Nabyta oporność na leki przeciwpadaczkowe w padaczce skroniowej jest spowodowana nadpobudliwością podstruktury hipokampu związaną z kanałami sodowymi Na1.6
Acquired pharmacoresistance in temporal lobe epilepsy is driven by Na1.6-mediated subicular hyperexcitability
W skrócie
Badacze odkryli, dlaczego niektórzy pacjenci z padaczką skroniową tracą wrażliwość na leki przeciwpadaczkowe mimo że wcześniej działały. Okazało się, że długotrwałe leczenie prowadzi do zwiększenia liczby specjalnych kanałów sodowych (Na1.6) w określonym obszarze mózgu, co powoduje nadmierną aktywność neuronów i odporność na działanie leków. Wyłączenie tych kanałów przywracało wrażliwość na leki, co daje nadzieję na nowe sposoby leczenia opornych postaci padaczki.
Oryginalny abstract (angielski)
Pharmacoresistance to anti-seizure medications (ASMs) remains a major unmet challenge in temporal lobe epilepsy (TLE), and occurs diversely, as classified to primary or acquired manner. The pathophysiological underpinnings of acquired pharmacoresistance remain elusive. Here, using a hippocampal kindling mouse model, we established that prolonged lamotrigine (LTG) treatment-either during or after kindling-induces broad-spectrum resistance to multiple ASMs, effectively recapitulating clinical patterns of acquired pharmacoresistance. Multimodal interrogation revealed hyperexcitability of subicular pyramidal neurons as a critical factor in pharmacoresistance, characterized by elevated c-Fos expression specifically within the subiculum, as well as hyperexcitability of subicular glutamatergic pyramidal neurons. This hyperexcitability phenotype stemmed from Na1.6 upregulation, driving both enhanced persistent sodium current (I) and a pro-excitatory shift in voltage-dependent activation kinetics of voltage-gated sodium channel (VGSC). Crucially, pharmacological activation of subicular Na1.6 sufficed to induce acquired pharmacoresistance in pharmaco-responsive mice. Conversely, subiculum-specific Na1.6 knockdown in pyramidal neurons (but not GABAergic neurons) prevented or reversed pharmacoresistance, while analogous genetic manipulation in the CA1 had no such impact. Chemogenetic inhibition of subicular pyramidal neurons (mimicking ASM effects) restored drug responsiveness, directly implicating compensatory increases in Na1.6 offsetting ASM's inhibitory function on subicular excitability in acquired pharmacoresistance. These findings collectively identify Na1.6 upregulation in subicular pyramidal neurons as a critical driver of acquired pharmacoresistance in TLE, highlighting a novel therapeutic target for refractory epilepsy.