Authors
Leonor Ribeiro-Rodrigues, Inga Griškova-Bulanova, Maria José Diógenes, Sara Xapelli
Published in
Pharmacological research. Pages 109702. Oct 25, 2026. Epub Oct 25, 2026.
Abstract
Despite the efficacy of current antiseizure medications in managing seizures, approximately one-third of patients develop refractory epilepsy, highlighting an urgent need to uncover the molecular mechanisms driving epileptogenesis. This process emerges from a complex interplay of molecular alterations, involving changes in neuronal signaling pathways. Among these, brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, the full-length tropomyosin receptor kinase B (TrkB-FL), are heavily implicated in epilepsy pathophysiology. While traditionally recognized for promoting synaptic plasticity, BDNF signaling can become maladaptive in pathological states. Consequently, BDNF exhibits a paradoxical dual role in epilepsy, acting as a proepileptogenic factor in the acute phase, while exerting antiepileptic effects during the chronic phase. Recently, a calpain-dependent proteolytic mechanism mediating TrkB-FL cleavage, previously described in Alzheimer's disease (AD) and cerebral ischemia, has been shown to occur during epileptogenesis. Elevated levels of the intracellular cleavage product of TrkB-FL, TrkB-ICD, have been observed in the hippocampus of patients with refractory epilepsy, establishing its clinical relevance. In vitro, TrkB-ICD overexpression depolarizes neuronal membranes, increases miniature excitatory postsynaptic current frequency, and alters the transcription of genes related to synaptic transmission and plasticity. In vivo, its overexpression induces long-term memory impairment, a common comorbidity in epilepsy. Moreover, in experimental epilepsy models, TrkB-ICD protein levels correlate with seizure frequency during the acute phase (status epilepticus) and remain elevated during the chronic phase (established epilepsy). These findings highlight TrkB-FL cleavage and TrkB-ICD formation as molecular determinants in epileptogenesis, providing a biological rationale for the contrasting effects of BDNF. Inhibiting this cleavage, using tools like cell-penetrating peptides, represents a promising therapeutic avenue. As the field moves forward, elucidating the precise functions, regulation, and translational potential of the TrkB-FL proteolysis and TrkB-ICD formation may yield innovative, disease-modifying strategies for epilepsy, moving beyond the symptomatic suppression offered by conventional antiseizure drugs.
PMID:
42927808
Bibliographic data and abstract were imported from PubMed on 26 Oct 2026.
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