Conotoxin loaded dextran microgel particles alleviate effects of spinal cord injury by inhibiting neuronal excitotoxicity

Abstract

Spinal cord injury (SCI) is a severe refractory disabling condition accompanied by complicated pathological processes, such as excessive glutamate release in the extracellular environment and massive influx of Ca2+ into cells. Dextran can absorb extracellular glutamate and Ca2+ to attenuate persistent excitatory processes that are detrimental to normal cells. Calcium channel inhibitors reduce the influx of Ca2+, thereby relieving subsequent cytotoxicity such as mitochondria damage. Here, a bifunctional microgel was designed for delivering GVIA, an N-type calcium ion channel blocker, to achieve a combinational therapy of simultaneously reducing the Ca2+ and glutamate concentrations in extracellular environment and inhibiting excess Ca2+ influx. The obtained dextran microgels could effectively encapsulate GVIA peptide, which displayed sustained release. Microgels loaded with GVIA (DexGVIA) played an excellent neuroprotective role by relieving the influx of Ca2+in vitro. DexGVIA also exhibited promising therapeutic effect in vivo via reducing the lesion cavity, saving neurons and gliacytes from the injury, and improving continuity and integrity of the spinal cord, thus distinctly accelerated motor functional recovery of SCI rats. Our work provided a combinational strategy against excitotoxicity, with potential applications not only in SCI, but also in other pathologically similar conditions of the central nervous system.