Pharmacol Res. 2026 Oct 25:109702. doi: 10.1016/j.phrs.2026.109702. Online ahead of print.
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 | DOI:10.1016/j.phrs.2026.109702