Down‐regulation of Connexions and Pannexin‐1 Coincides with Excitatory Amino‐Acid Transporters Up‐regulation on Glia Cells to Maintain Glutamate Homeostasis after IκB Kinase (IKK) Inhibition

Abstract

Background and objectives Inflammatory pathway and dysregulation of glutamate level are connected at the level of the glia, leading to numerous neurological disorders. In vitro models have revealed that the channel connexions (Cxs) are implied in glutamate release, while excitatory amino-acid transporters (EAATs) are crucial for glutamate re-uptake. Additionally, pannexin-1 (Panx-1) is involved in glutamate induced neuronal degeneration. However, the pattern of their expressions during inflammation and the effects of nuclear factor-kappa B (NF-κB) inhibition on the inflammatory- induced glutamate imbalance remain unknown. The aim of the study was to explore the roles of Cxs, Panx-1 and EAATS on glutamate induced neurotoxicity, and to clarify the relationship between NK-FB activation and the expressions of Cxs, Panx-1 and EAATS in lipopolysaccharide-induced neuroinflammation. Hypothesis we hypothesized that NF-κB may be involved in the development of glutamate neurotoxicity via regulating the expressions of Cxs, Panx-1 and EAATS on the activated glia cells. Material & Methods To study this, 30 male albino rats were injected with saline or lipopolysaccharide. Subsequently, LPS challenged rats were treated with either vehicle or BAY-117082 (an inhibitor of IκB Kinase (IKK)). Thereafter, reverse transcription polymerase chain reaction (RT-PCR), western blot, enzyme-linked immunosorbent assay (ELISA), and immune-histological analysis were carried out to assess the glia activity, NFKB activation, and glutamate level. Concomitantly, measurement of Cxs, Panx-1, and EAAts expressions in the brain was conducted. The electroencephalography (EEG) was used to record the neuronal activity. The present study was conducted following the FASEB Statement of Principles for the use of Animals in research and Education, and was approved by the Institutional Animal Care Committee (CU Ш F 55 17). Results Our results confirm the previous in- vitro findings that paradoxical changes in the expressions of Cxs, Panx-1, and EAATs may participate significantly in glutamate accumulation and subsequent neurotoxicity. Nuclear factor-kB (NF-κB) pathway significantly impacted the glutamate balance via regulating the expressions of Cxs, Panx-1, and EAATs. BAY-117082 ameliorated gliosis and provided a neuroprotection. Figure 1. Conclusion We concluded that NF-κB is a critical key player in the remodeling of Cxs, panx-1, and EAATs expressions and the initiation of glutamate toxicity.