Regulation of enolase activation to promote neural protection and regeneration in spinal cord injury

Spinal cord injury(SCI)is a debilitating condition characterized by damage to the spinal cord resulting in loss of function,mobility,and sensation with no U.S.Food and Drug Administration-approved cure.Enolase,a multifunctional glycolytic enzyme upregulated after SCI,promotes pro-and anti-inflammatory events and regulates functional recovery in SCI.Enolase is normally expressed in the cytosol,but the expression is upregulated at the cell surface following cellular injury,promoting glial cell activation and signal transduction pathway activation.SCI-induced microglia activation triggers pro-inflammatory mediators at the injury site,activating other immune cells and metabolic events,i.e.,Rho-associated kinase,contributing to the neuroinflammation found in SCI.Enolase surface expression also activates cathepsin X,resulting in cleavage of the C-terminal end of neuron-specific enolase(NSE)and non-neuronal enolase(NNE).Fully functional enolase is necessary as NSE/NNE C-terminal proteins activate many neurotrophic processes,i.e.,the plasminogen activation system,phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B,and mitogen-activated protein kinase/extracellular signal-regulated kinase.Studies here suggest an enolase inhibitor,ENOblock,attenuates the activation of Rho-associated kinase,which may decrease glial cell activation and promote functional recovery following SCI.Also,ENOblock inhibits cathepsin X,which may help prevent the cleavage of the neurotrophic C-terminal protein allowing full plasminogen activation and phosphatidylinositol-4,5-bisphosphate 3-kinase/mitogen-activated protein kinase activity.The combined NSE/cathepsin X inhibition may serve as a potential therapeutic strategy for preventing neuroinflammation/degeneration and promoting neural cell regeneration and recovery following SCI.The role of cell membrane-expressed enolase and associated metabolic events should be investigated to determine if the same strategies can be applied to other neurodegenerative diseases.Hence,this review discusses the importance of enolase activation and inhibition as a potential therapeutic target following SCI to promote neuronal survival and regeneration.

Implications of enolase in the RANKL-mediated osteoclast activity following spinal cord injury

Spinal Cord Injury(SCI)is a debilitating condition characterized by damage to the spinal cord,resulting in loss of function,mobility,and sensation.Although increasingly prevalent in the US,no FDA-approved therapy exists due to the unfortunate complexity of the condition,and the difficulties of SCI may be furthered by the development of SCI-related complications,such as osteoporosis.SCI demonstrates two crucial stages for consideration:the primary stage and the secondary stage.While the primary stage is suggested to be immediate and irreversible,the secondary stage is proposed as a promising window of opportunity for therapeutic intervention.Enolase,a metabolic enzyme upregulated after SCI,performs non-glycolytic functions,promoting inflammatory events via extracellular degradative actions and increased production of inflammatory cytokines and chemokines.Neuron-specific enolase(NSE)serves as a biomarker of functional damage to neurons following SCI,and the inhibition of NSE has been demonstrated to reduce signs of secondary injury of SCI and to ameliorate dysfunction.This Viewpoint article involves enolase activation in the regulation of RANK-RANKL pathway and summarizes succinctly the mechanisms influencing osteoclast-mediated resorption of bone in SCI.Our laboratory proposes that inhibition of enolase activation may reduce SCI-induced inflammatory response and decrease osteoclast activity,limiting the chances of skeletal tissue loss in SCI.