Epilepsy is a common neurological condition characterized by abnormal neuronal activity, often leading to cellular damage and death. There is evidence to suggest that lipid imbalances resulting in cellular death play a key role in the development of epilepsy, including changes in triglycerides, cholesterol, sphingolipids, phospholipids, lipid droplets, and bile acids (BAs). Disrupted lipid metabolism acts as a crucial pathological mechanism in epilepsy, potentially linked to processes such as cellular ferroptosis, lipophagy, and immune modulation of gut microbiota (thus influencing the gut-brain axis). Understanding these mechanisms could open up new avenues for epilepsy treatment. This study investigates the association between disturbances in lipid metabolism and the onset of epilepsy.

Spinal cord injury (SCI) is a serious disease characterized by hemorrhage, edema, local ischemia and hypoxia, inflammatory reaction, and degeneration of the injured spinal cord, which lacks effective clinical treatments. We design a PEG-SH-GNPs-SAPNS@miR-29a delivery system to repair impaired spinal cord by building a regenerative microenvironment for the recruitment of endogenous neural stem cells. The miR-29a, as an axonal regeneration-related miRNA that overexpression of miR-29a significantly inhibits the expression of PTEN and promotes axonal regeneration of the injured spinal cord. The gold nanoparticles and self-assembling peptide hydrogel composite scaffold (PEG-SH-GNPs-SAPNS@miR-29a delivery system) applied to deliver miR-29a, which recruit endogenous neural stem cells simultaneously. Sustained release of miR-29a and recruitment of endogenous neural stem cells give rise to favorable axonal regeneration and recovery of motor function after spinal cord injury. These findings suggest that the PEG-SH-GNPs-SAPNS@miR-29a delivery system may be an alternative strategy for the treatment of SCI.

Autophagy is associated with hippocampal injury following status epilepticus (SE) and is considered a potential therapeutic mechanism. Baicalin, an emerging multitherapeutic drug, has shown neuroprotective effects in patients with nervous system diseases due to its antioxidant properties.

To investigate the potential role of autophagy in LiCl-pilocarpine-induced SE.

The drugs were administered 30 min before SE. Nissl staining showed that Baicalin attenuated hippocampal injury and reduced neuronal death in the hippocampus. Western blotting and terminal deoxynucleotidyl transferase dUTP nick end labeling assay confirmed that Baicalin reversed the expression intensity of cleaved caspase-3 and apoptosis in hippocampal CA1 following SE. Fur-thermore, western blotting and immunofluorescence staining were used to measure the expression of autophagy markers (p62/SQSTM1, Beclin 1, and LC3) and apoptotic pathway markers (cleaved caspase-3 and Bcl-2).

Baicalin significantly upregulated autophagic activity and downregulated mitochondrial apoptotic pathway markers. Conversely, 3-methyladenine, a commonly used autophagy inhibitor, was simultaneously administered to inhibit the Baicalin-induced autophagy, abrogating the protective effect of Baicalin on the mitochondrial apoptotic level.

We illustrated that Baicalin-induced activation of autophagy alleviates apoptotic death and protects the hippocampus of SE rats.

Epilepsy can seriously affect children's cognitive and behavioral development. The mechanistic target of rapamycin(mTOR) pathway plays an important role in neurodevelopment and epilepsy, but the mechanism of mechanistic target of rapamycin complex 2 (mTORC2) in epilepsy is still unclear. Here, we compared the similarities and differences of the mechanisms of action of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 complex in the pathogenesis of epilepsy. Our research results show that the levels of apoptosis in cortical and hippocampal neurons were upregulated in epileptic rats (F = 32.15, 30.96; both P < 0.01), and epilepsy caused neuronal damage (F = 8.13, 9.43; both P < 0.01). The mTORC2-Akt pathway was activated in the cortex and hippocampus of epileptic rats. Inhibition of mTORC2 resulted in decreased levels of apoptosis and reduced neuronal damage in the cortex and hippocampus of epileptic rats. In the hippocampus, selective inhibition of mTORC2 increased lysosome-associated membrane protein 2 A (LAMP2A) protein expression compared with the control group, and the difference was statistically significant (F = 3.02, P < 0.05). Finally, we concluded that in the hippocampus, selective inhibition of mTORC2 can improve epileptic brain injury in rats by increasing chaperone-mediated autophagy (CMA) levels.

Post-traumatic epilepsy (PTE) caused by mild TBI (mild traumatic brain injury, mTBI) has a high incidence and poor prognosis, but its mechanisms are unclear. Herein, we investigated the role of reduced levels of neuronal autophagy during the latency period in the increased susceptibility to PTE. In the study, a gentle whole-body mechanical trauma rat model was prepared using Noble-Collip drums, and the extent of injury was observed by cranial CT and HE staining of hippocampal tissue. The incidence of epilepsy and its seizure form were observed 7-90 days after mTBI, and electroencephalography (EEG) was recorded during seizures in rats. Subcortical injection of non-epileptogenic dose of ferrous chloride (FeCl₂) was used to observe the changes of PTE incidence after mTBI. Western blot and Real-time PCR were used to detect the level of autophagy in hippocampal cells at different time points during the latency period of PTE, and its incidence was observed after up-regulation of autophagy after administration of autophagy agonist-rapamycin. The results showed that mTBI was prepared by Noble-Collip drum, which could better simulate the clinical mTBI process. There was no intracerebral hemorrhage and necrosis in rats, no early-onset seizures, and the incidence of PTE after mTBI was 26.7%. The incidence of PTE was 56.7% in rats injected cortically with FeCl₂ at a dose lower than the epileptogenic dose 48 h after mTBI, and the difference was significant compared with no FeCl₂ injection, suggesting an increased susceptibility to PTE after mTBI. Further study of neuronal autophagy during PTE latency revealed that autophagy levels were reduced, and the incidence of PTE was significantly reduced after administration of rapamycin to upregulate autophagy. Taken together, the decreased level of neuronal autophagy during the latency period may be a possible mechanism for the increased susceptibility to PTE after mTBI.

Autism spectrum disorder (ASD) is characterized by stereotyped behavior and deficits in communication and social interaction. There are no curative treatments for children with ASD. The ketogenic diet (KD) is a high-fat, appropriate-protein, and low-carbohydrate diet that mimics the fasting state of the body and is proven beneficial in drug-resistant epilepsy and some other brain diseases. An increasing number of studies demonstrated that a KD improved autistic behavior, but the underlying mechanisms are not known. We reviewed the neuroprotective role of a KD in ASD, which is likely mediated via improvements in energy metabolism, reductions in antioxidative stress levels, control of neurotransmitters, inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, and modulation of the gut microbiota. A KD is likely a safe and effective treatment for ASD.

Potent beneficial immunomodulatory and anti-inflammatory effects of whole-molecule erythropoietin have been demonstrated in a variety of animal disease models including experimental autoimmune encephalomyelitis (EAE); however, excessive hematopoiesis limits its use in clinical applications. Our group previously generated an Epo-derived small peptide JM4 that is side-effect free and has strong neuroprotective activity without hematologic effects. Here, we investigated the long-term clinical effects of brief treatment with JM4 in chronic relapsing EAE using bioluminescence imaging (BLI) in transgenic mice containing the luciferase gene driven by the murine GFAP promoter. EAE mice treated with JM4 exhibited marked improvement in clinical scores and showed fewer disease flareups than control animals. JM4 therapy concomitantly led to markedly decreased GFAP bioluminescence in the brain and spinal cord in both acute and chronic relapsing EAE mouse models. We found a marker for toxic A1 astrocytes, complement component C3, that is upregulated in the brain and cord of EAE mice and sharply reduced in JM4-treated animals. In addition, an abnormally leaky neurovascular unit permeability was rapidly normalized within 5 days by JM4 therapy. The prolonged therapeutic benefit seen following brief JM4 treatment in EAE mice closely resemble that recently described in humans receiving pulsed immune reconstitution therapy with the disease-modifying compounds, alemtuzumab and cladribine. Our study suggests that JM4 therapy may have widespread clinical applicability for long-term treatment of inflammatory demyelinating diseases and that BLI is a useful noninvasive means of monitoring murine disease activity of the central nervous system.

The most important activity of erythropoietin (EPO) is the regulation of erythrocyte production by activation of the erythropoietin receptor (EPO-R), which triggers the activation of anti-apoptotic and proliferative responses of erythroid progenitor cells. Additionally, to erythropoietic EPO activity, an antiapoptotic effect has been described in a wide spectrum of tissues. EPO low levels are found in the central nervous system (CNS), while EPO-R is expressed in most CNS cell types. In spite of EPO-R high levels expressed during the hypoxicischemic brain, insufficient production of endogenous cerebral EPO could be the cause of determined circuit alterations that lead to the loss of specific neuronal populations. In the heart, high EPO-R expression in cardiac progenitor cells appears to contribute to myocardial regeneration under EPO stimulation. Several lines of evidence have linked EPO to an antiapoptotic role in CNS and in heart tissue. In this review, an antiapoptotic role of EPO/EPO-R system in both brain and heart under hypoxic conditions, such as epilepsy and sudden death (SUDEP) has been resumed. Additionally, their protective effects could be a new field of research and a novel therapeutic strategy for the early treatment of these conditions and avoid SUDEP.

Nowadays, people diagnosed sepsis may develop acute kidney injury (AKI), resulting heavy burden of health care. Recombinant human erythroprotein (rhEPO) has been suggested to have multifunction and may be used in the prevention or treatment of AKI, and its underlying mechanism remains largely unknown.

In our study, cell model induced by LPS-activated cell apoptosis in vitro and AKI animal model caused by lipopolysaccharide (LPS) injection in vivo. MTT assay and Flow Cytometry were conducted to analyze cell viability and apoptosis, respectively. Western bot was used to analyze expressions of apoptosis and autophagy associated proteins, and effects on AMPK/SIRT1 pathway.

Our results suggested that rhEPO inhibited LPS-induced cell apoptosis in HK-2 and HEK-293. Moreover, we found that rhEPO activated autophagy to prevented cell apoptosis, changing the expression level of autophagy associated proteins such as LC3-I/LC3-II and P62, and AMPK/SIRT1 pathway was involved in its regulation. Additionally, both EX527 (SIRT1 inhibitor) and Compound C (AMPK inhibitor) blocked the autophagy effects caused by rhEPO and thus reversed the anti-apoptotic effects of rhEPO. Furthermore, our data demonstrated that rhEPO inhibited LPS-induced kidney tubular injury and decreased the expression level of apoptotic proteins by altering the expression level of autophagy related proteins and AMPK/SIRT1 pathway related proteins in vitro.

Collectively, rhEPO suppressed LPS-induced cell apoptosis via AMPK/SIRT1 pathway mediated autophagy, and modulating their levels may serve as potential way in preventing AKI.