Inhibition of apoptotic cell death by ghrelin improves functional recovery after spinal cord injury.
Spinal cord injury (SCI) induces massive cell death, leading to permanent neurological disability. No satisfactory treatment is currently available. Ghrelin, a gastric hormone, is known to stimulate GH release from the hypothalamus and pituitary gland. Here, we report that ghrelin administration improves functional recovery after SCI in part by inhibiting apoptosis of neurons and oligodendrocytes. Ghrelin was not detected in normal, uninjured spinal cords, but spinal cord neurons and oligodendrocytes expressed the ghrelin receptor. Ghrelin significantly inhibited apoptotic cell death of neurons and oligodendrocytes, release of mitochondrial cytochrome c, and activation of caspase-3 after moderate contusion SCI. Ghrelin also significantly increased the level of phosphorylated ERK but decreased the level of phosphorylated p38MAPK. In addition, ghrelin increased the level of ERK-dependent brain-derived neurotrophic factor expression and decreased the level of pronerve growth factor expression. Furthermore, the neuroprotective effects of ghrelin were mediated through the ghrelin receptor. Finally, ghrelin significantly improved functional recovery and reduced the size of the lesion volume and the loss of axons and myelin after injury. These results suggest that ghrelin may represent a potential therapeutic agent after acute SCI in humans.
Lee
Jee Y
JY
Neurodegeneration Control Research Center, and Age-Related and Brain Diseases Research Center, Department of Biochemistry and Molecular Biology and Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Medical Building, Seoul 130-701, Korea.
Chung
Hyunju
H
Yoo
Young S
YS
Oh
Young J
YJ
Oh
Tae H
TH
Park
Seungjoon
S
Yune
Tae Y
TY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D054439:Ghrelin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000534:rehabilitation*
D061945:Caspase Inhibitors; D054439:Ghrelin; D045304:Cytochromes c; D053148:Caspase 3