title: Selective inhibition of inducible nitric oxide synthase reduces neurological deficit but not cerebral edema following traumatic brain injury.
abstract: The role of inducible nitric oxide synthase (iNOS) in cerebral edema and neurological deficit following traumatic brain injury (TBI) is not yet clear-cut. Therefore, the aim of this study was to investigate the effect of three different iNOS inhibitors on cerebral edema and functional outcome after TBI. First, the time courses of blood--brain barrier (BBB) breakdown, cerebral edema, and neurological deficit were studied in a rat model of fluid percussion-induced TBI. The permeability of BBB to Evans blue was increased from 1 h to 24 h after TBI. Consistently, a significant increase in brain water content (BWC) was observed at 6 and 24 h post-TBI. A deficit in sensorimotor neurological functions was also observed from 6 h to 7 days with a maximum 24 h after TBI. Second, a single dose of aminoguanidine (AG; 100 mg/kg, i.p.), L-N-iminoethyl-lysine (L-NIL; 20 mg/kg, i.p.), or N-[3-(aminomethyl)benzyl]acetamide (1400W; 20 mg/kg, s.c.) was administered at 6 h post-TBI. Treatment with AG reduced by 71% the increase in BWC evaluated at 24 h, while L-NIL and 1400W had no effect. In contrast, the three iNOS inhibitors reduced the neurological deficit from 30% to 40%. Third, 1400W (20 mg/kg, s.c.) was administered at 5 min, 8 and 16 h post-TBI. Although this treatment paradigm had no effect on cerebral edema evaluated at 24 h, it significantly reduced the neurological deficit and iNOS activity. In conclusion, iNOS contributes to post-TBI neurological deficit but not to cerebral edema. The beneficial effect of iNOS inhibitors is not due to their anti-edematous effect, and the reduction of cerebral edema by AG is unlikely related to iNOS inhibition. The 6 h therapeutic window of iNOS inhibitors could allow their use in the treatment of functional deficit at the acute phase of TBI.
authors.affiliation: Université Paris Descartes, Faculté de Pharmacie, Laboratoire de Pharmacologie de la Circulation Cérébrale (UPRES EA 2510), 4, avenue de l'Observatoire, 75270 Paris Cedex 06, France.
authors.forename: G
authors.initials: G
authors.lastname: Louin
authors.forename: C
authors.initials: C
authors.lastname: Marchand-Verrecchia
authors.forename: B
authors.initials: B
authors.lastname: Palmier
authors.forename: M
authors.initials: M
authors.lastname: Plotkine
authors.forename: M
authors.initials: M
authors.lastname: Jafarian-Tehrani
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001834:Body Water / Q000187:drug effects; D001929:Brain Edema / Q000473:pathology* / Q000523:psychology; D001930:Brain Injuries / Q000473:pathology* / Q000523:psychology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009422:Nervous System Diseases / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D006146:Guanidines; C090663:N(6)-(1-iminoethyl)lysine; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D052247:Nitric Oxide Synthase Type II; D008239:Lysine; C004479:pimagedine