Astragaloside IV ameliorates motor deficits and dopaminergic neuron degeneration via inhibiting neuroinflammation and oxidative stress in a Parkinson's disease mouse model
Introduction
Parkinson's disease (PD) is a common progressive neurodegeneration disease which occurs with genetic and environmental onset. It characterize by extra pyramidal motor dysfunction including tremor, rigidity, bradykinesia and several non-motor symptoms such as sleep and cognitive problems [1]. The hallmark of the diseases is the progressive loss of dopaminergic neurons in substantia nigra compacta (SNpc) and striatum. Several studies assume that mitochondrial dysfunction, oxidative stress, neuroinflammation and apoptosis are involved with the pathological process of PD [[2], [3], [4], [5]]. Recently, oxidative stress and neuroinflammation are supported as the early and key pathological feature of PD [6,7]. Therefore, therapeutic intervention to inhibit oxidative stress and neuroinflammation would be an effective strategy to alleviate the progression of PD.
Neuroinflammation is a potent contributor to promote the progression of PD [2,8,9]. Recent studies showed that inflammasome activation is implicated in inflammatory neurodegenerative disorders such as AD, traumatic brain injury (TBI) and PD [3,10,11]. Nucleotide binding and oligomerization domain-like (Nod) receptor family pyrin domain-containing 3 (NLRP3) inflammasome is the most widely studied member of the NLR family, which is composed of nod-like receptor protein NLRP3, adaptor protein ASC and pro-cascapse-1. It can be activated to trigger a pro-inflammatory response under the stimulation of the pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular pattern (DAMPs) and ROS [12]. Activation of NLRP3 inflammasome demands two signals: The first signal is to activate the NFκB pathway to facilitate pro-IL-1β assembly and promote NLRP3 transcription and translation, which is the priming step of NLRP3 inflammasome activation. The second signal is to form the NLRP3 inflammasome complex including NLRP3, ASC and caspsase-1 and then in turn cleaves pro-IL-1β into IL-1β. The activation of NLRP3 inflammasome will promote the maturity and release of IL-1β, which is detrimental to the dopaminergic neuronal survival. Strategies to inhibition NLRP3 inflammasome activation are effective to ameliorate the neuroinflammation and dopaminergic neuronal degeneration of PD [[13], [14], [15], [16]].
Oxidative stress is often considered as a common feature of inflammatory responses, which is companied with an increased intracellular overproduction of ROS and reduced antioxidant capacity. ROS, on the other hand, exerts an upstream signal of NLRP3 inflammasome activation, which activates NLRP3 to trigger an inflammatory response [17,18]. Nuclear factor E2-related factor 2 (Nrf2) is a key endogenous regulator in anti-oxidant defense mechanisms, which plays a vital role in the amelioration of various inflammatory and oxidative stress-induced diseases [[19], [20], [21], [22]]. Recently studies showed that activating Nrf2 could negatively regulate NLRP3 inflammasome activity via inhibiting ROS production [17]. Another studies also demonstrated that Nrf2-activating compounds such as tertiary butylhydroquinone and sulforaphane is protective to the injured dopaminergic neuron [[23], [24], [25], [26], [27], [28]]. Therefore, activating Nrf2 may contribute to anti-oxidative stress and anti-inflammation, which is beneficial for attenuating the severity of PD.
Astragaloside IV is a saponin and serving as the predominant constituent of Astragalus membranaceus, which has been suggested to have anti-inflammatory, anti-oxidative and immuno-regulatory activities in various diseases [[29], [30], [31], [32]]. Recently, studies demonstrated that Astragaloside IV could alleviate neuroinflammation via inhibiting NFκB/NLRP3 inflammasome axis of depression mice [33]. There are also reports showing that Astragaloside IV could activate Nrf2-mediated antioxidant pathway to alleviate acute kidney injury and brain injury [[34], [35], [36]]. Although researchers also found Astragaloside IV is effective to against the motor injury induced by MPTP, however, the molecular mechanisms remain unclear [37]. In this study, we seek to investigate the potential mechanisms of Astragaloside IV in a MPTP-induced mouse model and LPS-induced BV2 microglia cells model of PD.
Section snippets
Antibodies and reagents
The primary antibodies including Rabbit monoclonal anti-NFκB, Rabbit monoclonal anti-p-NFκBp65, Rabbit monoclonal anti-NLRP3, Rabbit monoclonal anti-ASC, Rabbit monoclonal anti-Caspase-1, Rabbit monoclonal anti-IL-1β and Rabbit monoclonal anti-LaminB were purchased form Cell Signaling Technology, Inc. Rabbit monoclonal anti-TH, Rabbit monoclonal anti-Nrf2 and Rat monoclonal anti-CD68 were purchased form Abcam, Inc. Rabbit monoclonal anti- Iba-1 antibody were purchased from Woko, Inc. Mouse
Astragaloside IV alleviates motor impairment in MPTP-induced PD mice
In this study, we evaluated the effect of Astragaloside IV on PD by rotarod test and pole-climbing test. As shown in Fig. 1A, MPTP-treated mice exhibited a marked decrease in latency to fall compared with those in the control group on day 1, day 3 and day 5 after MPTP injection in rotarod test. However, Astragaloside IV treatment (40 mg/kg) significantly increased the latency to fall in rotarod test on day 3 and day 5 after MPTP injection. Similarly, mice in MPTP group showed a longer crawling
Discussion
In present study, we evaluated the effect and mechanisms of Astragaloside IV on oxidative stress and neuroinflammation of PD both in vivo and in vitro. We found that Astragaloside IV is effective to alleviate the motor dysfunction and dopaminergic neuron degeneration of MPTP mice. In addition, we determined Astragaloside IV inhibited the oxidative stress and neuroinflammation induced by MPTP. Furthermore, we found that Astragaloside IV suppressed NLRP3 inflammasome activation and activated Nrf2
Conclusions
In conclusion, our findings demonstrated that Astragaloside IV effectively protected motor deficits and dopaminergic neuron degeneration from oxidative stress and inflammation damage. This study provides beneficial evidence for the application of Astragaloside IV in the prevention of inflammasome and oxidative stress-associated diseases, especially PD.
Data availability
The data used to support the findings of this study are available from the corresponding author upon request.
Authors' contributions
Cong Yang and Yousheng Mo contributed equally to this work.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 81673627, No. 81673717, No. 81774199), Guangzhou Science Technology and Innovation Commission Technology Research Projects (201805010005, 201803010047).
Declaration of Competing Interest
The authors declare that there is no conflict of interest.
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These authors contributed equally to this work.