摘要Pharmacoresistance remains intractable in epilepsy,necessitating in-depth mechanism investigations.Cumulative data have pointed to active neuroinflammation in pharmacoresistant epilepsy,but the process between neuroinflammation and pharmacoresistance remains unknown.In this study we investigated how severe neuroinflammation altered anti-seizure drugs(ASMs)pharmacology.Hippocampal kindling or kainic acid-induced temporal lobe epilepsy(TLE)models were established in mice that had received intra-hippocampal LPS injection.Acute hippocampal slices were prepared;current-clamp recording was made in hippocampal pyramidal neurons to assess the impact of ASMs on neuronal excitability and sodium channels.We showed that intra-hippocampal LPS injection resulted in higher inflammatory cytokine levels in the hippocampus.LPS induced-neuroinflammation significantly decreased the antiseizure efficacy of phenytoin(PHT),carbamazepine(CBZ)and rufinamide(RUF),all the ASMs tested were unable to alleviate the seizure severities.We observed the"off-target"phenomena of ASMs,i.e.ASMs' loss of ability to suppress the firing of action potentials and the amplitudes of sodium currents in hippocampal pyramidal neurons from LPS-treated mice.We demonstrated that LPS induced-neuroinflammation promoted the degradation of spermine,an essential polyamine linked with ASM performance on sodium channels,through upregulating the catabolic enzyme spermidine/spermine N(1)-acetyltransferase(SSAT).Intra-hippocampal injection of SSAT agonist DENSPM mimicked LPS-induced"off-target"phenomena of ASMs,whereas injection of SSAT antagonist diminazene aceturate into hippocampus reversed the"off-target"phenomenon of ASMs in LPS-treated mice.Finally,intrahippocampal injection of spermine restored the efficacy of ASMs on action potential firings and sodium currents,resulting in the reversal of pharmacoresistance in LPS-treated TLE models.These results provide new evidence that neuroinflammation causes pharmacoresistance in TLE via promoting spermine degradation,and highlight spermine supplementation as a promising therapy for pharmacoresistant TLE.