A Calpain Inhibitor Enhances the Survival of Schwann CellsIn Vitroand after Transplantation into the Injured Spinal Cord

Abstract

Despite the diversity of cells available for transplantation into sites of spinal cord injury (SCI), and the known ability of transplanted cells to integrate into host tissue, functional improvement associated with cellular transplantation has been limited. One factor potentially limiting the efficacy of transplanted cells is poor cell survival. Recently we demonstrated rapid and early death of Schwann cells (SCs) within the first 24 h after transplantation, by both necrosis and apoptosis, which results in fewer than 20% of the cells surviving beyond 1 week. To enhance SC transplant survival, in vitro and in vivo models to rapidly screen compounds for their ability to promote SC survival are needed. The current study utilized in vitro models of apoptosis and necrosis, and based on withdrawal of serum and mitogens and the application of hydrogen peroxide, we screened several inhibitors of apoptosis and necrosis. Of the compounds tested, the calpain inhibitor MDL28170 enhanced SC survival both in vitro in response to oxidative stress induced by application of H 2 O 2 , and in vivo following delayed transplantation into the moderately contused spinal cord. The results support the use of calpain inhibitors as a promising new treatment for promoting the survival of transplanted cells. They also suggest that in vitro assays for cell survival may be useful for establishing new compounds that can then be tested in vivo for their ability to promote transplanted SC survival.

Long-term survival, axonal growth-promotion, and myelination of Schwann cells grafted into contused spinal cord in adult rats

“…The longest survival was observed at 1 y post-transplantation even without using an immunosuppressant in the last 9 mo. Our observation was different from previous studies by Hill et al reporting a 78% reduction in SC number within the first week after SC transplantation predominantly by necrosis (Hill et al, 2010; Hill et al, 2007). When comparing these studies to ours, four evident differences exist.…”

Hydrogen peroxide administered into the rat spinal cord at the level elevated by contusion spinal cord injury oxidizes proteins, DNA and membrane phospholipids, and induces cell death: Attenuation by a metalloporphyrin

“…However, these in vivo studies using various SCI models to investigate different cell types do not provide direct evidence of a causal relationship from ROS elevation, to oxidative indicator overproduction, to cell death following SCI. Most results directly correlating H 2 O 2 with oxidative damage and cell death come from cultured cells in which various [H 2 O 2 ] can be easily applied to various cell types in the settings of different insults (Hill et al, 2010; Siriphorn et al, 2010; Sakka et al, 2014; Zhao et al, 2014). However, because cultured cells lack normal extracellular environments, these results do not accurately represent the actual pathological conditions.…”

O papel da farmacoterapia na modificação do estado neurológico de traumatizados vértebro‐medulares

“…33 O tratamento com uma dose única intravenosa desse agente, ou com uma dose diária por via intraperitoneal, resultou numa melhoria da função motora, mas não da extensão da lesão. A combinação dessas duas formas de administração melhorou ambas as variáveis.…”