AQP4 Attenuated TRAF6/NFκB Activation in Acrylamide-Induced Neurotoxicity

Abstract

Acrylamide (ACR) is present in high-temperature-processed high-carbohydrate foods, cigarette smoke, and industrial pollution. Chronic exposure to ACR may induce neurotoxicity from reactive oxygen species (ROS); however, the mechanisms underlying ACR-induced neurotoxicity remain unclear. We studied 28-day subacute ACR toxicity by repeatedly feeding ACR (0, 15, or 30 mg/kg) to rats. We conducted RNA sequencing and Western blot analyses to identify differences in mRNA expression in the blood and in protein expression in the brain tissues, respectively, of the rats. AQP4 transient transfection was performed to identify potential associations with protein regulation. The rats treated with 30 mg/kg ACR exhibited hind-limb muscle weakness. Matrix metalloproteinase (MMP9) expression was higher in the ACR-treated group than in the control group. ACR induced MMP-9 and AQP4 protein expression in the brain tissues of the rats, which subsequently presented with neurotoxicity. In the in vitro study, Neuro-2a cells were transiently transfected with AQP4, which inhibited MMP-9 and TNF receptor-associated factor 6 (TRAF6) expression, and inhibited ACR induced expression of TRAF6, IκBα, and nuclear factor κB (NFκB). Using a combination of in vivo and in vitro experiments, this study revealed that depressive symptoms associated with ACR-induced neurotoxicity are associated with downregulation of AQP4 and induction of the TRAF6 pathway.

Kaempferol counteracts bupivacaine‐induced neurotoxicity in mouse dorsal root ganglia neurons by regulating TRAF6‐dependent NF‐κB signaling

“…This raises the possibility that KA mitigates BU‐induced neurotoxicity by regulating TRAF6. Moreover, it is widely recognized that inhibition of the TRAF6/NF‐κB pathway is an efficient way to protect against neurotoxicity 23 . Thus, the levels of TRAF6 and NF‐κB‐related proteins (NF‐κB‐p65 and p‐NF‐κB‐p65) were determined by western blotting.…”

“…Moreover, it is widely recognized that inhibition of the TRAF6/NF-κB pathway is an efficient way to protect against neurotoxicity. 23 Thus, the levels of TRAF6 and NF-κB-related proteins (NF-κB-p65 and p-NF-κB-p65) were determined by western blotting. As indicated in Figure 5A, BU stimulation led to an increase in the TRAF6 protein level; however, such an increase was reversed with the increase in the KA concentration.…”

“…TRAF6 upregulation and subsequent NF‐κB activation facilitate Aβ‐induced cognitive deficits and neuroinflammation 22 . Furthermore, TRAF6‐induced NF‐κB activation is deeply involved in acrylamide‐induced neurotoxicity in rats 23 . All these studies indicate a promoting role of TRAF6 in neurotoxicity.…”

“…22 Furthermore, TRAF6-induced NF-κB activation is deeply involved in acrylamide-induced neurotoxicity in rats. 23 All these studies indicate a promoting role of TRAF6 in neurotoxicity. Hence, TRAF6-dependent NF-κB signaling might play a critical role in KA-mediated neuroprotective effects.…”

Blood RNA‐sequencing analysis in acrylamide‐induced neurotoxicity and depressive symptoms in rats

“…Our results in this study showed ACR-induced neurotoxicity the same as previously reported that rodents treated with 30 mg/kg ACR developed certain symptoms of neurotoxicity, such as limb numbness, muscle weakness, and foot drop. 23,27 Using gait observations for the neurotoxicity index is bined with increased rearfoot extension on landing, reduced hind limb grip, and extensor thrust. 25 Similar symptoms were observed in Wistar rats treated with the same dose of ACR for 28 days.…”