Dataset Information

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

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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC4965401 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Wang Yi Y Ying Xiaoying X Chen Liying L Liu Yao Y Wang Ying Y Liang Jiao J Xu Cenglin C Guo Yi Y Wang Shuang S Hu Weiwei W Du Yongzhong Y Chen Zhong Z

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20160701 3

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 ...[more]

PMID: 27137202

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Project description:Partial seizures produce increased cerebral blood flow in the region of seizure onset. These regional cerebral blood flow increases can be detected by single photon emission computed tomography (ictal SPECT), providing a useful clinical tool for seizure localization. However, when partial seizures secondarily generalize, there are often questions of interpretation since propagation of seizures could produce ambiguous results. Ictal SPECT from secondarily generalized seizures has not been thoroughly investigated. We analysed ictal SPECT from 59 secondarily generalized tonic-clonic seizures obtained during epilepsy surgery evaluation in 53 patients. Ictal versus baseline interictal SPECT difference analysis was performed using ISAS (http://spect.yale.edu). SPECT injection times were classified based on video/EEG review as either pre-generalization, during generalization or in the immediate post-ictal period. We found that in the pre-generalization and generalization phases, ictal SPECT showed significantly more regions of cerebral blood flow increases than in partial seizures without secondary generalization. This made identification of a single unambiguous region of seizure onset impossible 50% of the time with ictal SPECT in secondarily generalized seizures. However, cerebral blood flow increases on ictal SPECT correctly identified the hemisphere (left versus right) of seizure onset in 84% of cases. In addition, when a single unambiguous region of cerebral blood flow increase was seen on ictal SPECT, this was the correct localization 80% of the time. In agreement with findings from partial seizures without secondary generalization, cerebral blood flow increases in the post-ictal period and cerebral blood flow decreases during or following seizures were not useful for localizing seizure onset. Interestingly, however, cerebral blood flow hypoperfusion during the generalization phase (but not pre-generalization) was greater on the side opposite to seizure onset in 90% of patients. These findings suggest that, with appropriate cautious interpretation, ictal SPECT in secondarily generalized seizures can help localize the region of seizure onset.

Project description:Generalized tonic-clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the 'default mode' regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic-clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic-clonic seizures. Understanding the networks involved in generalized tonic-clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.

Dataset Information

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

Publications

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

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