Continuous infusion of an agonist of the tumor necrosis factor receptor 2 in the spinal cord improves recovery after traumatic contusive injury

Abstract

Summary Aim The activation of the TNFR2 receptor is beneficial in several pathologies of the central nervous system, and this study examines whether it can ameliorate the recovery process following spinal cord injury. Methods EHD2‐sc‐mTNF R2 , an agonist specific for TNFR2, was used to treat neurons exposed to high levels of glutamate in vitro. In vivo, it was infused directly to the spinal cord via osmotic pumps immediately after a contusion to the cord at the T9 level. Locomotion behavior was assessed for 6 weeks, and the tissue was analyzed (lesion size, RNA and protein expression, cell death) after injury. Somatosensory evoked potentials were also measured in response to hindlimb stimulation. Results The activation of TNFR2 protected neurons from glutamate‐mediated excitotoxicity through the activation of phosphoinositide‐3 kinase gamma in vitro and improved the locomotion of animals following spinal cord injury. The extent of the injury was not affected by infusing EHD2‐sc‐mTNF R2 , but higher levels of neurofilament H and 2′, 3′‐cyclic‐nucleotide 3′‐phosphodiesterase were observed 6 weeks after the injury. Finally, the activation of TNFR2 after injury increased the neural response recorded in the cortex following hindlimb stimulation. Conclusion The activation of TNFR2 in the spinal cord following contusive injury leads to enhanced locomotion and better cortical responses to hindlimb stimulation.

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

“…In this line, we showed that coadministration of glutamate and EHD2-scTNF R2 into the magnocellular nucleus basalis of mice protected cholinergic neurons and their cortical projections from excitotoxic cell death induced by glutamate and reverted the injury-associated memory impairment testes by a passive avoidance paradigm (Dong et al, 2016). Similar, using a mouse model of contusive injury, Gerald et al showed that EHD2sc-mTNF R2 -mediated activation of TNFR2 in the spinal cord improved locomotion and cortical neural activity (Gerald et al, 2019). Due to the important role of TNFR2 for neuroprotection, we went on to study the neuroprotective role of TNFR2 in models of CNP.…”

Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway

“…The protective effect of zinc on astrocytes inhibits demyelination damage 47 . Zinc directly or indirectly affects the expression of related proteins, such as the regulation of the tumor necrosis factor receptor 2 48 . The changes in some central nervous system cells and related protein factors in the acute phase of spinal cord injury can effectively affect the pathological changes of spinal cord injury and promote wound healing.…”

“… 47 Zinc directly or indirectly affects the expression of related proteins, such as the regulation of the tumor necrosis factor receptor 2. 48 The changes in some central nervous system cells and related protein factors in the acute phase of spinal cord injury can effectively affect the pathological changes of spinal cord injury and promote wound healing. Anti‐inflammatory environment, the more anti‐inflammatory and antioxidant effects of zinc require further experiments to verify these conjectures and perfect the mechanism of action of zinc.…”

T‐cell infiltration, contribution and regulation in the central nervous system post‐traumatic injury

“…TBI can lead to a significant increase in patient mortality and poor long‐term prognosis, leaving many survivors with long‐term disabilities 3‐6 . SCI triggers a robust neuroinflammatory response and disrupts essential neuroimmune communication causing serious deficits in sensorimotor functions 7‐10 . The incidence rate of SCI varies from regions to countries and increases when human activities are increasingly greater 11 .…”