Yage Sun,Xinrui Zhao,Rong Yang,Meng Xiao,Wenguang Liu
Anti-epilepsy drugs (AEDs), a common therapeutic approach for clinically treating epilepsy, suffer from low permeability toward the blood-brain barrier (BBB), side effect risks, and a failure to regulate the pathological microenvironment. These issues hinder the complete control of epilepsy and lead to a vicious cycle of inflammation-epileptogenesis. Herein, an α-lipoic acid (LA)-based nanozyme that loads phenytoin (PHT) and complexes calcium ions (LA@PHT-Ca 2+ ) is developed. This nanozyme combines the functions of delivering AEDs across the BBB and regulating undesirable microenvironments to treat epilepsy. Amphipathic LA self-assembles into stable nanoparticles in water with BBB crossing ability endowed by the transporting of LA through sodium-dependent multivitamin transporter. LA's enzyme-like and redox functions provide LA@PHT-Ca 2+ with excellent scavenging effects on several free radicals via cascade reactions, thereby protecting neurons from oxidative stress. Moreover, Ca 2+ disrupts neuronal respiration, resulting in reduced production of bioenergetic adenosine triphosphate and an improved hypoxic microenvironment. This leads to decreased expression of P-glycoprotein, a drug-efflux gating protein. This novel lipoic acid-based nanozyme, with intrinsic BBB crossing capability, prolonged intracellular drug retention time, and the ability to block the inflammation-epileptogenesis cycle, presents a satisfactory therapeutic effect in epileptic rats, resulting in attenuated symptoms and an improved microenvironment.
Shuo Li,Alhamdu Adamu,Yucai Ye,Fankai Gao,Rulin Mi,Guofang Xue,Zhaojun Wang
Objective: To investigate the effect of (+)-borneol on neuroinflammation and microglia phenotype polarization in epileptogenesis and its possible mechanism.Methods: Based on mouse models of status epilepticus (SE) induced by pilocarpine, and treated with 15 mg/kg (+)-borneol, western-blot was used to detect the expressions of NeuN, Iba-1, TLR4, p65 and p-p65 in the hippocampus. Immunofluorescence was used to detect the expression of apoptosis-related proteins Bax and Bcl-2. To explore the effect of (+)-borneol on microglia in vitro, we used the kainic acid-induced microglia model and the concentration of (+)-borneol was 25 μM according to CCK-8 results. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-10 (IL-10) in the supernatant of each group was detected by ELISA. The nitric oxide (NO) content in the supernatant was detected by Griess method. The expressions of Iba-1 and TLR4-NFκB signaling pathway-related proteins (TLR4, p65, p-p65) were detected by Western-Blot. Immunofluorescence was used to detect microglia’s M1 and M2 phenotype polarization and the expression of Iba-1 and TLR4.Results: (+)-borneol reduced hippocampal neuronal injury, apoptosis, and microglia activation by inhibiting the TLR-NFκB signaling pathway in SE mice. TLR4 agonist LPS partially reversed the neuroprotective effect of (+)-borneol. In the KA-induced microglia model, (+)-borneol inhibited microglia activation, M1 phenotype polarization, and secretion of pro-inflammatory cytokines through the TLR4-NFκB signaling pathway. LPS treatment inhibited the therapeutic effects of (+)-borneol.Conclusion: (+)-borneol inhibits microglial neuroinflammation and M1 phenotype polarization through TLR4-NFκB signaling pathway and reduces neuronal damage and apoptosis in SE mice. Therefore, (+)-borneol may be a potential drug for epilepsy modification therapy.
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