Geranylgeranylacetone limits secondary injury, neuronal death, and progressive necrosis and cavitation after spinal cord injury.
This study evaluates the neuroprotective effects of geranylgeranylacetone (GGA), which is known as an antiulcer agent and more recently as a heat-shock and other neuroprotective protein inducer, on secondary degeneration after spinal cord injury in rats. Crush injuries were produced at the T8 level using an extradural approach. Optimal administration conditions of GGA were established in an initial experiment by evaluating the appearance of lesions 24 h after injury in sections stained with H-E. Then, in a second experiment, animals treated with the optimal condition (600 mg/kg, 24 h before injury and thereafter every 24 h) were allowed to survive for 6 and 24 h and 1, 3, and 8 weeks after injury, and spinal cords were prepared for histological evaluation by staining for H-E for general histopathology and by silver staining for axons. There was a significant reduction (46%) in lesion volume 24 h after injury in animals treated with optimal administration conditions. The increase in tumor necrosis factor-alpha (TNF-alpha) and the accumulation of neutrophils in the damaged segment of the spinal cord 4 h after injury were significantly inhibited in animals that received GGA. Lesion size and cavitation area remained smaller in treated animals throughout the post-injury survival interval. These results suggest that GGA administration significantly reduces the secondary degeneration that would otherwise occur. The mechanism by which GGA exerts its beneficial effect is unknown but may involve reduction of TNF-alpha activation at the injured cord and/or inhibition of inflammation.
Fujiki
Minoru
M
Department of Neurosurgery, School of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita 879-5593, Japan. fuijiki@med.oita-u.ac.jp
Furukawa
Yoshie
Y
Kobayashi
Hidenori
H
Abe
Tatsuya
T
Ishii
Keisuke
K
Uchida
Susumu
S
Kamida
Tohru
T
D000818:Animals; D003952:Diagnostic Imaging / Q000379:methods; D004224:Diterpenes / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D016179:Granulocyte Colony-Stimulating Factor; D016298:Hematopoietic Cell Growth Factors / Q000378:metabolism; D007377:Interleukin-3; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009336:Necrosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins; D016622:Silver Staining / Q000379:methods; D013119:Spinal Cord Injuries / Q000150:complications* / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004224:Diterpenes; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor; C031049:geranylgeranylacetone