Abstract
Epilepsy is a chronic neurological disorder generally defined to be caused by excessive neuronal activity. Thus, excessive neuronal activity is the main target of the currently used antiepileptic drugs (AEDs). However, as many as 30% of epileptic patients show drug resistance to currently available AEDs, which suggests that epilepsy should be attributed not only to neuronal cells but also to other brain cells, such as glial cells and vascular cells. Astrocytes, pericytes, and endothelial cells in particular comprise the blood–brain barrier (BBB), which tightly regulates the exchange of substances between the brain parenchyma and the circulating blood. It has been proposed that BBB dysfunction, especially barrier leakage, exacerbates epileptic progression, and conversely, that epileptic seizures induce barrier leakage. Furthermore, several studies have shown that BBB dysfunction is one of the main causes of drug resistance in epilepsy. To better understand the mechanisms that link BBB dysfunction and intractable epilepsy to gain insights for the future development of treatments, we review and discuss the relationships between epilepsy and brain vascular abnormalities, mainly by focusing on vascular malformation, BBB dysfunction, and excessive angiogenesis. Because these abnormalities have been reported to be caused by vascular endothelial growth factor (VEGF) in the ischemic brain, we discuss the possible role of VEGF in vascular abnormalities in the epileptic brain, in which the upregulation of VEGF levels has been reported. Both glial cells and endothelial cells express VEGF receptors (VEGFRs); thus, these cells are likely affected by increases in VEGF during seizures, which in turn could cause vascular abnormalities. In this review, we review the possible role of VEGF in epilepsy and discuss the mechanisms that link vascular abnormalities and intractable epilepsy.
Highlights
Epilepsy is a chronic neurological disorder accompanied by spontaneous and frequent seizures, which are induced by the aberrant hyperactivity of neurons
About one-third of patients with epilepsy remain resistant to antiepileptic drugs (AEDs), which suggests that the role of brain cells other than neurons should be studied in the epileptic brain
neurovascular unit (NVU), which consists of multiple cell types including neurons, astrocytes, pericytes, and endothelial cells, can be an essential therapeutic target for epilepsy
Summary
Epilepsy is a chronic neurological disorder accompanied by spontaneous and frequent seizures, which are induced by the aberrant hyperactivity of neurons. 20 years ago, the concept of the neurovascular unit (NVU) was proposed (Harder et al, 2002) According to this concept, neuronal activity is regulated by neurons themselves and by other cells surrounding blood vessels, including glial cells, pericytes, and endothelial cells (Figure 1). Endothelial cells produce vasoactive factors to regulate vessel diameters, possibly resulting in changes in neuronal activity (Muoio et al, 2014). BBB leakage could induce excessive angiogenesis and increase blood flow These abnormalities are possibly induced by vascular endothelial growth factor (VEGF), whose expression is reported to be increased in the brains of patients with TLE (Rigau et al, 2007; Castañeda-Cabral et al, 2019). We will describe vascular abnormalities in the epileptic brain, mainly by focusing on the roles of VEGF in their development
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