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.

Calpain activation and progression of inflammatory cycles in Parkinson's disease.

Parkinson's disease (PD) is a progressive, neurodegenerative condition of the central nervous system (CNS) affecting 6.3 million people worldwide with no curative treatments. Current therapies aim to mitigate PD's effects and offer symptomatic relief for patients. Multiple pathways are involved in the pathogenesis of PD, leading to neuroinflammation and the destruction of dopaminergic neurons in the CNS. This review focuses on PD pathology and the role of calpain, a neutral protease, as a regulator of various immune cells such as T-cells, microglia and astrocytes which lead to persistent neuroinflammatory responses and neuronal loss in both the brain and spinal cord (SC). Calpain plays a significant role in the cleavage and aggregation of toxic α-synuclein (α-syn), a presynaptic neural protein, and other organelles, contributing to mitochondrial dysfunction and oxidative stress. α-Syn aggregation results in the formation of Lewy bodies (LB) that further contribute to neuronal damage through lipid bilayer penetration, calcium ion (Ca2+) influx, oxidative stress and damage to the blood brain barrier (BBB). Dysfunctional mitochondria destabilize cytosolic Ca2+ concentrations, raising intracellular Ca2+; this leads to excessive calpain activation and persistent inflammatory responses. α-Syn aggregation also results in the disruption of dopamine synthesis through phosphorylation of tyrosine hydroxylase (TH), a key enzyme involved in the conversion of tyrosine to levodopa (L-DOPA), the amino acid precursor to dopamine. Decreased dopamine levels result in altered dopamine receptor (DR) signaling, ultimately activating pro-inflammatory T-cells to further contribute to the inflammatory response. All of these processes, together, result in neuroinflammation, degeneration and ultimately neuronal death seen in PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-a prodrug to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+)), rotenone (an environmental neurotoxin), and 6-hydroxydopamine (6-OHDA - a neurotoxic synthetic organic compound) induce PD-like conditions when injected into rodents. All three agents work through similar mechanisms and lead to degeneration of dopaminergic neurons in the substantia nigra (SN) and more recently discovered in motor neurons of the spinal cord (SC). These neurotoxins also increase calpain activity, furthering the neuroinflammatory response. Hence, calpain inhibitors have been posited as potential therapeutics for PD to prevent calpain-related inflammation and neurodegenerative responses in not only the SN but the SC as well.