Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

Abstract

Summary The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%‐70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood‐brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post–status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK‐STAT3, IL‐1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

“…Although TLR4 is expressed in neurons, TLR4 modulation of NMDAR‐dependent calcium entry was found to involve astroglial purinergic signaling or generation of the proinflammatory cytokine tumor necrosis factor α (TNFα) . Accordingly, glial signaling has been proposed to underlie the neurophysiological effects of TLR4 . Our demonstration that TLR4 activity modulates neuronal CP‐AMPAR currents, independent of glia, identifies a novel mechanism by which TLR4 promotes excitotoxic damage and epileptogenesis independent of inflammatory signaling.…”

“…There is growing evidence for interactions between inflammatory signaling and neuronal physiology in the normal brain and in disease . Brain injury and seizures lead to increases in endogenous damage‐associated molecular patterns (DAMPs), such as HMGB1, which can activate pattern‐recognition receptors, including TLR4 .…”

“…Although early increases in dentate excitability after brain injury have been proposed to contribute to epileptogenesis, a convincing demonstration of a causal association has been lacking. We recently showed that suppressing post‐traumatic increases in neurogenesis reduced dentate excitability and epileptogenesis in parallel, supporting the association between excitability and epileptogenesis .…”

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

“…IL‐1R type 1 (IL‐1R1) and TLR4, and their prototypical endogenous ligands (i.e., the pro‐inflammatory cytokine IL‐1β and the danger signal High Mobility Group Box 1 [HMGB1], respectively) are induced in neuronal and glial cells following various epileptogenic injuries in rodents—such as, status epilepticus (SE), stroke, neurotrauma, and CNS infection—as well as during seizures . In particular, the IL‐1R1‐TLR4 axis is rapidly and persistently activated in rodent models of SE‐induced epileptogenesis in brain areas involved in seizure generation and propagation .…”

Transient use of a systemic adenosine kinase inhibitor attenuates epilepsy development in mice

“…A significant proportion of epilepsies that emerge in the adult population are acquired, that is, caused by a precipitating injury, which can be as diverse as traumatic brain injury, febrile seizure, status epilepticus, or brain infection. Strikingly, diverse insults trigger common inflammatory responses entailing microglial and astroglial activation, which contribute to the development of epilepsy . Astroglial activation is associated with overexpression of the adenosine‐regulating enzyme adenosine kinase (ADK), which is linked to epileptogenesis and is a target for novel antiepileptogenic therapies.…”