Rapamycin increases neuronal survival, reduces inflammation and astrocyte proliferation after spinal cord injury.
Spinal cord injury (SCI) frequently leads to a permanent functional impairment as a result of the initial injury followed by secondary injury mechanism, which is characterised by increased inflammation, glial scarring and neuronal cell death. Finding drugs that may reduce inflammatory cell invasion and activation to reduce glial scarring and increase neuronal survival is of major importance for improving the outcome after SCI. In the present study, we examined the effect of rapamycin, an mTORC1 inhibitor and an inducer of autophagy, on recovery from spinal cord injury. Autophagy, a process that facilitates the degradation of cytoplasmic proteins, is also important for maintenance of neuronal homeostasis and plays a major role in neurodegeneration after neurotrauma. We examined rapamycin effects on the inflammatory response, glial scar formation, neuronal survival and regeneration in vivo using spinal cord hemisection model in mice, and in vitro using primary cortical neurons and human astrocytes. We show that a single injection of rapamycin, inhibited p62/SQSTM1, a marker of autophagy, inhibited mTORC1 downstream effector p70S6K, reduced macrophage/neutrophil infiltration into the lesion site, microglia activation and secretion of TNFα. Rapamycin inhibited astrocyte proliferation and reduced the number of GFAP expressing cells at the lesion site. Finally, it increased neuronal survival and axonogenesis towards the lesion site. Our study shows that rapamycin treatment increased significantly p-Akt levels at the lesion site following SCI. Similarly, rapamycin treatment of neurons and astrocytes induced p-Akt elevation under stress conditions. Together, these findings indicate that rapamycin is a promising candidate for treatment of acute SCI condition and may be a useful therapeutic agent.
Department of Neurobiology, Tel-Aviv University, Israel; Australian Regenerative Medicine Institute, Monash University, VIC, Australia. Electronic address: yona.goldshmit@monash.edu.
Yona
Y
Goldshmit
Department of Neurobiology, Tel-Aviv University, Israel.
Sivan
S
Kanner
Department of Neurobiology, Tel-Aviv University, Israel.
Maria
M
Zacs
Australian Regenerative Medicine Institute, Monash University, VIC, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Department of Ophthalmology, the University of Melbourne, East Melbourne VIC, Australia.
Frisca
F
Frisca
Australian Regenerative Medicine Institute, Monash University, VIC, Australia.
Alexander R
AR
Pinto
Australian Regenerative Medicine Institute, Monash University, VIC, Australia.
Peter D
PD
Currie
Department of Neurobiology, Tel-Aviv University, Israel. Electronic address: lironit@post.tau.ac.il.
Ronit
R
Pinkas-Kramarski
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000067778:ELAV-Like Protein 3 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D051381:Rats; D020123:Sirolimus / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000150:complications* / Q000473:pathology*; D013997:Time Factors
D039481:CD11b Antigen; D000067778:ELAV-Like Protein 3; D005904:Glial Fibrillary Acidic Protein; D007166:Immunosuppressive Agents; D019394:Ki-67 Antigen; D020123:Sirolimus
Akt; Astrogliosis; Inflammation; Neuronal survival; Rapamycin; Spinal cord injury