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Review
. 2022 Jan 14;11(1):157.
doi: 10.3390/antiox11010157.

The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

Anna L M Parsons  1 , Eboni M V Bucknor  1 , Enrico Castroflorio  1   2 , Tânia R Soares  1 , Peter L Oliver  1 , Daniel Rial  1
Affiliations
Review

The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

Anna L M Parsons et al. Antioxidants (Basel). .

Abstract

One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders of the nervous system, where pathological processes such as aberrant protein oxidation can ultimately lead to cellular dysfunction and death. Epilepsy, characterized by a long-term predisposition to epileptic seizures, is one of the most common of the neurological disorders associated with OS. Evidence shows that increased neuronal excitability-the hallmark of epilepsy-is accompanied by neuroinflammation and an excessive production of ROS; together, these factors are likely key features of seizure initiation and propagation. This review discusses the role of OS in epilepsy, its connection to neuroinflammation and the impact on synaptic function. Considering that the pharmacological treatment options for epilepsy are limited by the heterogeneity of these disorders, we also introduce the latest advances in anti-epileptic drugs (AEDs) and how they interact with OS. We conclude that OS is intertwined with numerous physiological and molecular mechanisms in epilepsy, although a causal relationship is yet to be established.

Keywords: astrocyte; epilepsy; neuroinflammation; neuron; neurotransmission; oxidative stress; seizure; synapse.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript.

Figures

Figure 1
Figure 1
Interconnected mechanisms of epilepsy involving OS. Reduced GABA-mediated inhibitory responses paired with increased glutamatergic tonus (through NMDA currents and/or astrocyte clearance dysfunction) leads to increased intracellular calcium concentration, which is the main source of hyperexcitability as well as OS-associated feedback. In addition, a reduction in the expression of antioxidant defence proteins (for example, GPx, SOD and Nrf2) have been reported in epileptic patients and in animal models of epilepsy. The increased formation of ROS and consequent mitochondrial dysfunction contribute synergistically to OS resulting in synaptic malfunction and cell death. These events are all supplemented by neuroinflammation (e.g., indicated by increase cytokine expression) that potentiates OS and induces astrogliosis, in-turn impacting NMDA function and causing cell death.
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