Interleukin-1 receptor antagonist attenuates the severity of spinal cord ischemic injury in rabbits.
OBJECTIVE
Thoracic and thoracoabdominal aortic surgery is sometimes complicated by subacute or delayed paraplegia. Pro-inflammatory cytokine interleukin-1 (IL-1) beta has been implicated in extensive inflammation and progressive neurodegeneration after ischemia. Using a rabbit model, we investigated the neuroprotective effects of IL-1 receptor antagonist (IL-1ra) in a temporal fashion.


METHODS
Spinal cord ischemia was induced by aortic cross-clamping in New Zealand White rabbits. The animals were assigned to three groups. Group C (n = 20) received saline (0.2-mL) and Group I (n = 20) received IL-1ra (200-microg/0.2-mL) intrathecally just after reperfusion. Group S (n = 3) underwent sham operation without aortic occlusion. We assessed the neuroprotective effects of IL-1ra by evaluating neurological function, histopathological changes, and in-situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL staining). We also measured the levels of Nitric Oxide (NO) and S100beta in cerebrospinal fluid (CSF). Each evaluation was performed sequentially within 120 hours after reperfusion.


RESULTS
Group C showed progressive deterioration of motor function which became statistically significant from 48 hours after the onset of reperfusion (P < .05, P < .01, P < .001, P < .001 at 48, 72, 96, and 120 hours, respectively). Compared to Group C, a higher number of viable neurons was observed with less severe spinal cord injury in Group I (P < .01, .05 and .05 at 24, 72, and 120 hours, respectively). TUNEL-positive neurons were also significantly reduced by the administration of IL-1ra (P <.01 and .05 at 24, and 120 hours, respectively). The difference between Group C and Group I with regard to NO was significant at 72 and 120 hours (P < .05), while that in terms of S100beta was significant only at 24 hours (P < .05).


CONCLUSIONS
Administration of IL-1ra attenuates spinal cord ischemic-reperfusion injury as evidenced by reducing both neuronal necrosis and apoptosis.
First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan. sakuzawa@hama-med.ac.jp
Satoshi
S
Akuzawa
Teruhisa
T
Kazui
Enyi
E
Shi
Katsushi
K
Yamashita
Abul Hasan Muhammad
AH
Bashar
Hitoshi
H
Terada
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D020287:In Situ Nick-End Labeling; D007278:Injections, Spinal; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009336:Necrosis; D009414:Nerve Growth Factors / Q000134:cerebrospinal fluid; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000134:cerebrospinal fluid; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000134:cerebrospinal fluid; D012720:Severity of Illness Index; D020760:Spinal Cord Ischemia / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D009569:Nitric Oxide