Prohibitin 1 gene delivery promotes functional recovery in rats with spinal cord injury.

ABSTRACT

Spinal cord injury (SCI) represents a severe health problem worldwide usually associated with severe disability and reduced quality of life. The aim of this work was to investigate the role of prohibitin 1 (PHB1) in the progression of SCI in rats. Firstly, we observed that expression of PHB1 was downregulated following SCI in rats. Then, we hypothesized that PHB1 overexpression by delivery of Ad-PHB1 could result in neuroprotection and promote functional recovery following SCI. Briefly, Wistar rats received a 35-g clip-compression injury and were administered Ad-PHB1 or Ad immediately following SCI. It was found that Ad-PHB1 administration significantly improved locomotor function and increased pain tolerance in rats with SCI. Furthermore, Ad-PHB1 administration following SCI attenuated axonal degradation and increased neuron sparing. Ad-PHB1 administration following SCI reduced apoptosis through inhibiting the Bcl-2/Bax/caspase-3 pathway. Ad-PHB1 administration following SCI suppressed endoplasmic reticulum stress, evidenced by reduced mRNA levels of CCAAT enhancer binding protein homologous protein, chaperone-ucose-regulated protein 78, and X-box protein 1. Ad-PHB1 administration following SCI restored mitochondrial adenosine triphosphate formation, reduced reactive oxygen species formation, and improved mitochondrial respiration rates. Finally, Ad-PHB1 administration following SCI activated downstream signals including phosphatidylinositol-3-kinase (PI3K)/Akt, extracellular signal-regulated kinase (ERK1/2), and nuclear factor-kappaB. These data indicate that the PHB1 plays an important role in the development of SCI and might provide a therapeutic target to promote recovery from SCI.