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NEUROPHARMACOLOGY

Inhibitors of Cyclooxygenase-2, but Not Cyclooxygenase-1 Provide Structural and Functional Protection against Quinolinic Acid-Induced Neurodegeneration

Division of Biological Research, Alkermes, Inc., Cambridge, Massachusetts (H.C.S.-B., D.F.E., S.B., K.H., S.R., D.L., B.P., L.N., K.F., A.S.B., R.T.B.); and Department of Neurological Sciences, Rush Presbyterian Medical Center, Chicago, Illinois (E.-Y.C., T.K., J.H.K.)

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.

Address correspondence to: Anthony S. Basile, Biological Research, Alkermes, Inc., 88 Sidney St., Cambridge, MA 02139. E-mail: anthony.basile{at}alkermes.com

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