Overexpression of zinc-α2-glycoprotein suppressed seizures and seizure-related neuroflammation in pentylenetetrazol-kindled rats

Abstract

BackgroundZinc-α2-glycoprotein (ZAG) is a 42-kDa protein reported as an anti-inflammatory adipocytokine. Evidences from clinical and experimental studies revealed that brain inflammation plays important roles in epileptogenesis and seizure. Interestingly, closely relationship between ZAG and many important inflammatory mediators has been proven. Our previous study identified ZAG in neurons and found that ZAG is decreased in epilepsy and interacts with TGFβ and ERK. This study aimed to investigate the role of ZAG in seizure and explore its effect on seizure-related neuroinflammation.MethodsWe overexpressed AZGP1 in the hippocampus of rats via adeno-associated virus vector injection and observed their seizure behavior and EEG after pentylenetetrazol (PTZ) kindling. The level of typical inflammation mediators including TNFα, IL-6, TGFβ, ERK, and ERK phosphorylation were determined.ResultsThe overexpression of AZGP1 reduced the seizure severity, prolonged the latency of kindling, and alleviated epileptiform discharges in EEG changes induced by PTZ. Overexpression of AZGP1 also suppressed the expression of TNFα, IL-6, TGFβ, and ERK phosphorylaton in PTZ-kindled rats.ConclusionsZAG may inhibit TGFβ-mediated ERK phosphorylation and inhibit neuroinflammation mediated by TNFα and IL-6, suggesting ZAG may suppress seizure via inhibiting neuroinflammation. ZAG may be a potential and novel therapeutic target for epilepsy.

Zinc‐α2‐glycoprotein relieved seizure‐Induced neuronal glucose uptake impairment via insulin‐like growth factor 1 receptor‐regulated glucose transporter 3 expression

“…For the first time, we identified that ZAG increased glucose uptake in neurons. Interestingly, ZAG has been found to be decreased in epilepsy and has an anti‐epileptic effect (Liu et al., 2017, 2018; Wei et al., 2019). As glucose hypometabolism is known to be a trigger of epileptogenesis (Malkov et al., 2018; Samokhina et al., 2017), a ZAG decrease in epilepsy/seizure may be a metabolic mechanism of epileptogenesis.…”

“…Zinc‐α2‐glycoprotein (ZAG) is known to participate in glucose metabolism (Wei et al., 2019b) and has an anti‐epileptic effect (Liu et al., 2017, 2018). ZAG was found to be significantly decreased in the neurons of epilepsy patients, animal models, and a neuronal model, whereas over‐expressing ZAG alleviated seizures in epileptic rats (Liu et al., 2017, 2018; Wei et al., 2019). However, the mechanism by which ZAG regulates glucose metabolism and suppresses seizures remains unclear.…”

QiangGuYin Modulates the OPG/RANKL/RANK Pathway by Increasing Secretin Levels during Treatment of Primary Type I Osteoporosis

“…Animals were raised in an SPF environment for 1 week prior to the start of the study and were kept in standard environmental conditions of temperature (26 ± 2°C), humidity (70%), and light (12 h/12 h light/dark). Adeno-associated virus (AAV) was injected into the caudal vein to establish mouse models of secretin knockdown and secretin overexpression [ 24 ]. The DNA sequence for secretin overexpression was combined with the AAV vector containing a green fluorescent protein (GFP) sequence, which was named the secretin overexpression group.…”

The association of the adipokine zinc‐alpha2‐glycoprotein with non‐alcoholic fatty liver disease and related risk factors: A comprehensive systematic review

“…Transforming growth factor‐β (TGF‐β) and extracellular regulated protein kinase (ERK) pathway play key roles in inflammatory responses. It is demonstrated that ZAG may inhibit TGFβ‐mediated ERK phosphorylation 83 . Recent evidence suggests that ZAG inversely regulates liver inflammatory factors in human hepatocytes and NAFLD mice 63 (see Figure 3).…”

“…It is demonstrated that ZAG may inhibit TGFβ-mediated ERK phosphorylation. 83 Recent evidence suggests that ZAG inversely regulates liver inflammatory factors in human hepatocytes and NAFLD mice 63 (see Figure 3).…”