Tacrolimus (FK506) increases neuronal expression of GAP-43 and improves functional recovery after spinal cord injury in rats.
Tacrolimus (FK506), a widely used immunosuppressant drug, has neurite-promoting activity in cultured PC12 cells and peripheral neurons. The present study investigated whether tacrolimus affects the expression of the neuronal growth-associated protein, GAP-43, as well as functional recovery after photothrombotic spinal cord injury in the rat. In injured animals receiving tacrolimus, the number of neurons expressing GAP-43 mRNA and protein approximately doubled compared to that in injured animals receiving vehicle alone. This increase in GAP-43-positive cells was paralleled by a significant improvement in neurological function evaluated by open-field and inclined plane tests. Another FKBP-12 ligand (V-10,367) had similar effects on GAP-43 expression and functional outcome, indicating that the observed effects of tacrolimus do not involve inhibition of the phosphatase calcineurin. Thus, tacrolimus, a drug which is already approved for use in humans, as well as other FKBP-12 ligands which do not inhibit calcineurin, could potentially enhance functional outcome after CNS injury in humans.
Madsen
J R
JR
Department of Neurosurgery, Children's Hospital, Boston, Massachusetts, 02115, USA. madsen_j@a1.tch.harvard.edu
MacDonald
P
P
Irwin
N
N
Goldberg
D E
DE
Yao
G L
GL
Meiri
K F
KF
Rimm
I J
IJ
Stieg
P E
PE
Benowitz
L I
LI
D000818:Animals; D000906:Antibodies; D001522:Behavior, Animal / Q000502:physiology; D019703:Calcineurin / Q000378:metabolism; D019922:GAP-43 Protein / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017403:In Situ Hybridization; D008264:Macrophages / Q000502:physiology; D017628:Microglia / Q000502:physiology; D016501:Neurites / Q000737:chemistry / Q000201:enzymology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology*
D000906:Antibodies; D019922:GAP-43 Protein; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D019703:Calcineurin; D016559:Tacrolimus