GGF2 (Nrg1‐β3) treatment enhances NG2⁺ cell response and improves functional recovery after spinal cord injury

Abstract

The adult spinal cord contains a pool of endogenous glial precursor cells, which spontaneously respond to spinal cord injury (SCI) with increased proliferation. These include oligodendrocyte precursor cells that express the NG2 proteoglycan and can differentiate into mature oligodendrocytes. Thus, a potential approach for SCI treatment is to enhance the proliferation and differentiation of these cells to yield more functional mature glia and improve remyelination of surviving axons. We previously reported that soluble glial growth factor 2 (GGF2)- and basic fibroblast growth factor 2 (FGF2)-stimulated growth of NG2(+) cells purified from injured spinal cord in primary culture. This study examines the effects of systemic administration of GGF2 and/or FGF2 after standardized contusive SCI in vivo in both rat and mouse models. In Sprague-Dawley rats, 1 week of GGF2 administration, beginning 24 h after injury, enhanced NG2(+) cell proliferation, oligodendrogenesis, chronic white matter at the injury epicenter, and recovery of hind limb function. In 2',3'-cyclic-nucleotide 3'-phosphodiesterase-enhanced green fluorescent protein mice, GGF2 treatment resulted in increased oligodendrogenesis and improved functional recovery, as well as elevated expression of the stem cell transcription factor Sox2 by oligodendrocyte lineage cells. Although oligodendrocyte number was increased chronically after SCI in GGF2-treated mice, no evidence of increased white matter was detected. However, GGF2 treatment significantly increased levels of P0 protein-containing peripheral myelin, produced by Schwann cells that infiltrate the injured spinal cord. Our results suggest that GGF2 may have therapeutic potential for SCI by enhancing endogenous recovery processes in a clinically relevant time frame.

Improved differentiation of oligodendrocyte precursor cells and neurological function after spinal cord injury in rats by oscillating field stimulation

“…Significant differences in the latencies and amplitudes were observed between the OFS group and the SCI group in the period from the 2nd to the 8th week after SCI, especially from the 2nd to the 6th week ( ⁄ p < 0.05 and ⁄⁄ p < 0.01, respectively). recovery following SCI is associated with remyelination of the injured spinal cord (Whittaker et al, 2012). After SCI, bilateral hindlimb locomotor activity improved gradually in the SCI and OFS groups.…”

“…Restoring myelination is a major goal of repairing the injured spinal cord to improve neurological function after SCI. In vivo, the activation of OPCs and their subsequent differentiation into myelinating OLs may be very important for remyelination after SCI (Li et al, 2010;Whittaker et al, 2012).…”

“…Remyelination plays a very important role in the reconnection of neural pathways following SCI (Falnikar et al, 2014). Remyelination could be regulated by endogenous and exogenous factors (Whittaker et al, 2012). In previous studies, electrical stimulation has been shown to enhance remyelination and to lead to the recovery of motor function in CNS injury (Becker et al, 2010;Li et al, 2010).…”

Effects of lithium chloride and methylprednisolone on experimental spinal cord injury

“…Treatment results of patients with spinal cord injury are still poor despite various treatment approach and efforts. The aim of the entire treatment effort is to prevent secondary tissue damage [3][4][5]. There are reports suggesting that LiCl protects the cultured neurons against glutamateinduced excitotoxicity and apoptosis mediated by N-methyl-D-aspartate (NMDA) receptors [6].…”

Análise dos mecanismos de neuroplasticidade na porção lombar da medula espinal do rato submetida à lesão isquêmica fototrombótica e tratada pela injeção local de PEDF

“…O BDNF é capaz de reduzir a apoptose e promover a regeneração de neurôrios lesados, sendo útil na redução da lesão secundária (Kamei et al, 2007;Sasaki et al, 2009;Zong et al, 2011). Em contra partida, o FGF-2 possui propriedades gliogênicas e neurotróficas (Szebenyi e Fallon, 1999;Whittaker et al, 2011) e também está envolvido na proliferação de células progenitoras de oligodendrócito (Tripathi e McTigue, 2008). Em experimentos realizados em ratos, a regulação da expressão do FGF-2 ocorre em regiões próximas à área de lesão, entre a primeira e a quarta semana após lesão medular (Mocchetti et al,1996;Tripathi e McTigue, 2008).…”