Akademik Veri Yönetim Sistemi
Neuropharmacology, cilt.294, 2026 (SCI-Expanded, Scopus)
The proBDNF/p75 neurotrophin receptor (p75NTR) signaling pathway has been implicated in neuronal hyperexcitability, synaptic remodeling, and neuroinflammation during epileptogenesis. We investigated whether pharmacological modulation of p75NTR with the small-molecule ligand LM11A-31 attenuates seizure progression and network dysfunction, defined as increased ECoG power and RMS amplitude reflecting enhanced neuronal synchronization and hyperexcitability in a pentylenetetrazole (PTZ) kindling model. Male C57BL/6 mice were subjected to alternate-day PTZ injections (35 mg/kg, i.p.) for a total of eight injections to induce kindling. LM11A-31 (50 mg/kg, i.p.) treatment was initiated 7 days prior to the first PTZ injection and continued throughout the experimental period. Mice were divided into four groups: control (C, n = 10), LM11A-31 (L, n = 10), PTZ (P, n = 9), and PTZ + LM11A-31 (P + L, n = 9). Seizure severity was assessed using Racine scoring and cumulative seizure burden (AUC). Cortical electrocorticography (ECoG) recordings were performed to evaluate mean power and RMS amplitude. Synaptic proteins (PSD-95, synaptophysin), inflammatory markers (TNF-α, IL-6), and oxidative stress indices (TAS, TOS, TBARS) were quantified in cortical and hippocampal tissues. LM11A-31 significantly attenuated the progression of PTZ-induced seizure severity and reduced cumulative seizure burden compared with PTZ alone. PTZ kindling markedly increased cortical ECoG power and RMS amplitude, reflecting enhanced network hyperexcitability; these changes were significantly normalized by LM11A-31. PTZ induced substantial reductions in PSD-95 and synaptophysin levels in both cortex and hippocampus, which were restored by LM11A-31 treatment. TNF-α levels were robustly elevated following PTZ administration and were significantly reduced by LM11A-31, whereas IL-6 remained unchanged. In parallel, LM11A-31 partially restored antioxidant capacity and reduced oxidant load and lipid peroxidation. Pharmacological modulation of p75NTR signaling with LM11A-31 suppresses seizure progression and mitigates electrophysiological, synaptic, inflammatory, and oxidative alterations associated with PTZ kindling.