Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling.

Jyun-Bin Huang,Chung-Yao Hsu,Jie-Hau Li,Hsiu-Yung Pan,Xuan-Ping Liu,Yao-Chung Chuang,Shu-Fang Chen,Shang-Der Chen,Hung-Yi Chuang,Nai-Ching Chen,Chia-Wei Liou,Tsu-Kung Lin,Shih-Pin Hsu

doi:10.3390/ijms21197247

Abstract

Status epilepticus may cause molecular and cellular events, leading to hippocampal neuronal cell death. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is an important regulator of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), also known as fetal liver kinase receptor 1 (Flk-1). Resveratrol is an activator of PGC-1α. It has been suggested to provide neuroprotective effects in epilepsy, stroke, and neurodegenerative diseases. In the present study, we used microinjection of kainic acid into the left hippocampal CA3 region in Sprague Dawley rats to induce bilateral prolonged seizure activity. Upregulating the PGC-1α pathway will increase VEGF/VEGFR2 (Flk-1) signaling and further activate some survival signaling that includes the mitogen activated protein kinase kinase (MEK)/mitogen activated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways and offer neuroprotection as a consequence of apoptosis in the hippocampal neurons following status epilepticus. Otherwise, downregulation of PGC-1α by siRNA against pgc-1α will inhibit VEGF/VEGFR2 (Flk-1) signaling and suppress pro-survival PI3K/AKT and MEK/ERK pathways that are also accompanied by hippocampal CA3 neuronal cell apoptosis. These results may indicate that the PGC-1α induced VEGF/VEGFR2 pathway may trigger the neuronal survival signaling, and the PI3K/AKT and MEK/ERK signaling pathways. Thus, the axis of PGC-1α/VEGF/VEGFR2 (Flk-1) and the triggering of downstream PI3K/AKT and MEK/ERK signaling could be considered an endogenous neuroprotective effect against apoptosis in the hippocampus following status epilepticus.

Highlights

Epilepsy is one of the most common serious brain conditions characterized by the recurrence of unprovoked seizures, affecting more than 70 million people worldwide [1]
We propose that PGC-1α may be activated during experimental status epilepticus and regulate the vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway, and further protects against apoptotic neuronal cell death in the hippocampus following status epilepticus through survival signaling and phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase kinase (MEK)/ERK-dependent pathways
After unilateral microinjection of kainic acid (KA; 0.5 nmol) into the left CA3 subfield, pgc-1α mRNA expression exhibited a significantly incremental change in the right hippocampal CA3 area 1 h after the elicitation of prolonged seizure activities, followed by a progressive decrement that returned to base line at 24 h (Figure 1a)

Summary

Introduction

Epilepsy is one of the most common serious brain conditions characterized by the recurrence of unprovoked seizures, affecting more than 70 million people worldwide [1]. Sustained seizure activities during status epilepticus usually result in significant neuronal damage in the cerebral cortex, in the hippocampus [2,3]. Evidence has shown both in human and animal studies that prolonged seizures may lead to a large number of changes of molecular and cellular cascades, including axonal sprouting, gliosis, network reorganization, activation of neuroinflammation, acquired channelopathies, oxidative stress, mitochondrial dysfunctions, angiogenesis, neurogenesis, and activation of some late cell death pathways, which contribute to neurodegeneration and brain damage [4,5,6,7]. Recent evidence suggests that VEGF has therapeutic potential as a neuroprotective factor in many neurological diseases [12,15], such as stroke [16,17,18], epilepsy [14,19], and neurodegenerative diseases [12,20,21,22]

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Results

Discussion

Conclusion