Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury.
We investigated whether permeability transition-mediated release of mitochondrial cytochrome c is a potential therapeutic target for treating acute spinal cord injury (SCI). Based on previous reports, minocycline, a second-generation tetracycline, exerts neuroprotection partially by inhibiting mitochondrial cytochrome c release and reactive microgliosis. We first evaluated cytochrome c release at the injury epicenter after a T10 contusive SCI in rats. Cytochrome c release peaked at approximately 4-8 h postinjury. A dose-response study generated a safe pharmacological regimen that enabled i.p. minocycline to significantly lower cytosolic cytochrome c at the epicenter 4 h after SCI. In the long-term study, i.p. minocycline (90 mg/kg administered 1 h after SCI followed by 45 mg/kg administered every 12 h for 5 days) markedly enhanced long-term hind limb locomotion relative to that of controls. Coordinated motor function and hind limb reflex recoveries also were improved significantly. Histopathology suggested that minocycline treatment alleviated later-phase tissue loss, with significant sparing of white matter and ventral horn motoneurons at levels adjacent to the epicenter. Furthermore, glial fibrillary acidic protein and 2',3' cyclic nucleotide 3' phosphodiesterase immunocytochemistry showed an evident reduction in astrogliosis and enhanced survival of oligodendrocytes. Therefore, release of mitochondrial cytochrome c is an important secondary injury mechanism in SCI. Drugs with multifaceted effects in antagonizing this process and microgliosis may protect a proportion of spinal cord tissue that is clinically significant for functional recovery. Minocycline, with its proven clinical safety, capability to cross the blood-brain barrier, and demonstrated efficacy during a clinically relevant therapeutic window, may become an effective therapy for acute SCI.
Department of Neurosurgery, Harvard Medical School/Children's Hospital Boston/Brigham and Women's Hospital, Boston, and SCI Laboratory, VA Boston Healthcare System, MA, USA. yang_teng@hms.harvard.edu
Yang D
YD
Teng
Howard
H
Choi
Renna C
RC
Onario
Shan
S
Zhu
Federico C
FC
Desilets
Shoumin
S
Lan
Eric J
EJ
Woodard
Evan Y
EY
Snyder
Marc E
ME
Eichler
Robert M
RM
Friedlander
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D007700:Kinetics; D008911:Minocycline / Q000627:therapeutic use*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology
D045304:Cytochromes c; D008911:Minocycline