Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role in a range of neurological disorders, such as neurodegenerative diseases, spinal cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently, VPA has been reported to exert neurotrophic effects and promote neurite outgrowth, but its molecular mechanism is still unclear. In the present study, we investigated whether VPA inhibited ER stress and promoted neuroprotection and neuronal restoration in SH-SY5Y cells and in primary rat cortical neurons, respectively, upon exposure to thapsigargin (TG). In SH-SY5Y cells, cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and the expression of ER stress-related apoptotic proteins such as glucose‑regulated protein (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase-12/-3 were analyzed with Western blot analyses and immunofluorescence assays. To explore the pathway involved in VPA-induced cell proliferation, we also examined p-AKT, GSK3β, p-JNK and MMP-9. Moreover, to detect the effect of VPA in primary cortical neurons, immunofluorescence staining of β-III tubulin and Anti-NeuN was analyzed in primary cultured neurons exposed to TG. Our results demonstrated that VPA administration improved cell viability in cells exposed to TG. In addition, VPA increased the levels of GRP78 and p-AKT and decreased the levels of ATF6, XBP-1, GSK3β, p-JNK and MMP-9. Furthermore, the levels of the ER stress-induced apoptosis response proteins CHOP, cleaved caspase-12 and cleaved caspase-3 were inhibited by VPA treatment. Meanwhile, VPA administration also increased the ratio of Bcl-2/Bax. Moreover, VPA can maintain neurite outgrowth of primary cortical neurons. Collectively, the neurotrophic effect of VPA is related to the inhibition of ER stress-induced apoptosis in SH-SY5Y cells and the maintenance of neuronal growth. Collectively, our results suggested a new approach for the therapeutic function of VPA in neurological disorders and neuroprotection.

Spinal cord injury (SCI) is a severe nervous system disease that may lead to lifelong disability. Studies have shown that autophagy plays a key role in various diseases; however, the mechanisms regulating crosstalk between autophagy, inflammation and endoplasmic reticulum (ER) stress during SCI recovery remain unclear. This study was designed to investigate the mechanism by which chloroquine (CQ) inhibits autophagy-associated inflammation and ER-stress in rats during their recovery from acute SCI. We evaluated the locomotor function, level of autophagy, and levels of inflammatory cytokines and ER-stress associated proteins and examined the degradation of the key regulator of inflammation I-κBα through autophagy by analyzing the colocalization of I-κBα, p62 and LC3-II. In addition, overexpression of the p62 and ATF4 silencing plasmids was used to verify the important roles for autophagic degradation and ER-stress. In this study, locomotor function is improved, and autophagy and inflammation are significantly inhibited by CQ treatment in the model rats. In addition, CQ significantly inhibits the degradation of ubiquitinated I-κBα and blocks the nuclear translocation of NF-κB p65 and expression of inflammatory factors. Overexpression of p62 increases I-κB degradation and improves inflammatory responses. Moreover, CQ treatment also inhibits the activation of ER-stress in the rat SCI model, and the ATF4 signaling pathway is required for ER-stress induced activation of autophagy. These findings reveal a novel mechanism underlying the beneficial effects of CQ on the recovery of SCI, particularly the mechanisms regulating crosstalk between autophagy, inflammation and ER-stress.

Spinal cord injury (SCI) is significantly hampered by an inflammatory microenvironment, prompting continued efforts in drug development to address inflammation. Research shows that quercetin (Que) exhibits excellent performance in reducing inflammation and neuroprotection. However, its application is limited by poor solubility, notable side effects, and the unique pathophysiology of the spinal cord. In this study, we introduce a novel multifunctional liposome hydrogel drug delivery system (QLipTC@HDM), obtained by incorporating liposomes with blood-spinal cord barrier penetration and injury site targeting properties (LipTC) into a dual-network viscous hydrogel (HDM). Our results demonstrate that encapsulating Que in LipTC (QLipTC) enhances solubility, minimizes toxic side effects, facilitates lesion targeting, and aids in crossing the blood-spinal cord barrier. Moreover, encapsulation in HDM significantly prolongs the retention of QLipTC at the injury site after local administration. Crucially, our findings reveal that QLipTC@HDM induces M2 phenotype transformation in glial cells and in mice with SCI, thereby mitigating inflammation. This intervention additionally preserves the integrity of the blood-spinal cord barrier, optimizes the spinal cord microenvironment, reduces glial scarring, promotes axonal regeneration, and enhances motor function recovery in SCI mice. In summary, our investigations highlight the potential of this disease-specific drug delivery system as a promising therapeutic approach for the treatment and management of SCI.