Anti-seizure medicines constitute a common yet important modality to treat epilepsy. However, some of them are associated with serious side effects including hepatotoxicity and hypersensitivity. Furthermore, the blood–brain barrier (BBB) is an insurmountable obstacle for brain drug delivery. Fortunately, the introduction of the nanoparticles for drug delivery is a feasible approach to overcome these obstacles. Encapsulating drugs into nanoparticles and delivering them to specific sites shows great potential for improving the efficiency of drug delivery and reducing systemic toxicity. Several in vivo studies have investigated the effect of nanoparticle size on biodistribution in mice, but very few have investigated its effects on efficient drug delivery while crossing the BBB. Therefore, we designed a methoxy poly(lactide-co-glycolide)-b-poly(ethylene glycol) methyl ether (mPEG–PLGA) nanoparticle delivery system and explored the cell uptake efficiency of nanoparticles with different sizes and their ability to penetrate the BBB while carrying carbamazepine (CBZ). CBZ-loaded nanoparticles could significantly reduce the cytotoxicity of CBZ to L929 cells at high concentrations. Results from the endocytosis experiment involving human cerebral microvessel endothelial cell/D3 showed that the DiR-loaded mPEG_5K–PLGA_10K nanoparticles possessed the highest cell uptake efficiency. The endocytosis efficiency was 90% at 30 min, which far exceeded that of the other groups. Moreover, similar results were obtained from subsequent experiments where fluorescence images of the isolated organs of the mice were acquired. To summarize, our study demonstrated that drug delivery to the brain using nanocarriers is size dependent. Nanoparticles with the smallest particle size can be internalized more effectively, and easily penetrate the BBB, and accumulate in the brain.

Aims: Epileptic seizures or status epilepticus (SE) can cause hippocampal neuronal death, which has detrimental effects. Parthanatos, a new form of programmed cell death, is characterized by hyperactivation of poly (ADP‐ribose) polymerase‐1 (PARP‐1), excessive synthesis of poly ADP‐ribose polymer, mitochondrial depolarization, and nuclear translocation of apoptosis‐inducing factor, observed in various neurodegenerative disorders but rarely reported in epilepsy. We aimed to investigate whether parthanatos participates in the mechanism of seizure‐induced hippocampal neuronal death.Methods: Glutamate‐mediated excitotoxicity cell model was used to study the mechanism of seizure‐induced cell injury. Injection of kainic acid into the amygdala was used to establish the epileptic rat model. Corresponding biochemical tests were carried out on hippocampal tissues and HT22 cells following indicated treatments.Results: In vitro, glutamate time‐dependently induced HT22 cell death, accompanied by parthanatos‐related biochemical events. Pretreatment with PJ34 (PARP‐1 inhibitor) or small interfering RNA‐mediated PARP‐1 knockdown effectively protected HT22 cells against glutamate‐induced toxic effects and attenuated parthanatos‐related biochemical events. Application of the antioxidant N‐acetylcysteine (NAC) rescued HT22 cell death and reversed parthanatos‐related biochemical events. In vivo, PJ34 and NAC afforded protection against SE‐induced hippocampal neuronal damage and inhibited parthanatos‐related biochemical events.Conclusion: Parthanatos participates in glutamate‐induced HT22 cell injury and hippocampal neuronal damage in rats following epileptic seizures. ROS might be the initiating factor during parthanatos.

Neuropathic pain (NP) is one of the intractable complications of spinal cord injury (SCI), with poor prognosis and seriously affects the quality of life of patients. This study aims to determine the treatment effect and mechanism of multimodal therapies in a rat model of SCI-induced NP by combining treatment with the anti-inflammatory agent minocycline (MC) and botulinum toxin (BoNT). The combined utilization alleviated SCI-induced NP and reduced apoptosis, inflammation, and oxidative stress of SCI by activating SIRT1 and dampening pAKT, P53, and p-NF-KB. BoNT with a concentration of 0.1 nm and MC with a concentration of 20 uM were selected for the experiment in the primary microglia and astrocytes treated with LPS. It was found that the combination of BoNT and MC obviously inhibits the inflammatory response and oxidative stress of glial cells, and notably activates SIRT1 and restrains pAKT, P53, and p-NF-KB. Therefore, in the treatment of SCI-induced NP, the combination of BoNT and MC markedly improves the therapeutic effect of NP by promoting the SIRT1 expression, thereby inactivating NF-KB, P53, and PI3K/AKT signaling pathway, inhibiting inflammation and oxidative stress as well as relieving SCI-induced NP.

As a chronic brain disease, epilepsy affects ~50 million people worldwide. The traditional antiepileptic drugs (AEDs) are widely applied but showing various problems. Although the new AEDs have partially solved the problems of traditional AEDs, the current clinical application of traditional AEDs are not completely replaced by new drugs, particularly due to the large individual differences in drug plasma concentrations and narrow therapeutic windows among patients. Therefore, it is still clinically important to continue to treat patients using traditional AEDs with individualized therapeutic plans. To date, our understanding of the molecular and genetic mechanisms regulating plasma concentrations of AEDs has advanced rapidly, expanding the knowledge on the effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of AEDs. It is increasingly imperative to summarize and conceptualize the clinical significance of recent studies on individualized therapeutic regimens. In this review, we extensively summarize the critical effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of several commonly used AEDs as well as the clinical significance of testing genotypes related to drug metabolism on individualized drug dosage. Our review provides solid experimental evidence and clinical guidance for the therapeutic applications of these AEDs. Graphical Abstract