Therapeutic strategies to restore network stability in epilepsy.
| Therapeutic logic | Main target/mechanism | What it aims to stabilize | Potential strengths | Key limitations/challenges | Translational status |
|---|---|---|---|---|---|
| Restoring inhibitory balance | Enhancement of GABAergic signaling, strengthening inhibitory restraint, improving receptor-mediated inhibition, increasing synaptic inhibitory tone | Excitation–inhibition balance, seizure threshold, circuit containment of abnormal firing | Conceptually directed, clinically familiar, and often effective for acute seizure control or symptomatic suppression | May not correct upstream glial, inflammatory, calcium-linked, or remodeling mechanisms; efficacy can vary across syndromes and chronic stages; tolerance or incomplete disease modification may limit long-term impact | Established clinical strategy for seizure control, but often insufficient alone for durable modification of epileptogenic instability [41, 252] |
| Modulating astrocyte dysfunction | Improving potassium buffering, glutamate uptake, water regulation, metabolic support, and limiting maladaptive astrocyte reactivity | Extracellular homeostasis, neurotransmitter balance, ionic stability, propagation permissiveness, recovery capacity | Mechanistically attractive because astrocytes regulate the extracellular conditions that directly shape excitability and seizure spread | Therapeutic targeting remains biologically complex; astrocyte responses are context dependent; restoring homeostatic function without disrupting adaptive support is challenging | Emerging and largely preclinical/translational, with strong conceptual rationale but limited clinical implementation [14, 83, 234] |
| Modulating microglial dysfunction | Limiting maladaptive inflammatory activation, altering cytokine release, reducing harmful synaptic remodeling, and reshaping context-dependent microglial responses | Inflammatory amplification, maladaptive synaptic/environmental signaling, chronic seizure-prone tissue states | May interrupt feedback loops between tissue stress, immune signaling, glial activation, and progressive destabilization | Microglia can be protective, maladaptive, or mixed depending on timing and context; indiscriminate suppression may be counterproductive | Emerging and mechanistically promising, but still limited by context specificity and incomplete translational precision [241, 243] |
| Targeting calcium/intracellular stress | Reducing pathological calcium overload, modulating intracellular calcium store signaling, limiting calcium-dependent stress cascades and endoplasmic reticulum stress coupling | Cellular stress burden, excitability-linked injury signaling, maladaptive plasticity, calcium-driven propagation of instability | Attractive because calcium links neurons, glia, inflammatory signaling, and remodeling across multiple timescales | Calcium signaling is essential to normal physiology, so therapeutic selectivity is difficult; dominant calcium sources and effectors may vary across contexts | Early translational and mostly preclinical, with strong mechanistic relevance but limited clinically mature strategies [129, 151] |
| Limiting inflammatory amplification | Targeting cytokine pathways, innate immune signaling, blood–brain barrier-related dysfunction, or persistent inflammatory feedback loops | Seizure threshold, recovery environment, glia-mediated amplification, progression from acute disturbance to chronic instability | May be especially valuable in contexts where inflammation helps drive epileptogenic transition or chronic vulnerability | Inflammatory mechanisms are heterogeneous across syndromes and stages; broad immunosuppression may be ineffective or poorly targeted | Translationally active and biologically important, but likely to require more selective mechanism-guided use than generalized anti-inflammatory treatment [241, 243] |
| Network-level/precision approaches | Neuromodulation, biomarker-guided stratification, surgery where appropriate, patient-specific models, systems-guided therapy selection | Large-scale network synchrony, seizure propagation, patient-specific instability architecture, treatment matching | Most aligned with the review’s systems framework because it recognizes epilepsy as heterogeneous and mechanistically layered | Requires reliable biomarkers, better subtype stratification, and integration of mechanistic knowledge with patient-specific decision-making | Already partly established in selected forms, but still evolving toward more precise and mechanism-guided implementation [229, 244, 246] |
MMN: Conceptualization, Writing—original draft, Writing—review & editing. The author read and approved the submitted version.
The author declares that there are no conflicts of interest.
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