Combination of Chondroitinase ABC, Glial Cell Line–Derived Neurotrophic Factor and Nogo A Antibody Delayed-Release Microspheres Promotes the Functional Recovery of Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is one of the most devastating injuries for patients. Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic factor for the regeneration of the spinal neuraxial bundle, but GDNF would degrade rapidly if the protein was injected into the site of injury; thus, it cannot exert its fullest effects. Therefore, we introduced a delivery system of GDNF, poly(lactide-co-glycolic acid) (PLGA) delayed-release microspheres, in the current study and observed the effect of PLGA-GDNF and the combination of PLGA-GDNF and another 2 agents PLGA-chondroitinase ABC (ChABC) and PLGA-Nogo A antibody in the treatment of SCI rats. Our results showed that PLGA-GDNF and the combination of chABC, GDNF, and Nogo A antibody microspheres could elevate the locomotor scores of SCI rats. The effect of PLGA-GDNF was much better than that of GDNF. The cortical somatosensory evoked potential was also improved by PLGA-GDNF and the combination of chABC, GDNF, and Nogo A antibody microspheres. Our results suggest that PLGA delayed-release microsphere may be a useful and effective tool in delivering protein agents into the injury sites of patients with SCI. This novel combination therapy may provide a new idea in promoting the functional recovery of the damaged spinal cord.

Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair

“…Thus, a combinatorial approach is urgently needed. Various combinatorial approaches involving drugs and interventions including Chondroitinase ABC (ChABC)/neurotrophic factors 50 , cells/neurotrophic factors 51 , 52 , and anti-myelin-associated glycoproteins (MAG)/other anti-inhibitory factors 51 , 53 , 54 , have been proposed for effective regeneration after SCI. Nevertheless, most of them are neuroprotective and do not promote the restoration of severed axonal connections, or they try to overcome only one of the obstacles to regeneration.…”

History of Glial Cell Line-Derived Neurotrophic Factor (GDNF) and Its Use for Spinal Cord Injury Repair

“…The radiolabeled GDNF in this study was provided to the DRGs and motor neurons by Schwann cells and oligodendrocytes respectively, thus indicating another potential cell source of GDNF within the nervous system. In 2004, a novel in vivo study was published, showing for the first time the endogenous release of GDNF from astrocytes, which was neuroprotective to neighboring neuronal populations, in utero during development [ 40 ]. The production of GDNF from astrocytes, oligodendrocytes, and Schwann cells has made these cells important potential points of intervention for SCI therapies.…”

“…In addition to its neuroprotective effects [ 38 , 41 , 42 ], GDNF has also been shown to: (1) attenuate astrocyte cell death via reduced activation of caspase-3 [ 43 ], as well as through caspase-3/Akt independent mechanisms [ 44 ]; (2) minimize activation of microglia and production of nitric oxide [ 43 , 45 ]; and (3) promote the survival [ 46 ] and proliferation [ 40 , 47 ] of Schwann cells. GDNF activates rat primary cortical microglial cells through GFRα-1 and cRET receptors, with downstream signaling through the MAPK pathway, as illustrated in a study by Honda et al [ 47 ].…”

Role of GDNF in Spinal Cord Injury Repair

“…The radiolabeled GDNF in this study was provided to the DRGs and motor neurons and by Schwann cells and oligodendrocytes, respectively. In 2004, a novel in vivo study was published showing for the first time the endogenous release of GDNF from astrocytes, which was neuroprotective to neighboring neuronal populations, in utero during development [76].…”

“…In this study, GDNF promoted increased functional recovery, increased numbers of intralesional and perilesional neurites, reduced astrogliosis, and increased intralesional vasculature, as compared to controls. Using PLGA (polylactide-co-glycolic acid) microspheres for slow release, Zhang et al [76] administered GDNF,…”