α-Lipoic Acid Vaginal Administration Contrasts Inflammation and Preterm Delivery in Rats

Abstract

α-Lipoic acid (ALA) is a safe natural molecule involved in the immunomodulation of many physiological processes. Orally administered ALA has been reported to treat several inflammatory pathologies and support pregnancy. Our study aimed at testing ALA vaginal administration in female Wistar rats evaluating its tissue distribution (experiment I), impact on implantation process (experiment II), and effectiveness in contrasting induced preterm birth (experiment III). In experiment I, rats were intravaginally treated with 50 mg/kg or 500 mg/kg ALA, or with a physiologic solution, for 4 days. α-Lipoic acid distribution in uterus and cervical tissues was evaluated by immunohistochemical analyses. In experiment II, rats received intravaginally the above treatments for 5 days, then they were mated and, if pregnant, included in the experiment to evaluate both implantation rate and the content of implantation mediators in uterus tissues. In experiment III, pregnant rats were pretreated with placebo or with vaginal ALA for 4 days and then induced to delivery with mifepristone plus PGE2 on the 19th day of pregnancy. The delivery time was recorded, and the messenger RNA (mRNA) levels of pro-inflammatory cytokines were detected in the uterine tissues by real-time polymerase chain reaction. Immunohistochemistry was also performed. Results showed that vaginal ALA was well absorbed and distributed. The treatment did not affect the implantation process and was able to significantly revert mifepristone plus prostaglandin E2 effects, delaying the timing of delivery and significantly decreasing mRNA synthesis and release of pro-inflammatory cytokines. We provide for the first time new information on vaginal ALA use, even during pregnancy, opening a perspective for further studies.

Insights on the Use of α-Lipoic Acid for Therapeutic Purposes

“…Considering the promising antioxidant potential of ALA and its impact in multiple inflammatory conditions, recent evidences have increasingly highlighted its impact in physiological processes, such as pregnancy. Interestingly, Micili et al [90] assessed the impact of ALA vaginal administration in female Wistar rats, namely testing its tissue distribution, impact on implantation process and effectiveness in contrasting induced preterm birth. Curiously, the authors found that vaginal ALA is well-absorbed and distributed, without affecting the implantation process and was even able to significantly revert mifepristone plus prostaglandin E2 effects, thus, delaying the delivery timing and decreasing the synthesis of mRNA and pro-inflammatory cytokines release [90].…”

Alpha-lipoic acid ameliorates cytarabine-induced developmental anomalies in rat fetus

“…87 Further, in a recent experimental study, ALA proved to contrast preterm delivery induced by mifepristone and PGE2 in rats. 44 Further, fetal tissue is more vulnerable to oxidative damage due to rapid cell proliferation. 81 Ara-C is known to cause fetotoxicity which includes fetal resorption, still birth, weight reduction, and various external and internal developmental anomalies.…”

“…The use of ALA in pregnancy found to be very promising in improving pregnancy outcomes and have no adverse effects on pregnancy. 40,44,45 Further, ALA protective role in ameliorating the pregnancy-related disorders like subchorionic hematomas, miscarriage, and preterm delivery 44,[85][86][87] or chemical-or disease-induced developmental toxicity has been demonstrated in several studies. 47,84,94 Coadministration of ALA showed a significant reduction in OS markers, the incidence of fetal resorption, death, hematoma and increase in weight reduction, crown-to-rump length as compared to group received Ara-C only and is clearly indicating its protective effect.…”

“…43 The use of ALA in pregnancy found to be very promising in improving pregnancy outcomes. 40,44,45 Several experimental studies revealed the protective effect of ALA on the fetus in maternal diabetic or drug- or toxicant-exposure conditions. 40,46,47 Further, ALA reported to promote bone formation and prevent bone loss in various pathological conditions.…”

Bioinformatics and integrated pharmacology network to identify the therapeutic targets and potential molecular mechanism of alpha-lipoic acid on primary ovarian insufficiency

“…follicle development in vitro is improved by the reduction of reactive oxygen species (ROS) levels and the increase of antioxidant capacity in follicles [11]. Moreover, it is associated with the prevention of miscarriage [12,13] and the treatment of endometriosis and vestibulodynia [14,15]. ALA treatment has shown to be effective in many POI animal models, such as in cyclophosphamideinduced and 4-vinyl cyclohexene dioxide induced POI rats [16,17].…”