyl-4-phenylpyridinium ion (MPP + ). The ef®ciency of both toxins and oestradiol was evaluated by tyrosine hydroxylase (TH) immunocytochemistry, [ 3 H]dopamine ([ 3 H]DA) uptake, length of dopaminergic processes and lactate dehydrogenase (LDH) release measurement. In cultures grown in serum-supplemented medium, a 2-h pre-treatment with high concentrations (10±100 lM) of 17b-oestradiol or 17a-oestradiol, the stereoisomer with weak oestrogenic activity, protected both dopaminergic and non-dopaminergic neurones from toxicity induced by 6-hydroxydopamine (6-OHDA; 40 or 100 lM) and by the high MPP + concentrations (50 lM) necessary to obtain significant neuronal death under those culture conditions. At these concentrations, MPP + was no longer selective for dopaminergic neurones but affected all cells present in the culture. In contrast, the hormonal treatments did not protect against selective degeneration of dopaminergic neurones induced by lower MPP + concentrations (below 10 lM), related to inhibition of complex I of respiratory chain. In cultures grown in serum-free medium, oestradiol concentrations higher than 1 lM induced neuronal degeneration and no protection against 6-OHDA or MPP + toxicity was observed at lower concentrations of the steroid. The neuroprotective effects of 17a-or 17b-oestradiol evidenced in this model might be due to the antioxidant properties of these compounds. However, other non-genomic effects of the steroids cannot be excluded. An increasing body of data suggests neuroprotective activity of oestrogens. It was previously shown that replacement therapy with oestrogens in post-menopausal women delays the onset of Alzheimer's disease and improves cognitive performances of Alzheimer patients (Paganini-Hill and Anderson 1994;Tang et al. 1996). In vitro studies also demonstrated that oestrogens could afford protection against neurotoxicity induced by various agents such as excitatory amino acids, b-amyloid peptide or oxidative stress (Goodman et al. 1996;Green, Gridley and Simpkins 1996;Behl et al. 1997).Parkinson's disease is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurones in the basal ganglia (McGeer et al. 1988). Clinical and epidemiological studies reporting a higher incidence of this

Neuroprotective Effects of Bak Foong Pill in 1-Methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-Induced Parkinson's Disease Model Mice

“…35) That the present study did not detect significant effect of estrogen on TH expression suggest that at least the estrogen dose used and duration of administration were not appropriate to produce significant neuroprotective effect on TH expression. It is interesting to note that TH gene expression measured in rat locus ceruleus was not regulated by chronic estrogen administration.…”

A Fetal Risk Factor for Parkinson’s Disease

“…Epidemiological and clinical studies indicate that there is a higher prevalence of PD among men [Diamond et al, 1990;Baldereschi et al, 2000]. An estrogen-dependent protection of neural integrity has been demonstrated using the dopaminergic neurotoxicants MPTP and 6-OHDA, where males show greater susceptibility to damage by these compounds than females [Dluzen et al, 1996;Miller et al, 1996;Callier et al, 2002]. In primates, estrogen has been suggested to exert neuroprotective effects on nigrostriatal dopaminergic cells, allowing greater neuronal preservation over time, which may in turn slow the development of PD [Leranth et al, 2000].…”

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

“…This may use PI3K/Akt signaling, which may involve CREB as a downstream effector (Morissette et al, 2008a;Quesada et al, 2008), with possible effects on expression of genes for antiapoptotic, growth factor, and antioxidant activity. These might be considered nonspecific effects on processes common to neuroprotection against many forms of injury in different brain regions and are known to require concentrations of estradiol that are orders of magnitude greater than levels in the circulation, even at proestrus (Sawada et al, 1998(Sawada et al, , 2002Green and Simpkins, 2000;Behl, 2002;Callier et al, 2002;Garcia-Ovejero et al, 2005). It remains to be determined whether these responses are sexually dimorphic.…”