Ellagic Acid Protects Dopamine Neurons via Inhibition of NLRP3 Inflammasome Activation in Microglia

Abstract

Neuroinflammation plays a crucial role in the pathological process of Parkinson’s disease (PD). Nod-like receptor protein 3 (NLRP3) inflammasome was highly located in microglia and involved in the process of neuroinflammation. Activation of the NLRP3 inflammasome has been confirmed to contribute to the progression of PD. Thus, inhibition of NLRP3 inflammasome activation could be an important breakthrough point on PD therapy. Ellagic acid (EA) is a natural polyphenol that has been widely found in soft fruits, nuts, and other plant tissues with anti-inflammatory, antioxidant, and neuroprotective properties. However, the mechanisms underlying EA-mediated anti-inflammation and neuroprotection have not been fully elucidated. In this study, a lipopolysaccharide- (LPS-) induced rat dopamine (DA) neuronal damage model was performed to determine the effects of EA on the protection of DA neurons. In addition, the DA neuronal MN9D cell line and microglial BV-2 cell line were employed to explore whether EA-mediated neuroprotection was through an NLRP3-dependent mechanism. Results indicated that EA ameliorated LPS-induced DA neuronal loss in the rat substantia nigra. Further, inhibition of microglial NLRP3 inflammasome signaling activation was involved in EA-generated neuroprotection, as evidenced by the following observations. First, EA reduced NLRP3 inflammasome signaling activation in microglia and subsequent proinflammatory cytokines’ excretion. Second, EA-mediated antineuroinflammation and further DA neuroprotection from LPS-induced neurotoxicity were not shown upon microglial NLRP3 siRNA treatment. In conclusion, this study demonstrated that EA has a profound effect on protecting DA neurons against LPS-induced neurotoxicity via the suppression of microglial NLRP3 inflammasome activation.

Inflammasomes as therapeutic targets in human diseases

“… 103 These studies suggest that the dopamine signaling pathway and the NLRP3 inflammasome are mutually regulated, and PD patients may benefit from inhibition of the inflammatory process in the neurons. 104 – 108 …”

Pomegranate Juice Ameliorates Dopamine Release and Behavioral Deficits in a Rat Model of Parkinson’s Disease

“…These findings corroborate previous results from Wei et al (2020), who showed that treatment with ellagic acid (EA) resulted in improvements in the motor performance of rotenone-treated rats [ 40 ]. EA also has been reported to protect against 6-hydroxydopamine (6-OHDA) and lipopolysaccharide-induced DA neuronal damage and related motor impairment [ 41 , 42 , 43 , 44 ].…”

“…EA, a component of PJ, has been reported to alleviate other non-motor symptoms, including hyperalgesia, cognitive deficiency, and memory performance in the 6-OHDA-induced rat model of PD [ 46 , 47 ]. Accumulating evidence supports the beneficial effect of treatment with EA, pomegranate’s natural precursor of UA, against DAergic neuronal loss and related DA depletion and motor and non-motor dysfunctions in PD models [ 41 , 42 , 43 , 44 ]. Recently, it has been demonstrated that treatment with extract of Eclipta alba rich in EA significantly downregulated the overexpression of α-synuclein at both protein and mRNA levels in the midbrain, prevented loss of DAergic neurons in SNpc, and mitigated behavioral deficits in the MPP+-mediated PD rat model [ 47 ].…”

Differential Effects of Whole Red Raspberry Polyphenols and Their Gut Metabolite Urolithin A on Neuroinflammation in BV-2 Microglia

“…This result stands in contrast to observations made using a N9 murine microglial model, where a post in vitro digestion model of raspberries rich in ellagitannin and EA provided neuroprotection for up to 24 h post-LPS stimulation by suppressing the MAPK/NFAT/NF-ĸB signaling pathways [ 10 ]. In another study, EA pre-treatment decreased TNF-ĸ and NO production from BV-2 microglia by attenuating MyD88/NF-ĸB and p38/Erk/JNK signaling pathways after stimulation with a high dose of LPS (1 ug/mL) for 24 h [ 28 , 29 ]. The inconsistent potency of our whole red raspberry polyphenol extract with respect to regulating neuroinflammatory responses may stem from its composition, as it contains not only free EA but also significant amounts of anthocyanins and epicatechins.…”