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. 2016 Jul;13(3):603-13.
doi: 10.1007/s13311-016-0431-9.

Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures

Yi Wang  1 , Xiaoying Ying  1   2 , Liying Chen  1 , Yao Liu  1 , Ying Wang  1 , Jiao Liang  1 , Cenglin Xu  1 , Yi Guo  3 , Shuang Wang  3 , Weiwei Hu  1 , Yongzhong Du  2 , Zhong Chen  4   5   6
Affiliations

Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures

Yi Wang et al. Neurotherapeutics. 2016 Jul.

Abstract

Previously, we developed electroresponsive hydrogel nanoparticles (ERHNPs) modified with angiopep-2 (ANG) to facilitate the delivery of the antiseizure drug phenytoin sodium (PHT). However, the electroresponsive characteristics were not verified directly in epileptic mice and the optimal preparation formula for electroresponsive ability is still unclear. Here, we further synthesized PHT-loaded ANG-ERHNPs (ANG-PHT-HNPs) and PHT-loaded nonelectroresponsive hydrogel nanoparticles (ANG-PHT-HNPs) by changing the content of sodium 4-vinylbenzene sulfonate in the preparation formulae. In vivo microdialysis analysis showed that ANG-PHT-ERHNPs not only have the characteristics of a higher distribution in the central nervous system, but also have electroresponsive ability, which resulted in a strong release of nonprotein-bound PHT during seizures. In both electrical- (maximal electrical shock) and chemical-induced (pentylenetetrazole and pilocarpine) seizure models, ANG-PHT-ERHNPs lowered the effective therapeutic doses of PHT and demonstrated the improved antiseizure effects compared with ANG-PHT-HNPs or PHT solution. These results demonstrate that ANG-ERHNPs are able to transport PHT into the brain efficiently and release them when epileptiform activity occurred, which is due to the content of sodium 4-vinylbenzene sulfonate in formula. This may change the therapeutic paradigm of existing drug treatment for epilepsy into a type of on-demand control for epilepsy in the future.

Keywords: Electroresponsive; Epilepsy; Microdialysis; Nanoparticle; Sodium 4-vinylbenzene sulfonate.

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Figures

Fig. 1
Fig. 1
The in vitro electroresponsive behavior of the nanoparticles with regard to diameter and drug release. (a) The effect of sodium 4-vinylbenzene sulfonate (NaSS) content on the original particle size and electroresponsive behavior, which was measured as fold increase in diameter of nanoparticles under a 100-μA electric field (n = 3); (b) the diameter of the angiopep-2 hydrogel nanoparticles (ANG-HNPs) and ANG electroresponsive HNP (ANG-ERHNP) after the application of different currents for 10 min (**p < 0.01, ***p < 0.001, t-test); (c) the diameter of the ANG-HNPs and ANG-ERHNPs after the application of 100 μA current for different times (***p < 0.001, t-test); (d) phenytoin sodium (PHT) released from ANG-PHT-HNPs and ANG-PHT-ERHNPs with or without an external 100-μA electric field for 4 h (*p < 0.05, **p < 0.01) compared with first group, 1-way ANOVA with post-hoc fishers least significant difference (LSD) test
Fig. 2
Fig. 2
The in vivo antiepileptic effect of the nanoparticles in the maximal electroshock (MES) model. (a) Design of experiment and seizure scores in the MES model; (b-d) the effect of nanoparticles at different doses on seizures stage (b), incidence of tonic seizures (c), and tonic seizure duration (d); the number of rats used in the experiment is indicated in column B (*p < 0.05, **p < 0.01, ***p < 0.001 compared with the first group, # p < 0.05 compared with groups with the same dose; χ2 tests were used to compare the incidence of tonic seizures; Kruskal-Wallis ANOVA followed by post-hoc Dunn’s tests were used to compare seizure stage, and 1-way ANOVA followed by post-hoc fishers least significant difference (LSD) tests were used to compare tonic seizure duration) PHT = phenytoin sodium; ANG = angiopep-2; HNP = hydrogel nanoparticles; ERHNP = electroresponsive HNP
Fig. 3
Fig. 3
The in vivo antiepileptic effect of the nanoparticles in the pentylenetetrazole (PTZ) model. (a) Design of experiment; (b-e) the effect of nanoparticles at different doses on seizures stage (b), incidence of generalized seizures (GS) (c), latency to GS (d), and latency to nonconvulsive seizure (e). The number of rats used in the experiment is indicated in the column of B (*p < 0.05, **p < 0.01, ***p < 0.001 compared with the first group; # p < 0.05 compared with groups with same dose; the χ2 tests were used to compare the incidence of GS, Kruskal-Wallis ANOVA followed by post-hoc Dunn’s tests were used to compare seizure stage; and 1-way ANOVA followed by a post-hoc fishers least significant difference (LSD) test were used to compare latency to GS and nonconvulsive seizure PHT = phenytoin sodium; ANG = angiopep-2; HNP = hydrogel nanoparticles; ERHNP = electroresponsive HNP; EEG = electroencephalography
Fig. 4
Fig. 4
Representative electroencephalographies (EEGs) during pentylenetetrazole (PTZ)-induced seizures. (a) Representative EEGs recorded from the hippocampus of rats and corresponding power spectral analysis during PTZ-induced seizures when rats were injected with saline, phenytoin sodium (PHT) solution, angiopep-2 (ANG)-PHT-hydrogel nanoparticles (HNPs) or ANG-PHT-electroresponsive HNPs (ERHNPs) (20 mg/kg); arrow, PTZ injection time; grey triangle, the initial time of nonconvulsive seizure onset; black triangle, the initial time of generalized seizure onset; right panel, enlarged views of boxes in the EEGs. (b) Spectrum analysis of the EEG
Fig. 5
Fig. 5
The in vivo antiepileptic effect of the nanoparticles in pilocarpine model. (a) Design of experiment; (b-e) the effect of nanoparticles at different doses on seizures stage (d), incidence of death (e), latency to generalized seizure (GS) (f), and latency to status epilepticus (SE) (g); the number of rats used in the experiment is indicated in the column of B (*p < 0.05, ** p < 0.01 compared with first group; # p < 0.05, ## p < 0.01 compared with groups with same dose; χ2 tests were used to compare the incidence of death; Kruskal-Wallis ANOVA followed by post-hoc Dunn’s tests were used to compare seizure stage; and 1-way ANOVA followed by a post-hoc fishers least significant difference (LSD) test were used to compare latency to GS and SE PHT = phenytoin sodium; ANG = angiopep-2; HNP = hydrogel nanoparticles; ERHNP = electroresponsive HNP; EEG = electroencephalography
Fig. 6
Fig. 6
The in vivo electroresponsive release of phenytoin sodium (PHT) from nanoparticles during seizures. (a) Design of the microdialysis experiment (n = 6 for each group); (b) PHT time profiles in brain dialysate of naïve rat after an intraperitoneal injection of PHT at a dose of 20 mg/kg; (c) statistics of area under the curve (AUC) in (b) (*p < 0.05, compared with the first group; 1-way ANOVA followed by post-hoc LSD tests); (d) PHT time profiles in brain dialysate of epileptic rat after an intraperitoneal injection of PHT at a dose of 20 mg/kg; (e) free PHT concentration in brain dialysate before and 0.5 h after PTZ-induced seizures; (***p < 0.001, paired t-test); (f) statistics of AUC in (d) (*p < 0.05, **p < 0.01 compared with first group, 1-way ANOVA followed by post-hoc fishers least significant difference (LSD) tests) PTZ = pentylenetetrazole; ANG = angiopep-2; HNP = hydrogel nanoparticles; ERHNP = electroresponsive HNP; EEG = electroencephalography
Fig. 7
Fig. 7
The in vivo electroresponsive release of phenytoin sodium PHT from nanoparticles during seizures with different intensity. (a) Representative electroencephalographies (EEGs) recorded from the hippocampus of rats during seizures induced by pentylenetetrazole (PTZ) at different doses; (b) PHT time profiles in brain dialysate of epileptic rats with different seizure intensity; (c) free PHT concentration in brain dialysate before and 0.5 h after seizures with different intensity (**p < 0.01, ***p < 0.001, paired t-test, ## p < 0.01 t-test)
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