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 patholog- ical processes, such as excessive glutamate release in the extracellular environment and massive influx of Ca 2 + into cells. Dextran can absorb extracellular glutamate and Ca 2 + to attenuate persistent excita- tory processes that are detrimental to normal cells. Calcium channel inhibitors reduce the influx of Ca 2 + , 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 Ca 2 + and glutamate concentrations in extracellular environment and in- hibiting excess Ca 2 + influx. The obtained dextran microgels could effectively encapsulate GVIA peptide, which displayed sustained release. Microgels loaded with GVIA (DexGVIA) played an excellent neuropro- tective role by relieving the influx of Ca 2 + in vitro . DexGVIA also exhibited promising therapeutic effect in vivo via reducing the lesion cavity, saving neurons and gliacytes from the injury, and improving con- tinuity 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.