1,2-Dichloroethane causes anxiety and cognitive dysfunction in mice by disturbing GABA metabolism and inhibiting the cAMP-PKA-CREB signaling pathway.

1,2-Dichloroethane (1,2-DCE) is a powerfully toxic neurotoxin, which is a common environmental pollutant. Studies have indicated that 1,2-DCE long-term exposure can result in adverse effects. Nevertheless, the precise mechanism remains unknown. In this study, behavioral results revealed that 1,2-DCE long-term exposure could cause anxiety and learning and memory ability impairment in mice. The contents of γ-aminobutyric acid (GABA) and glutamine (Gln) in mice's prefrontal cortex decreased, whereas that of glutamate (Glu) increased. With the increase in dose, the activities of glutamate decarboxylase (GAD) decreased and those of GABA transaminase (GABA-T) increased. The protein and mRNA expressions of GABA transporter-3 (GAT-3), vesicular GABA transporter (VGAT), GABA A receptor α2 (GABAARα2), GABAARγ2, K-Cl cotransporter isoform 2 (KCC2), GABA B receptor 1 (GABABR1), GABABR2, protein kinase A (PKA), cAMP-response element binding protein (CREB), p-CREB, brain-derived neurotrophic factor (BDNF), c-fos, c-Jun and the protein of glutamate dehydrogenase (GDH) and PKA-C were decreased, while the expression levels of GABA transporter-1 (GAT-1) and Na-K-2Cl cotransporter isoform 1 (NKCC1) were increased. However, there was no significant change in the protein content of succinic semialdehyde dehydrogenase (SSADH). The expressions of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) contents were also reduced. In conclusion, the results of this study show that exposure to 1,2-DCE could lead to anxiety and cognitive impairment in mice, which may be related to the disturbance of GABA metabolism and its receptors along with the cAMP-PKA-CREB pathway.

ADSC-Exos enhance functional recovery after spinal cord injury by inhibiting ferroptosis and promoting the survival and function of endothelial cells through the NRF2/SLC7A11/GPX4 pathway.

BACKGROUND: Spinal cord injury (SCI) is a devastating disease that causes major motor, sensory and autonomic dysfunctions. Currently, there is a lack of effective treatment. In this study, we aimed to investigate the potential mechanisms of Exosomes from adipose-derived stem cells (ADSC-Exos) in reducing ferroptosis and promoting angiogenesis after spinal cord injury. METHODS: We isolated ADSC-Exos, the characteristics of which were confirmed. In vitro, we tested the potential of ADSC-Exos to promote the survival and function of human brain microvascular endothelial cells (HBMECs) and analyzed the ferroptosis of HBMECs. In vivo, we established rat models of SCI and locally injected ADSC-Exos to verify their efficacy. RESULTS: ADSC-Exos can reduce reactive oxygen species (ROS) accumulation and cell damage induced by an excessive inflammatory response in HBMECs. ADSC-Exos inhibit ferroptosis induced by excessive inflammation and upregulate the expression of glutathione peroxidase 4(GPX4) in HBMECs. It can also effectively promote proliferation, migration, and vessel-like structure formation. In vitro, ADSC-Exos improved behavioral function after SCI and increased the number and density of blood vessels around the damaged spinal cord. Moreover, we found that ADSC-Exos could increase nuclear factor erythroid-2-related factor 2(NRF2) expression and nuclear translocation, thereby affecting the expression of solute carrier family 7 member 11(SLC7A11) and GPX4, and the NRF2 inhibitor ML385 could reverse the above changes. CONCLUSION: Our results suggest that ADSC-Exos may inhibit ferroptosis and promote the recovery of vascular and neural functions after SCI through the NRF2/SLC7A11/GPX4 pathway. This may be a potential therapeutic mechanism for spinal cord injury.