A safe and effective therapy for epilepsy requires a drug delivery system that can penetrate the blood-brain barrier and subsequently release antiepileptic drugs rapidly to suppress neuronal discharges in a timely manner. We have developed electro-responsive hydrogel nanoparticles (ERHNPs) modified with angiopep-2 (ANG) to facilitate the delivery of the antiepileptic drug phenytoin sodium. The resulting ANG-ERHNPs had an average diameter of (102.3±16.8) nm and were electro-sensitive with regard to particle size and drug release in vitro. ANG-ERHNPs have the characteristics of penetrate the BBB easily, resulting in a higher distribution in the central system. The improved antiepileptic effects were investigated with the amygdala kindling model. The results demonstrate that the ANG-ERHNPs were able to transport antiepileptic drugs into the brain and release them under electroencephalograph epileptiform abnormalities to greatly improve the therapeutic index of existing drugs in clinical use.

A safe and effective therapy for epilepsy requires a drug delivery system that can penetrate the blood-brain barrier and subsequently release antiepileptic drugs rapidly to suppress neuronal discharges in a timely manner. We have developed electro-responsive hydrogel nanoparticles (ERHNPs) modified with angiopep-2 (ANG) to facilitate the delivery of the antiepileptic drug phenytoin sodium. The resulting ANG-ERHNPs had an average diameter of (102.3 AE 16.8) nm and were electro-sensitive with regard to particle size and drug release in vitro. ANG-ERHNPs have the characteristics of penetrate the BBB easily, resulting in a higher distribution in the central system. The improved antiepileptic effects were investigated with the amygdala kindling model. The results demonstrate that the ANG-ERHNPs were able to transport antiepileptic drugs into the brain and release them under electroencephalograph epileptiform abnormalities to greatly improve the therapeutic index of existing drugs in clinical use.

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Introduction: The upregulation of Nav1.8 in primary afferents plays a critical role in the development and persistence of neuropathic pain. The mechanisms underlying the upregulation are not fully understood. Aims: The present study aims to investigate the regulatory effect of histamine on the expression of Nav1.8 in primary afferent neurons and its involvement in neuropathic pain. Results: Histamine at 10 À8 M increased the expression of Nav1.8 in cultured DRG neurons. This effect could be blocked by H 2 receptor antagonist cimetidine or famotidine, but not by H 1 receptor antagonist pyrilamine or dual H 3 /H 4 antagonist thioperamide. Peri-sciatic administration of histamine increased Nav1.8 expression in the sciatic nerve and L4/L5 DRG neurons in a dose-dependent manner, accompanied with remarkable mechanical allodynia and heat hyperalgesia in the ipsilateral hindpaw. Famotidine but not pyrilamine or thioperamide inhibited Nav1.8 upregulation and pain hypersensitivity. In addition, famotidine (40 mg/kg, i.p.) not only suppressed autotomy behavior in the rat neuroma model of neuropathic pain but also attenuated mechanical allodynia and thermal hyperalgesia following partial sciatic nerve ligation. Moreover, famotidine inhibited Nav1.8 upregulation in the neuroma and ligated sciatic nerve. Conclusions: Our findings indicate that histamine increases Nav1.8 expression in primary afferent neurons via H 2 receptor-mediated pathway and thereby contributes to neuropathic pain. H 2 receptor antagonists may potentially be used as analgesics for patients with neuropathic pain.