Abstract
Neuron death in spinal cords is caused primarily by apoptosis after spinal cord injury (SCI). Autophagy can act as a cellular response to maintain neuron homeostasis that can reduce apoptosis. Although more studies have shown that an epigenetic enzyme called Lysine-specific demethylase 1 (LSD1) can negatively regulate autophagy during cancer research, existing research does not focus on impacts related to LSD1 in nerve injury diseases. This study was designed to determine whether inhibiting LSD1 could enhance autophagy against apoptosis and provide effective neuroprotection in vitro and vivo after SCI. The results showed that LSD1 inhibition treatment significantly reduced spinal cord damage in SCI rat models and was characterized by upregulated autophagy and downregulated apoptosis. Further research demonstrated that using both pharmacological inhibition and gene knockdown could enhance autophagy and reduce apoptosis for in vitro simulation of SCI-caused damage models. Additionally, 3-methyladenine (3-MA) could partially eliminate the effect of autophagy enhancement and apoptosis suppression. These findings demonstrated that LSD1 inhibition could protect against SCI by activating autophagy and hindering apoptosis, suggesting a potential candidate for SCI therapy.
Highlights
Spinal cord injury (SCI) is a severe neurological disorder that can damage sensation and motor functions and lead to multiple organ dysfunction
This study investigated the impacts of Lysine-specific demethylase 1 (LSD1) inhibition after SCI in vitro and in vivo and explored the relationships among LSD1 and autophagy and apoptosis development, which might provide a potential strategy for treating SCI
Compared with the SCI group, SP2509 intervention significantly promoted increased expression of LC3-phosphatidylethanolaminse conjugate (LC3II)/I, Beclin[1], ATG5, and ATG7, but decreased expression of p62 (Fig. 2c, d). These results demonstrated that SCI could activate autophagy, and using SP2509 to inhibit LSD1 could increase the effect of autophagy
Summary
Spinal cord injury (SCI) is a severe neurological disorder that can damage sensation and motor functions and lead to multiple organ dysfunction. After SCI’s initial phase that is typically caused by mechanical injuries such as acute compression, lacerations, and shear forces, SCI’s second phase causes an ischemic and hypoxic extracellular environment around neurons[2]. The second phase is an available target for therapeutic mediation of SCI, which often exhibits inflammation, hypoxia, glial scar formation, apoptosis, and autophagy[3,4]. Neuronal apoptosis after SCI that results in hypoxic-ischemic damage is a major cause of neurological deficits and mortality[5]. It is critical to study the mechanisms of SCI to reduce apoptosis and improve the prognosis of SCI rapidly
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