An In Situ Assembled Trapping Gel Repairs Spinal Cord Injury by Capturing Glutamate and Free Calcium Ions

Abstract

Increased glutamate (Glu) and free calcium ions are two major factors contributing to secondary injuries. Glu is the most abundant excitatory neurotransmitter that can lead to the hyperexcitability of adjacent neurons. [4] Hyperexcited neurons cause persistent pain in patients. [5] Various studies have identified Glu inhibition as an important therapeutic strategy for SCI. For example, multiple intrathecal injections of neuregulin-1 beta1 could protect spinal cord-injured neurons from Glu-induced excitotoxicity. [6] Excess CNS Glu can flow into the peripheral blood. To eliminate the blood Glu, Goldshmit et al. [7,8] treated SCI mice with daily injections of glutamateoxaloacetate transaminase (rGOT1) and its cosubstrate oxaloacetic acid (OxAc). rGOT1 catalyzes Glu into aspartate, thereby decreasing blood Glu levels and promoting SCI recovery. Besides Glu, free Ca 2+ also increases during SCI, as a result of neuron damage and Glu stimulation. [9,10] Influx of Ca 2+ into healthy neurons leads to calcium-dependent neuronal apoptosis and further aggravates SCI. [10] Orem et al. used ryanodine to inhibit Ca 2+ release and the secondary axonal degeneration caused by SCI was correspondingly alleviated. [11] Unfortunately, all these indirect ways to decrease Glu and calcium levels are challenged by the blood-brain barrier, rapid flux, and frequent injections. Therefore, the direct elimination of these harmful molecules in injury lesions is a more powerful method to prevent secondary injuries.Herein, we developed an in situ assembled trapping hydrogel (PF-SA-GAD) to directly and sustainedly capture Glu Spinal cord injury (SCI) can lead to devastating autonomic dysfunction. One of the most challenging issues for functional repair in SCI is the secondary damage caused by the increased release of glutamate and free Ca 2+ from injured cells. Here, an in situ assembled trapping gel (PF-SA-GAD) is developed to sweep glutamate and Ca 2+ , promoting SCI repair. The hydrogel solution is a mixture of recombinant glutamate decarboxylase 67 (rGAD67) protein, sodium alginate (SA), and pluronic F-127 (PF-127). After intrathecal administration, temperature-sensitive PF-127 promoted in situ gelation. Glutamate (Glu) is captured and decarboxylated by rGAD67 into γ-aminobutyric acid (GABA). SA reacted with the free Ca 2+ to generate gellable calcium alginate. Thereby, this in situ trapping gel retarded secondary neuron injury caused by Glu and free Ca 2+ during SCI. In rat models of SCI, PF-SA-GAD reduces the lesion volume and inflammatory response after SCI, restores the motor function of rats with SCI. Together, the in situ assembled trapping gel is a long-term effective and minimally invasive sweeper for the direct elimination of glutamate and Ca 2+ from injury lesions and can be a novel strategy for SCI repair by preventing secondary injury.

Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury

“…As shown in Figure A, a total of 152 genes were upregulated and 157 genes were downregulated in the Ri@EGCG-2 NP group compared with the SCI group. Remarkably, among the upregulated genes in the Ri@EGCG-2 NP group, there were numerous genes related to SCI repair including nerve regeneration, synaptic remodeling, and extracellular mechanism remodeling (Figure B), such as Galr2, Mospd4, Lilrb3a, Col22a1, Col2a1, etc. − Similarly, the significant enrichments in Gene Ontology (GO) biological processes (BP), molecular function (MF), and cellular component (CC) (Figure C, Figures S16 and S17) showed that the pathways related to stem cell proliferation, axon regeneration, neuron regeneration, synaptic remodeling, and extracellular matrix remodeling were significantly enriched in the Ri@EGCG-2 NPs group compared with the SCI group. − To confirm the results of RNA sequencing, sections and immunofluorescence staining were performed on the spinal cord tissue at the injury site. As shown in the immunofluorescence staining with DAPI and Nestin (to label neural stem cells (NSCs)) images in Figure D and quantitative analysis in Figure E, there was a small amount of Nestin-positive NSCs in SCI groups, and more noticeable Nestin-positive NSCs filled the injury site in the Ri@EGCG-2 NPs group.…”

Research progress on the inhibition of oxidative stress by teriparatide in spinal cord injury

“…The intracellular homeostasis is disrupted after SCI, characterized by increased excitotoxicity of glutamate, elevated levels of free iron, and increased membrane permeability of Ca 2+ ( 21 ). The elevated intracellular Ca 2+ levels activate the nicotinamide adenine dinucleotide, which promotes ATP production while also increasing the production of ROS ( 22 , 23 ). Excessive ROS can increase the permeability of Ca 2+ membranes, leading to an increased influx of Ca 2+ , which causes a decrease in membrane potential.…”

Marine biomaterials in biomedical nano/micro-systems

“…In a recent study, Huang et al developed an in situ assembled trapping gel composed of recombinant glutamate decarboxylase 67 (rGAD67) protein, alginate, and temperature-sensitive Pluronic F-127 for the direct elimination of glutamate (Glu) and free Ca 2+ released from injured cells during spinal cord injury (SCI) secondary damage [ 150 ]. Following intrathecal administration, Pluronic F-127 promoted in situ gelation while free Ca 2+ auto-exchanged with Na + from sodium alginate to form gellable calcium alginate.…”