Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease

Moreira, Sara; Fonseca, I.; Nunes, Maria João; Rosa, Agostinho; Lemos, Luisa de; Rodrigues, Elsa; Carvalho, Andreia; Outeiro, Tiago F.; Rodrigues, C.M.P.; Gama, Maria João; Castro-Caldas, Margarida

doi:10.1016/j.expneurol.2017.05.009

Cited by 86 publications

(72 citation statements)

References 52 publications

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“…Keap1 inhibits the activation of Nrf2. Keap1 also facilitates the proteasomal degradation of Nrf2 [26]. Inhibition of Nrf2-mediated transcription augments a vulnerability of dopaminergic neurons to oxidative stress [27].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of Danshensu on rotenone-induced Parkinson’s disease models in vitro and in vivo

Wang

Han

et al. 2020

BMC Complement Med Ther

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Background: 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. Methods: 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. Results: 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. Conclusions: The neuroprotective effects of Danshensu on rotenone-induced PD are attributed to the antioxidative properties by activating PI3K/AKT/Nrf2 pathway and increasing Nrf2-induced expression of HO-1, GCLC, and GCLM, at least in part.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of Danshensu on rotenone-induced Parkinson’s disease models in vitro and in vivo

Wang

Han

et al. 2020

BMC Complement Med Ther

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“…A phase 1, open-label trial evaluating the safety and pharmacokinetics of 50mg/kg/day UDCA in 20 patients with PD is currently underway (NCT02967250) while a trial of UDCA in PD patients to evaluate the effect of on disease progression has received funding and is due to start imminently. PD-specific pharmacokinetic data regarding UDCA is awaited though in view of the potential issues regarding incomplete absorption of UDCA from the gut, interest is growing in the UDCA derivative tauro-ursodeoxycholic acid (TUDCA) (not currently approved for use), which has demonstrated better orally bioavailability, crosses the blood-brain barrier and has demonstrated neuroprotection against MPTP-and α-synuclein-induced stress in vitro and in vivo [72,[77][78][79] and indicated potential benefits in a small RCT in 34 patients with ALS [80] and may offer better potential.…”

Section: Ursodeoxycholic Acid (Udca)mentioning

confidence: 99%

Drug Repurposing in Parkinson’s Disease

Foltynie

2018

CNS Drugs

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The development of an intervention to slow or halt disease progression remains the greatest unmet therapeutic need in Parkinson's disease. Given the number of failures of various novel interventions in disease-modifying clinical trials in combination with ever increasing and lengthy drug development costs, attention is being turned to utilising existing compounds approved for other indications as novel treatments in Parkinson's disease. Advances in rational and systemic drug repurposing has identified a number of drugs with potential benefits for Parkinson's disease pathology and offers a potentially quicker route to drug discovery. Here, we review the safety and potential efficacy of the most promising candidates repurposed as potential disease-modifying treatments for Parkinson's disease in the advanced stages of clinical testing. Running head: Drug repurposing in Parkinson's disease Key points:  Disease modifying treatments are a great unmet need in Parkinson's disease  Drug repurposing represents a potentially more efficient, less costly route to drug discovery.

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“…But how exactly TUDCA affects the production of proinflammatory cytokines remains unclear. Recently, several different mechanisms, such as the inhibition of glial nuclear factor-κB [12] and the activation of G protein-coupled bile acid receptor 1/Takeda G protein-coupled receptor 5 (GPBAR1/ TGR5) in microglia have been revealed to mediate this effect of TUDCA [22]. But whether these mechanisms are involved in the antidepressant-like effect of TUDCA remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Tauroursodeoxycholic Acid Ameliorates Lipopolysaccharide-Induced Depression Like Behavior in Mice via the Inhibition of Neuroinflammation and Oxido-Nitrosative Stress

Huang

Chen

2018

Pharmacology

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Depression is a mental disease that causes severe economic and social burdens. The mechanism for the onset of depression remains largely unknown. Recently, more and more attention is being given to the role of neuroinflammation and oxidative stress in depression. Tauroursodeoxycholic acid (TUDCA), a clinically available agent used to treat cholesterol gallstone and protect neurons against neurodegeneration, has been reported to prevent neuroinflammation and oxidative stress. In this study, we investigated the effect of TUDCA on lipopolysaccharide (LPS)-induced depression-like behavior, neuroinflammation, and oxido-nitrosative stress in mice. Results showed that TUDCA pretreatment (once daily for 7 consecutive days) at the dosage of 200 and 400 mg/kg, but not 100 mg/kg, markedly attenuated LPS (0.83 mg/kg)-induced behavioral abnormalities in the tail suspension test, forced swim test, and sucrose preference test. Further analysis showed that the TUDCA pretreatment (200, 400 mg/kg) not only inhibited the production of proinflammatory cytokines induced by LPS stimulation, such as interleukin-6 and tumor necrosis factor-α, but attenuated LPS-triggered oxido-nitrosative stress in the hippocampus and prefrontal cortex. Taken together, our results provide evidence to show that the TUDCA could be a potential antidepressant, and its antidepressive mechanism may be associated with the inhibition of the neuroinflammatory response and oxido-nitrosative stress in the brain.

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Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease

Cited by 86 publications

References 52 publications

Neuroprotective effects of Danshensu on rotenone-induced Parkinson’s disease models in vitro and in vivo

Neuroprotective effects of Danshensu on rotenone-induced Parkinson’s disease models in vitro and in vivo

Drug Repurposing in Parkinson’s Disease

Tauroursodeoxycholic Acid Ameliorates Lipopolysaccharide-Induced Depression Like Behavior in Mice via the Inhibition of Neuroinflammation and Oxido-Nitrosative Stress

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