Distinct Cell-specific Roles of NOX2 and MyD88 in Epileptogenesis

Abstract

It is well established that temporal lobe epilepsy (TLE) is often related to oxidative stress and neuroinflammation. Both processes subserve alterations observed in epileptogenesis and ultimately involve distinct classes of cells, including astrocytes, microglia, and specific neural subtypes. For this reason, molecules associated with oxidative stress response and neuroinflammation have been proposed as potential targets for therapeutic strategies. However, these molecules can participate in distinct intracellular pathways depending on the cell type. To illustrate this, we reviewed the potential role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and myeloid differentiation primary response 88 (MyD88) in astrocytes, microglia, and neurons in epileptogenesis. Furthermore, we presented approaches to study genes in different cells, employing single-cell RNA-sequencing (scRNAseq) transcriptomic analyses, transgenic technologies and viral serotypes carrying vectors with specific promoters. We discussed the importance of identifying particular roles of molecules depending on the cell type, endowing more effective therapeutic strategies to treat TLE.

Specific inhibition of NADPH oxidase 2 modifies chronic epilepsy

“…Among the NOX isoforms, NOX2 has been particularly related to neuronal damage and death, as well as to the resolution of the subsequent inflammatory response after brain injury including SE [ 72 ]. It is argued that besides being the major contributor to SE-induced ROS production in acquired epilepsies, NOX2, expressed mainly in microglia, is thought to be the major contributor to the neuroinflammation response [ 73 ]. In agreement with these data, we demonstrated that NOX2 was also expressed in the cortex, as well as in CA1 and CA3 of the hippocampus 1 week after SE ( Supplementary Fig.…”

The lactate receptor HCAR1: A key modulator of epileptic seizure activity

“…Whether HCAR1 influences epileptogenesis leading to chronic recurrent epileptic events has still to be determined. Epileptogenesis is a complex process driven by oxidative stress and neuroinflammation 68 and involving cellular and network reorganization, that includes ryanodine receptors and various synaptic proteins. 69 The understanding of factors favoring epileptogenesis will likely benefit from omics approaches, such as the analysis of plasma proteins used as biomarkers in individuals experiencing recent and recurrent seizures.…”

Evaluation of the Antioxidant Activity of Levetiracetam in a Temporal Lobe Epilepsy Model

“…In the development of TLE, the involvement of OS and neuroinflammation have been well established as important factors, in part because the large amount of energy required by the brain is considered to be a possible mechanism involved in epileptogenesis [ 12 , 21 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. In recent studies, it was observed that the specific inhibition of NADPH oxidase (NOX), the main producer of OS through O 2 •− synthesis, modified chronic epilepsy in a TLE rat model, preventing ROS generation, mitochondrial depolarization, and neuronal death.…”