Neferine Protects against Hypoxic‐Ischemic Brain Damage in Neonatal Rats by Suppressing NLRP3‐Mediated Inflammasome Activation

Abstract

Hypoxic-ischemic encephalopathy (HIE) is recognized as the main cause of neonatal death, and efficient treatment strategies remain limited. Given the prevalence of HIE and the associated fatality, further studies on its pathogenesis are warranted. Oxidative stress and neuroinflammatory injury are two important factors leading to brain tissue injury and nerve cell loss in HIE. Neferine, an alkaloid extracted from lotus seed embryo, exerts considerable effects against several diseases such as cancers and myocardial injury. In this study, we demonstrated the neuroprotective effect of neferine on HIE and hypothesized that it involves the inhibition of neuronal pyroptosis, thereby ameliorating neurological inflammation and oxidative stress. We demonstrated that the mRNA levels of proteins associated with pyroptosis including caspase-1, the caspase adaptor ASC, gasdermin D, interleukin- (IL-) 18, IL-1β, and some inflammatory factors were significantly increased in neonatal HIBD model rats compared to those in the control group. The increase in these factors was significantly suppressed by treatment with neferine. We stimulated PC12 cells with CoCl2 to induce neuronal HIBD in vitro and investigated the relationship between neferine and pyroptosis by altering the expression of the NLRP3 inflammasome. The overexpression of NLRP3 partially reversed the neuroprotective effect of neferine on HIBD, whereas NLRP3 knockdown further inhibited caspase-1 activation and IL-1β and IL18 expression. In addition, simultaneous alteration of NLRP3 expression induced changes in intracellular oxidative stress levels after HIBD. These findings indicate that neferine ameliorates neuroinflammation and oxidative stress injury by inhibiting pyroptosis after HIBD. Our study provides valuable information for future studies on neferine with respect to neuroinflammation and pyroptosis.

Glycyrrhizin Attenuates Hypoxic-Ischemic Brain Damage by Inhibiting Ferroptosis and Neuroinflammation in Neonatal Rats via the HMGB1/GPX4 Pathway

“…Our recent research has also shown an intimate link between HIBD and ferroptosis [ 15 ]. The characteristics of ferroptosis are iron-dependent ROS accumulation, inflammation, and mitochondria-dependent damage within the cell, which are also the underlying pathogeneses of HIBD [ 4 , 5 , 20 , 34 , 35 ]. In the current study, we investigated the effect of GL on oxidative stress levels, mitochondrial damage, and neuroinflammation in HIBD.…”

“…Survivors exhibit an increased incidence of severe and permanent neurological sequelae, including cerebral palsy, cognitive impairment, learning impairment, developmental delay, and epilepsy; these sequelae compromise the quality of life of HIBD children and impose an immense economic and psychological burden on families and society [ 1 – 3 ]. To date, hypothermia is the only recognized therapy for newborns with moderate to severe HIBD; however, this treatment has limited efficacy [ 2 , 4 ]. The exact pathogenesis of HIBD is a complex process that is not fully understood; it includes oxidative stress, mitochondrial damage, and inflammation, eventually leading to progressive neuronal death [ 4 , 5 ].…”

“…To date, hypothermia is the only recognized therapy for newborns with moderate to severe HIBD; however, this treatment has limited efficacy [ 2 , 4 ]. The exact pathogenesis of HIBD is a complex process that is not fully understood; it includes oxidative stress, mitochondrial damage, and inflammation, eventually leading to progressive neuronal death [ 4 , 5 ].…”

Protective effects of Liensinine, Isoliensinine, and Neferine on PC12 cells injured by amyloid‐β

“…Aβ 25-35 is a segment of Aβ peptide, which contains 11 amino acids and represents the functional region that mediates the toxic effects in AD (Yankner et al, 1990). The Aβ 25-35injured PC12 cell model is considered to be a typical cell model of AD Zhang et al, 2013), and 20-50 μM Aβ 25-35 is often used to induce PC12 cell injury (Huang et al, 2019;You et al, 2017;Zhang et al, 2021) Neferine has been demonstrated to improve the viability of PC12 cells damaged by caffeine (J. , CoCl 2 (Zhu et al, 2021), or tert-butyl hydroperoxide (Wu et al, 2019) in vitro.…”

“…Neferine has been demonstrated to improve the viability of PC12 cells damaged by caffeine (J. Chen et al, 2020), CoCl 2 (Zhu et al, 2021), or tert‐butyl hydroperoxide (Wu et al, 2019) in vitro. Our results in Figure 3 revealed that Neferine, Liensinine, and Isoliensinine also have significant protective effects on PC12 cells injured by Aβ 25–35 (the toxic protein in AD).…”