A calpain inhibitor enhances the survival of Schwann cells in vitro and after transplantation into the injured spinal cord.
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 H2O2, 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.
Hill
Caitlin E
CE
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, USA. cah2024@med.cornell.edu
Guller
Yelena
Y
Raffa
Scott J
SJ
Hurtado
Andres
A
Bunge
Mary Bartlett
MB
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D051381:Rats; D011916:Rats, Inbred F344; D012583:Schwann Cells / Q000187:drug effects / Q000201:enzymology* / Q000637:transplantation*; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000473:pathology* / Q000601:surgery
D004151:Dipeptides; D002154:Calpain; C058076:calpain inhibitor III