Key Mediators of Neuroinflammation
Over the past ten years, the number of research papers focused on neuroinflammation of epilepsy has escalated dramatically (Ngadimon et al., 2024). Thus, neuroinflammation is central to both the initiation (epileptogenesis) of epilepsy and the support for repetitive seizures. A great deal is known about the inflammatory pathways active in epilepsy (Aguilar-Castillo et al., 2024; Ngadimon et al., 2024). Furthermore, several key mediators of neuroinflammation are now potential biomarkers of epilepsy (Aguilar-Castillo et al., 2024). These select biomarkers are possible new diagnostic tools poised to replace the traditional EEG.
This blog will discuss one of the key mediators of neuroinflammation of epilepsy, termed High-Mobility Group Box 1, also known as HMGB1 (Aguilar-Castillo et al., 2024; Ngadimon et al., 2024; Chen et al., 2023) . HMGB1 has the potential to be an innovative and relevant diagnostic tool to identify and monitor the disease of epilepsy.
Unmet Medical Needs – Biomarkers and Selective Drugs
Several key neuroinflammatory mediators including HMGB1 and others are present in serum and importantly are associated with the severity and frequency of seizures (see studies below) (Ngadimon et al, 2024). The ability of the traditional EEG to diagnosis new onset epilepsy is poor and its predictive capability for repeat seizures is limited. It is, therefore, critical to pursue research to fill this unmet medical need and to identify novel molecules exclusive to epilepsy as valid diagnostic and prognostic tools.
Key Mediators of Neuroinflammation as drug targets
Moreover, select neuroinflammatory mediators and their target receptors have potential as targets for new drug therapy (Maroso et al., 2010). Current anti-seizure drugs, although there are many, have adverse side effects that cause many patients to discontinue use (Chen et al., 2023). These drugs suppress seizures but do nothing about the progression of the disease. Furthermore, 30% of epileptic patients do not benefit from present day drugs. They are considered drug-resistant. Thus, there is a need to develop more selective drugs. Therefore, focus on development of drugs that inhibit the epilepsy-promoting effects of key mediators of neuroinflammation should prove of value.
Neuroinflammation of epilepsy – instigator?
Neuroinflammation is an inflammatory disturbance in and among the cells of the brain. “Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation.” (Webster et al., 2017). Approximately half of all acquired epilepsies occur following a prior neurological injury that produces neuroinflammation. Neurological injuries are injuries such as a brain tumor/infection, traumatic brain injury, or exposure to destructive nerve agents (Klein et al., 2018; Chen et al., 2023). Neuroinflammation is also the common denominator between epilepsy and sleep disorders (see blog 11)
Animal Models, Human Epileptic Tissue
Results of studies in animal models of epilepsy and data from human epileptic tissue specimens, define the brain pathways and mechanisms of neuroinflammation. In general, a latent phase follows a brain injury and progresses to a chronic phase. These changes eventually heighten the excitability of nerves, giving rise to seizures. Neuroinflammation is characterized by abnormal alterations in brain support cells e.g. astrocytes and glial cells, harmful modifications in the blood-brain barrier (making it more porous susceptible to entry of unwanted cells and proteins), infiltration of immune cells, nerve cell death and reorganization of remaining neurons (Klein et al., 2018; Chen et al., 2023)(see Figure below).
Importantly, these revisions produce an abundance of significant pro-inflammatory substances whose effects modify nerve activity favoring excitability. High-Mobility Group Box 1 (HMGB1) is among one of the significant pro-inflammatory substances. Data show its amplified presence enhances nerve excitability and participates in continued hyper excitability (Maroso et al., 2010; Kamasak et al., 2020).
High-Mobility Group Box 1 (HMGB1) -Major Culprit?
HMGB1 is a nuclear protein with a normal activity of assisting DNA in gene expression (“turning genes off and on”), maintenance and repair. Therefore, residing in the nucleus it remains beneficial. However, stress-induced movement to the cytoplasm and the extracellular fluid renders it harmful. Thus, when released from cells, actively or via cell death, HMGB1 acts as a pro-inflammatory initiator binding to one of two receptors (Toll-like Receptor 4, TLR4 and receptor for advanced glycation endproducts, RAGE) (Paudel et al., 2018; Chen et al., 2023).
HMGB1 Consequences
This interaction sets off a cascade of changes that continue to generate other proinflammatory factors (cytokines, chemokines, growth factors, lipids) that support continued inflammation, keep the vicious cycle going by enabling more HMGB1 release and induce unwanted nerve hyperactivity. Thus, HMGB1 is one of the key mediators of neuroinflammation.
HMGB1 – Role in humans with epilepsy
As reviewed by Aronica and Crino (2011), there are several studies using resected (surgically removed) human epilepsy foci. These specimens clearly show the presence of neuroinflammation. Compared to normal brain tissue, specific inflammation mediators and their receptors are present in large amounts in tissue from epilepsy patients. It is suggested that these distinct changes account for the neuroinflammation and are responsible for promotion of neuronal hyperactivity. In particular, elevated levels of HMGB1and its receptor TLR4 were identified in human epilepsy foci, specifically in proactive astrocytes and microglia (Aronica and Crino, 2011). This positions HMGB1 as one of the key mediators of neuroinflammation.
Biochemical Analysis
More recently, biochemical analysis of brain tissue removed from patients with intractable epilepsy compared to normal tissue showed HMGB1 not only in the nuclei of neurons and glia cells (normal tissue location) but also in the cytoplasm where its release would be expected (Shi et al., 2018). HMGB1, its two receptors (TLR4, RAGE) were significantly elevated in tissue from epilepsy patients compared to normal controls (Shi et al., 2018).
Activated and possibly damaged brain cells release HMGB1 in epileptic regions and, therefore, it should be detectable in serum. Indeed, three studies reported elevated HMGB1 levels in children with epilepsy (Zhu et al., 2018), adults with drug resistant epilepsy (Walker et al., 2022) and case-control study of 105 epilepsy patients compared to 100 healthy controls (Kan et al, 2019).
Serum Levels of HMGB1
The insights gained from these studies are important. The first study measured HMGB1 24 hours prior to a seizure. Thus, the high levels of HMGB1 (and other inflammatory mediators) was predictive of seizure onset and frequency in children (Zhu et al., 2018), a prognostic benefit. In the second study, drug-resistant epilepsy patients showed higher HMGB1 levels compared to those controlled with drugs and normal controls. This suggests a possible screening tool to identify those resistant to standard drugs, all of which dampen ion channels and have no effect on neuroinflammation (Walker et al, 2022).
Significant Human Study
The third study found that the levels of HMGB1 and TLR4 were higher in patients with more than 3 seizure/month and these levels additionally correlated with duration of the seizure of greater than 5 minutes. HMGB1 levels were independent of the type of seizure (partial, general) or length of the disease (Kan et al., 2019). These are important findings but are correlative. Additional studies such as long term clinical trials are required to establish cause-and-effect.
Conclusions
Clearly there is a need for validated and precise diagnostic tools to promptly and correctly identify the beginning stage and progression of epilepsy. Misdiagnosis or delayed diagnosis prove fatal. The neuroinflammatory mediator, HMGB1, is a reasonable diagnostic and prognostic candidate since it is one of the key mediators of neuroinflammation. Initial stages of epilepsy exhibit higher levels of HMGB1 and serum levels correlate with onset, frequency and duration of epilepsy in humans. However, the information at present, although promising, is limited and requires more studies, better assays to detect all forms of HMGB1 and definitely a serious research effort with a large clinical trial.
References (http://Pubmed)
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