Elsevier

Neuroscience

Volume 220, 18 September 2012, Pages 237-246
Neuroscience

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

https://doi.org/10.1016/j.neuroscience.2012.06.002Get rights and content

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 might contribute to the development and presentation of TLE. The study subjects consisted of six TLE patients and three 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 to 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 dystrophin, the key constituents of AQP4 multi-molecular complex. These tissues also demonstrated changes in inflammatory factors (COX-2, TGF-β, NF-κB) 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 might 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 tissues from TLE patients.

Highlights

► We evaluated astrocyte activation and inflammation involvement in human epilepsy samples. ► High GFAP is associated with increased AQP4, CX43, m-calpain, and L-type Ca2+ channels. ► Kir4.1, dystrophin, and α-syntrophin are decreased in human epilepsy. ► Inflammatory markers and glutamate receptors/subunits are also increased. ► Astrocyte-related inflammation may be a significant target for new epilepsy therapy.

Section snippets

Background

Epilepsy is a chronic brain disorder, defined by spontaneous recurrent seizures. Temporal lobe epilepsy (TLE), the most common form in adults, is generally characterized by a unilateral temporal lobe seizure foci (Cascino, 2005, Sharma et al., 2007). Due to the lack of effective pharmacotherapies, a relatively large percentage of the TLE patients suffer from medically intractable seizures. As a result, invasive resection of the seizure focus is often recommended as a final alternative to

Acquisition of human epileptic samples

Patient samples were collected following temporal lobe resection performed as treatment for refractory TLE. Patient consent was obtained for tissue use before surgery. All patients included in this study were diagnosed as epileptic according to the criteria defined by the International League Against Epilepsy (Commission of Classification and Terminology of the International League Against Epilepsy). Patients were evaluated based on clinical history, physical examination, ictal EEG recording,

Demographic and clinical characteristics of subjects

The mean age of the epilepsy patients was 33.5 ± 8.73 years, with three men and three women in the experimental group (Table 2). The mean duration of seizure recurrence was 8.9 ± 3.06 years. Clinical information from all patients is summarized in Table 2. Epilepsy patients experienced seizure recurrence for at least 5 years, with three in six having recurrences for more than 10 years. The sudden death control group consisted of three men, with an average age of 30.90 ± 8.65 years. Statistical analysis

Discussion

Histological and molecular changes associated with TLE are complex and still poorly defined. Neuronal hypertrophy and increased expression of pro-inflammatory factors are hallmarks of TLE and generally suggest astrocytic activation. In this regard, our work has confirmed previous findings. Changes in extracellular osmotic and ionic gradients have been implicated as a mechanism by which dysfunctional astrocytes may promote neuronal hyperexcitability in TLE (Yang et al., 2010). Hypo-osmotic

Disclosure

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent.

Acknowledgements

This work was supported in part by the grants from the National Institute of Neurological Disorders and Stroke (NS-31622, NS-38146, and NS-41088) and the South Carolina Spinal Cord Injury Research Fund.

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