Abnormal Rat Cortical Development Induced by Ventricular Injection of rHMGB1 Mimics the Pathophysiology of Human Cortical Dysplasia

Abstract

Cortical dysplasia (CD) is a common cause of drug-resistant epilepsy. Increasing studies have implicated innate immunity in CD with epilepsy. However, it is unclear whether innate immune factors induce epileptogenic CD. Here, we injected recombinant human high mobility group box 1 (rHMGB1) into embryonic rat ventricles to determine whether rHMGB1 can induce epileptogenic CD with pathophysiological characteristics similar to those of human CD. Compared with controls and 0.1 μg rHMGB1-treated rats, the cortical organization was severely disrupted in the 0.2 μg rHMGB1-treated rats, and microgyria and heterotopia also emerged; additionally, disoriented and deformed neurons were observed in the cortical lesions and heterotopias. Subcortical heterotopia appeared in the white matter and the gray–white junction of the 0.2 μg rHMGB1-treated rats. Moreover, there was decreased number of neurons in layer V–VI and an increased number of astrocytes in layer I and V of the cortical lesions. And the HMGB1 antagonist dexmedetomidine alleviated the changes induced by rHMGB1. Further, we found that TLR4 and NF-κB were increased after rHMGB1 administration. In addition, the excitatory receptors, N-methyl-D-aspartate receptor 1 (NR1), 2A (NR2A), and 2B (NR2B) immunoreactivity were increased, and immunoreactivity of excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2) were reduced in 0.2 μg rHMGB1-treated rats compared with controls. While there were no differences in the glutamic acid decarboxylase 65/67 (GAD65/67) immunoreactivity between the two groups. These results indicate that the excitation of cortical lesions was significantly increased. Furthermore, electroencephalogram (EEG) showed a shorter latency of seizure onset and a higher incidence of status epilepticus in the 0.2 μg rHMGB1-treated rats; the frequency and amplitude of EEG were higher in the treated rats than controls. Intriguingly, spontaneous electrographic seizure discharges were detected in the 0.2 μg rHMGB1-treated rats after 5 months of age, and spike-wave discharges of approximately 8 Hz were the most significantly increased synchronous propagated waves throughout the general brain cortex. Taken together, these findings indicate that rHMGB1 exposure during pregnancy could contribute to the development of epileptogenic CD, which mimicked some pathophysiological characteristics of human CD.

Inflammatory mechanisms of Ginkgo Biloba extract in improving memory functions through lncRNA‐COX2/NF‐κB pathway in mice with status epilepticus

“… 8 These results suggested that HMGB1 may trigger seizures by inflammation pathways. 9 Lipopolysaccharide (LPS) is an effective inducer of inflammatory signaling, exacerbating inflammatory factors in peripheral and central systems of mice. 10 A noticeable increase in the severity of epileptic seizures and a decrease in the latency were observed in pilocarpine‐induced epilepsy model mice with LPS pretreatment.…”

“…Excessive high mobility group box 1(HMGB1), a rich nuclear and cytoplasmic protein in mammalian cells, was released after cell death or through active secretion, further resulted in inflammation 8 . These results suggested that HMGB1 may trigger seizures by inflammation pathways 9 . Lipopolysaccharide (LPS) is an effective inducer of inflammatory signaling, exacerbating inflammatory factors in peripheral and central systems of mice 10 .…”

Downregulated formyl peptide receptor 2 expression in the epileptogenic foci of patients with focal cortical dysplasia type IIb and tuberous sclerosis complex

“…We have shown that chronic neuroinflammation with the CD47 and CD200 signaling pathways was activated in FCD brain samples 8 . Moreover, Toll‐like receptors (TLRs) and high‐mobility group box 1 (HMGB1) are upregulated in neurons and glial cells in FCDIIb and TSC 9,10 . HMGB1 belongs to the damage‐associated molecular patterns (DAMPs) and promotes the upregulation of downstream inflammatory factors in epilepsy, including nuclear factor‐κB (NF‐κB), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α) 11 .…”

“… 8 Moreover, Toll‐like receptors (TLRs) and high‐mobility group box 1 (HMGB1) are upregulated in neurons and glial cells in FCDIIb and TSC. 9 , 10 HMGB1 belongs to the damage‐associated molecular patterns (DAMPs) and promotes the upregulation of downstream inflammatory factors in epilepsy, including nuclear factor‐κB (NF‐κB), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α). 11 In addition, glucocorticoid therapy has achieved the prevention and treatment of epilepsy and epileptic encephalopathy by directly inhibiting the expression and release of IL‐1β and TNF‐α, 12 , 13 but has serious side effects (such as hypertension and osteoporosis).…”

FPR2 contributes to the dysfunction of inflammation resolution and neuronal excitability in focal cortical dysplasia type IIb and tuberous sclerosis complex

“…We have shown that chronic neuroin ammation with the CD47 and CD200 signaling pathways was activated in FCD brain samples (Sun et al, 2016). Moreover, toll-like receptors (TLRs) and high-mobility group box 1 (HMGB1) are upregulated in FCDIIb and TSC (Zhang et al, 2018;Yang et al, 2021). HMGB1 belongs to the damage-associated molecular patterns (DAMPs) and upregulates downstream in ammatory factors in epilepsy, including nuclear factor kappa-B (NF-κB), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) (Wang et al, 2018).…”