Hippocampal tissue of patients with refractory temporal lobe epilepsy is associated with astrocyte activation, inflammation, and altered expression of channels and receptors

Abstract

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy. Previous research has demonstrated several trends in human tissue that, undoubtedly, contribute to the development and progression of TLE. In this study we examined resected human hippocampus tissue for a variety of changes including gliosis that may contribute to the development and presentation of TLE. The study subjects consisted of 6 TLE patients and 3 sudden-death controls. Clinicopathological characteristics were evaluated by H&E staining. Immunohistological staining and Western blotting methods were used to analyze the samples. Neuronal hypertrophy was observed in resected epileptic tissue. Immunohistological staining demonstrated that activation of astrocytes was significantly increased in epileptic tissue as compared corresponding regions of the control group. The western blot data also showed increased CX43 and AQP4 in the hippocampus and downregulation of Kir4.1, α-syntrophin, and dystrophinin, which are the key constituents of AQP4 multi-molecular complex. These tissues also demonstrated changes in inflammatory factors (COX-2, TGF-β, NFkB) suggesting that these molecules may play an important role in TLE pathogenesis. In addition we detected increases in metabotropic glutamate receptor (mGluR) 2/3, mGluR5 and kainic acid receptor subunits KA1 (Grik4) and KA2 (Grik5) in patients' hippocampi. We noted increased expression of the α1c subunit comprising Class C L-type Ca2+ channels and calpain expression in these tissues, suggesting that these subunits may have an integral role in TLE pathogenesis. These changes found in the resected tissue suggest that they may contribute to TLE and that the Kainic acid receptor (KAR) and deregulation of GluR2 receptor may play an important role in TLE development and disease course. This study identifies alterations in number of commonly studied molecular targets associated with astrogliosis, cellular hypertrophy, water homeostasis, inflammation, and modulation of excitatory neurotransmission in hippocampal tissue from TLE patients.

Curcumin attenuates inflammatory response and cognitive deficits in experimental model of chronic epilepsy

“…It has been previously reported that changes in transcription and protein expression of GFAP can affect the morphology of astrocytes in brain (Morgan et al, 1997). In present study, the animals showed astrocyte activation after repeated PTZ administration as shown by the animal models of epilepsy (Bechstein et al, 2012;Das et al, 2012). Astrocyte undergoes various functional changes including proliferation (i.e.…”

Expressional Analysis of Inwardly Rectifying Kir4.1 Channels in Groggy Rats, a Rat Model of Absence Seizures

“…medial amygdaloid nucleus and basomedial amygdaloid nucleus) (18) ( Table 1). In addition, recent clinical studies showed that Kir4.1 expression was significantly diminished in patients with temporal lobe epilepsy (20)(21)(22). All these results suggest that the reduced activity of astrocytic Kir4.1 channels evokes GTC and/or temporal lobe seizures, probably by disrupting spatial K + buffering, which consequently elevates extracellular K + and glutamate concentrations.…”

“…All of the mutations in patients with EAST syndrome cause drastic decreases in K + buffering currents mediated by both Kir4.1 and Kir4.1/5.1 channels, implying that the impaired functioning of Kir4.1 disrupts spatial K + buffering and causes epileptic seizures (15)(16)(17). In addition, it has also been shown that expressional levels of Kir4.1 were altered in animal models of epilepsy (18,19), as well as in patients with temporal lobe epilepsy (20)(21)(22). All these findings strongly suggest that Kir4.1 channels are involved in the pathogenesis of GTC and/or temporal lobe seizures.…”

Altered Cerebrospinal Fluid Concentrations of TGFβ1 in Patients with Drug-Resistant Epilepsy

“…Some studies have indicated that TGFb1 involved in neuronal excitability and/or glial scar formation in epilepsy via inflammatory process [6,15]. We hypothesize that altered TGFb1 may participate in inflammatory event, thus leading to seizure-induced neuronal damage in the brain; recurrent seizures eventually contribute to intractable epilepsy.…”