Targeting endothelin receptors A and B attenuates the inflammatory response and improves locomotor function following spinal cord injury in mice

Abstract

After spinal cord injury (SCI), the disruption of blood-spinal cord barrier by activation of the endothelin (ET) system is a critical event leading to leukocyte infiltration, inflammatory response and oxidative stress, contributing to neurological disability. In the present study, we showed that blockade of ET receptor A (ETAR) and/or ET receptor B (ETBR) prevented early inflammatory responses directly via the inhibition of neutrophil and monocyte diapedesis and inflammatory mediator production following traumatic SCI in mice. Long-term neurological improvement, based on a series of tests of locomotor performance, occurred only in the spinal cord-injured mice following blockade of ETAR and ETBR. We also examined the post-traumatic changes of the microenvironment within the injured spinal cord of mice following blockade of ET receptors. Oxidative stress reflects an imbalance between malondialdehyde and superoxide dismutase in spinal cord-injured mice treated with vehicle, whereas blockade of ETAR and ETBR reversed the oxidation state imbalance. In addition, hemeoxygenase-1, a protective protease involved in early SCI, was increased in spinal cord-injured mice following the blockade of ETAR and ETBR, or only ETBR. Matrix metalloproteinase-9, a tissue-destructive protease involved in early damage, was decreased in the injured spinal cord of mice following blockade of ETAR, ETBR or a combination thereof. The findings of the present study therefore suggested an association between ETAR and ETBR in regulating early pathogenesis of SCI and determining the outcomes of long-term neurological recovery.

Tocotrienol alleviates inflammation and oxidative stress in a rat model of spinal cord injury via suppression of transforming growth factor-β

“…Post-SCI oxidative stress damages the ion steady state inside and outside the mitochondrial membrane, Ca 2+ accumulates inside the mitochondria, causing mitochondrial damage and aerobic energy metabolic disorders and inhibiting the synthesis of ATP (4). Following SCI, excessive activity of free radicals may be applied to the postsynaptic neuron, activating nearby astrocytes and microglia, causing ionic imbalance at the neuronal cell membrane (21).…”

“…The former consists of instantaneous mechanical damage that is reversible. Secondary damage gradually forms in the weeks following primary damage, and is accompanied by a series of cell metabolism and gene expression changes, including excitatory amino acid release, free radical damage, decrease in ion inflow, inflammation and cell apoptosis, resulting in more harm than primary damage (4,5). Numerous studies have shown that post changes of SCI gene expression play an important role in the pathological process (4,5).…”

Schisandrin B attenuates the inflammatory response, oxidative stress and apoptosis induced by traumatic spinal cord injury via inhibition of p53 signaling in adult rats

“…The spinal cord water content was assessed by the following equation: [(wet weight -dry weight)/wet weight] ×100% (8). …”

Propitious Therapeutic Modulators to Prevent Blood-Spinal Cord Barrier Disruption in Spinal Cord Injury

“…Accordingly, therapeutic strategies that employ ET-1 antagonists to impede ET-1-mediated vasoconstriction are beneficial in terminating SCI progression. ET receptor antagonists likewise prevent or delay axonal degeneration after SCI [149], and blockade of ET A R and/or ET B R reduces inflammatory responses and oxidative stress, overturns MMP-9 activation, and enhances long-term neurological function post-injury [151]. Following spinal cord trauma, vascular ET A R/ET B R activation plays a critical role in post-traumatic ischemia, whereas astrocyte-only ET B R activation is associated with reactive gliosis [143].…”