L-DOPA in the hu man ovarian follicular fluid acts as an antioxidant factor on granulosa cells

Abstract

BackgroundA previous study showed that dopamine (DA), which is contained in follicular fluid (FF) from IVF patients, strongly increased the production of reactive oxygen species (ROS) by cultured human granulosa cells (GCs). ROS, including H2O2, are assumed to play roles in ovarian physiology and pathology. Ovarian DA could be derived from the circulation, ovarian innervation and/or unknown ovarian sources. L-DOPA is the direct precursor of DA in its synthetic pathway. It was not yet described in FF. We examined L-DOPA levels in FF from IVF patients. As it may exert anti-oxidative and ROS-scavenging functions, we studied whether it exerts such actions in human GCs and whether DOPA-decarboxylase (DDC), the enzyme converting L-DOPA to DA, is expressed in the human ovary.ResultsELISA measurements revealed that human IVF-derived FF contains L-DOPA. In cultured human GCs automated confluence analyses showed that L-DOPA enhanced their survival. This is in contrast to the actions of DA, which reduced cell survival. A dose-dependent mode of action of L-DOPA was identified using a fluorescent ROS indicator. The results showed that it antagonized intracellular ROS accumulation induced by exogenous H2O2. DDC was absent in follicular GCs, but immunohistochemistry identified it in theca cells (TCs) of large follicles in the human ovary. Laser micro-dissection followed by RT-PCR corroborated the expression. DDC was also identified in the steroidogenic cells of the corpus luteum.ConclusionsL-DOPA in FF is an antioxidant factor and exerts positive influences on GCs. Ovarian DA is derived from L-DOPA and has opposite actions. Exogenous L-DOPA is a standard therapy for Parkinson’s disease, and the results raise the possibility that it may be able to exert positive actions as an antioxidant in ovarian conditions, as well.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0269-0) contains supplementary material, which is available to authorized users.

Dopamine synthesis and dopamine receptor expression are disturbed in recurrent miscarriages

“…Less production of amines may further lead to a decrease in epinephrine synthesis and consequently a reduced D2R expression. Blohberger et al detected DDC expression in theca cells of the ovary and assume a correlation between DDC expression and higher dopamine levels within the ovary ( 6 ). Generation of dopamine from L-DOPA is the standard treatment for Parkinson’s disease ( 20 , 21 , 22 ).…”

“…The enzyme l -dopa-decarboxylase (aromatic amino acid decarboxylase, DDC), which is expressed by the placenta, is responsible for the conversion of l -dopa into dopamine ( 5 , 6 ). Additionally, DDC is involved in the synthesis of serotonin, tryptamine, phenylethylamine and histamine ( 12 ).…”

l-Dopa and Fluoxetine Upregulate Astroglial 5-HT2B Receptors and Ameliorate Depression in Parkinson’s Disease Mice

“…When L-dopa is decarboxylated to dopamine (DA) by aromatic L-amino acid decarboxylase (AADC), ROS are generated that could ultimately lead to cell death [47]. Nevertheless, L-dopa in some in vivo and in vitro experiments had no toxic effects, or even showed antioxidant capabilities [48][49][50][51]. Oxidative stress in peripheral blood mononuclear cells from patients with PD is negatively correlated with L-dopa dosage [48].…”

“…In the perinatal 6-OHDA lifelong model of PD, elevated basal levels of ROS occurring in denervated dopaminergic striatum are suppressed by L-dopa treatment [50]. L-Dopa in follicular fluid is an antioxidant factor and exerts positive influences on cultured human granulosa cells, whereas DA derived from L-dopa has opposite actions [51]. In the present work, we have found that L-dopa corrects 6-OHDA-induced decrease of 5-HT 2B receptor in astrocytes in primary cultures, suggesting L-dopa that may protect cells by its antioxidant effects.…”

Advanced oxidation protein products from the follicular microenvironment and their role in infertile women with endometriosis

“…Extreme oxidative stress is able to induce granulosa cell apoptosis (57); however, the antioxidant factor would exert a positive effect. L-DOPA in FF as an antioxidant factor that exerts positive influences on granular cells, including decreasing H 2 O 2 production and promoting cell survival (58). Based on these observations, AOPPs may decrease P 4 production via impairing the function of granulosa cells.…”