Investigation of the dose-dependent neuroprotective effects of agmatine in experimental spinal cord injury: a prospective randomized and placebo-control trial.
OBJECTIVE
No definitive treatment for spinal cord injuries (SCIs) exists, and more research is required. The use of agmatine [4-(aminobutyl)-guanidine-NH2-CH2-CH2-CH2-CH2-NH-C(-NH2)(=NH)], a guanidinium compound formed by decarboxylation of L-arginine by arginine decarboxylase, is a neurotransmitter-neuromodulator with both N-methyl-D-aspartate receptor (NMDAR)-antagonizing and nitric oxide synthase (NOS)-inhibiting activities. The purpose of this study was to demonstrate the dose-dependent activity of agmatine, an inducible NOS (iNOS) inhibitor and selective NMDAR antagonist, on biochemical and functional recovery in an experimental rat SCI model.


METHODS
This study involved 40 Wistar albino male rats. The rats were subjected to sleep-awake cycles for 7 days before surgery. In each group, general anesthesia was induced by a 60-mg/kg ketamine injection. For the surgical SCI model, a Yaşargil aneurysm clip was placed in the spinal cord. The study was conducted in the following four main groups: Group I (control group) laminectomy only; Group II, trauma-only group and SCI; Group III, laminectomy, SCI and agmatine 50 mg/kg for 10 days; and Group IV, laminectomy, SCI, and agmatine 100 mg/kg for 10 days. On Day 1, no statistical difference was observed in any group (p < 0.005, analysis of variance [ANOVA] and the Fisher protected least significant difference [PLSD]). On Day 2, no statistical difference was noted among Groups II, III, and IV (p = 0.27, p = 0.42, and p = 0.76, respectively; ANOVA and Fisher PLSD). Beginning on Day 3, recovery in Groups III and IV differed significantly from that in Group II (p < 0.005, ANOVA and Fisher PLSD), and a statistically significant difference between Groups III and IV was observed, which also was present on Days 5, 7, and 10 (p = 0.003, p = 0.0024, and p = 0.0036, respectively; ANOVA and Fisher PLSD). Several observations were noteworthy: motor function scores were reduced significantly in the spinal cord-injured rats compared with the controls (p < 0.005); on Day 1, the agreement of motor function scores in rats in each SCI group indicated that the traumatic event had been replicated equally across all groups (p = 0.59, p = 0.59, and p = 0.28); a statistically significant difference in motor function scores developed on Day 3 between the rats subjected to trauma alone (Group II) and those treated with agmatine (Groups III and IV) (p < 0.005); and no statistically significant intergroup difference in motor function existed at any postinjury interval between the 50- and 100-mg/kg/day agmatine-treated rats (p > 0.005).


CONCLUSIONS
Agmatine administration following SCI was shown to reduce NO levels significantly. No statistically significant intergroup difference in the reduction of NO levels was found between rats treated with 50- and 100-mg/kg/day doses of agmatine. Administration of a 100-mg/kg/day dose of agmatine reduced the NO levels to those measured in controls. The authors conclude that with additional studies into the role of agmatine, this drug may be helpful in the treatment of patients with SCIs.
Kotil
Kadir
K
Department of Neurosurgery, Haseki Educational and Research Hospital, Istanbul, Turkey. kadirkotil@superonline.com
Kuscuoglu
Ufuk
U
Kirali
Mehmet
M
Uzun
Hafize
H
Akçetin
Mustafa
M
Bilge
Turgay
T
D000376:Agmatine / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007796:Laminectomy; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000376:Agmatine; D008315:Malondialdehyde; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D016194:Receptors, N-Methyl-D-Aspartate; D017392:Thiobarbituric Acid Reactive Substances