3-4-dihydroxyphenyllactic-acid and Parkinson-Disease

Danshensu is an active constituent in the extracts of Danshen which is a traditional Chinese medical herb. Rotenone inhibits complex I of the mitochondrial electron transport chain in dopaminergic neurons leading to glutathione (GSH) level reduction and oxidative stress. The aim of this study is to investigate neuroprotective effects of Danshensu on rotenone-induced Parkinson's disease (PD) in vitro and in vivo.. In vitro, SH-SY5Y human neuroblastoma cell line was pretreated with Danshensu and challenged with rotenone. Then the reactive oxygen species (ROS) production was assayed. In vivo, male C57BL/6 mice were intragastrically administered with Danshensu (15, 30, or 60 mg/kg), followed by oral administration with rotenone at a dose of 30 mg/kg. Pole and rotarod tests were carried out at 28 d to observe the effects of Danshensu on PD.. Danshensu repressed ROS generation and therefore attenuated the rotenone-induced injury in SH-SY5Y cells. Danshensu improved motor dysfunction induced by rotenone, accompanied with reducing MDA content and increasing GSH level in striatum. Danshensu increased the number of TH positive neurons, the expression of TH and the dopamine contents. The expressions of p-PI3K, p-AKT, Nrf2, hemeoxygenase (HO-1), glutathione cysteine ligase regulatory subunit (GCLC), glutathione cysteine ligase modulatory subunit (GCLM) were significantly increased and the expression of Keap1 was decreased in Danshensu groups.. The neuroprotective effects of Danshensu on rotenone-induced PD are attributed to the anti-oxidative properties by activating PI3K/AKT/Nrf2 pathway and increasing Nrf2-induced expression of HO-1, GCLC, and GCLM, at least in part.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Disease Models, Animal; Flow Cytometry; Humans; Lactates; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinson Disease; Rotarod Performance Test; Rotenone

We previously reported a novel danshensu derivative ([Formula: see text])-(3,5,6-Trimethylpyrazinyl) methyl-2-acetoxy-3-(3,4-diacetoxyphenyl) propanoate (ADTM), which conferred cardioprotective and anti-thrombotic effects in vitro and in vivo. Here, we examined the neuroprotective actions of ADTM on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PC12 cells 1 in vitro and zebrafish in vivo. Pretreatment with ADTM significantly inhibited 6-OHDA-induced cytotoxicity and production of reactive oxygen species (ROS) in PC12 cells through Akt signaling. Moreover, treatment with ADTM also inhibited expression of inducible nitric oxide synthase (iNOS) and production of intracellular nitric oxide (NO), which are associated with inflammation. In addition, ADTM exhibited significant protection against 6-OHDA-induced loss of tyrosine hydroxylase-positive dopaminergic neurons in a zebrafish model. Taken together, our findings suggest that ADTM is also a potential effective therapeutic agent for neurodegenerative conditions such as Parkinson's disease (PD) through anti-oxidant cytoprotective and anti-inflammatory actions.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Disease Models, Animal; Dopaminergic Neurons; Lactates; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidopamine; Parkinson Disease; PC12 Cells; Phytotherapy; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; Signal Transduction; Tyrosine 3-Monooxygenase; Zebrafish

The overproduction of reactive oxygen species (ROS) has been implicated in the development of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Previous studies have indicated that danshensu (beta-3,4-dihydroxyphenyl-lactic acid), a main hydrophilic component of the Chinese materia medica Radix Salviae Miltiorrhizae (Danshen, Pharmacopoeia of PR China), has ROS scavenging and antioxidant activities, however its mechanism of action was not clear. In this study, we investigated whether the protective effects of danshensu against neurotoxin 6-hydroxydopamine (6-OHDA)-induced oxidative stress involved the Nrf2/HO-1 pathways. Pretreatment with danshensu in PC12 cells significantly attenuated 6-OHDA-induced cytotoxicity and the production of ROS. Danshensu activated the nuclear translocation of Nrf2 to increase heme oxygenase-1 (HO-1), conferring protection against ROS. Danshensu induced the phosphorylation of Akt, and its cytoprotective effect was abolished by PI3K, Akt and HO-1 inhibitors. These results confirmed the crucial role of PI3K/Akt and HO-1 signaling pathways as the underlying mechanistic action of danshensu. Taken together, the results suggest that danshensu enhances HO-1 expression to suppress 6-OHDA-induced oxidative damage via PI3K/Akt/Nrf2 signaling pathways. Moreover, 6-OHDA-induced dopaminergic neuronal loss in zebrafish could be reduced by danshensu, further supporting the neuroprotective potential of danshensu.

Topics: Animals; Antioxidant Response Elements; Cell Death; Dopaminergic Neurons; Drugs, Chinese Herbal; Heme Oxygenase-1; Lactates; Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Oxidopamine; Parkinson Disease; PC12 Cells; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; Signal Transduction; Zebrafish