PT  - JOURNAL ARTICLE
AU  - Heather C. Salzberg-Brenhouse
AU  - Er-Yun Chen
AU  - Dwaine F. Emerich
AU  - Sam Baldwin
AU  - Ken Hogeland
AU  - Sharon Ranelli
AU  - Denise Lafreniere
AU  - Brigido Perdomo
AU  - Leah Novak
AU  - Theodora Kladis
AU  - Karen Fu
AU  - Anthony S. Basile
AU  - Jeffrey H. Kordower
AU  - Raymond T. Bartus
TI  - Inhibitors of Cyclooxygenase-2, but Not Cyclooxygenase-1 Provide Structural and Functional Protection against Quinolinic Acid-Induced Neurodegeneration
AID  - 10.1124/jpet.103.049700
DP  - 2003 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 218--228
VI  - 306
IP  - 1
4099  - http://jpet.aspetjournals.org/content/306/1/218.short
4100  - http://jpet.aspetjournals.org/content/306/1/218.full
SO  - J Pharmacol Exp Ther2003 Jul 01; 306
AB  - Cyclooxygenases (COXs) are implicated in neurodegenerative processes associated with acute and chronic neurological diseases. Given the potential utility of COX inhibitors in treating these disorders, we examined the nonselective COX inhibitor flurbiprofen, the specific COX-1 inhibitor valeryl salicylate (VS), and the COX-2 inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide (NS-398) for their abilities to protect striatal neurons against a quinolinic acid (QA)-induced excitotoxic lesion. Rats were administered COX inhibitors 10 min before a unilateral QA lesion of the striatum, and then tested 2 to 3 weeks later in a battery of motor tasks (bracing, placing, akinesia, and apomorphine-induced rotations). Lesion volume was assessed using immunohistochemical methods 1 month after lesioning. Orally administered flurbiprofen (50 mg) was highly neuroprotective, preserving 84 to 99% of motor performance (ED50 = 8.6–9.7 mg) while reducing lesion volume 75% (ED50 = 3.2 mg). The identities of the COX isoforms associated with QA-induced neurodegeneration were determined using VS and NS-398. Oral VS was ineffective in virtually all indices of functional neuroprotection. In contrast, oral NS-398 was highly effective, preserving approximately 83% of motor performance at2mg(ED50 = 0.1–0.4 mg), and reducing lesion volume 100% (ED50 = 0.4 mg). Similar results were obtained using inhaled flurbiprofen (2 mg), which preserved 88 to 100% of motor performance while reducing striatal lesion size 92%. These results demonstrate that COX-2 inhibition protects neurons from acute, excitotoxic neurodegeneration. Moreover, formulating a nonselective COX inhibitor into an inhalable preparation dramatically improves its potency in treating acute neuronal damage, a situation where the rapidity of drug delivery and onset of action is critical to clinical efficacy. The American Society for Pharmacology and Experimental Therapeutics