Objective: Excitotoxicity is a multistep process that results in either necrosis or apoptosis. It has been associated with neuronal death in trauma, ischemia, and neurodegeneration. The final step in necrotic cell death is the rupture of a cell's plasma membrane; repair of this membrane rupture is a potentially powerful technique of neuroprotection. Poloxamer 188 (P-188) is a synthetic surfactant that seals experimentally porated membranes. This study investigated the usefulness and time dependence of intrathecal P-188 in protecting neurons in an in vivo model of excitotoxicity in the rat.
Methods: Twenty-eight Sprague-Dawley rats underwent striatal infusion of quinolinic acid to produce a spherical excitotoxic lesion. Each animal then received either vehicle or P-188 at 10 minutes, 4 hours, or both time points after surgery by direct cisterna magna injection. Animals were killed at 1 week, and brains were stained immunohistochemically for the neuronal marker Neu-N. Volumes of neuronal loss were calculated and compared between groups by analysis of variance.
Results: All animals were found to have spherical, stereotyped lesions. The animals that received intrathecal poloxamer at the early injection time had statistically smaller lesions (8.16 +/- 6.12 mm(3); n = 5; P = 0.0015) than controls (18.25 +/- 11.42 mm(3); n = 11). Those animals that received poloxamer at both injection times also had statistically smaller lesions (10.57 +/- 9.00 mm(3); n = 7; P = 0.0095). The group that received poloxamer at the late injection time only did not have significantly decreased lesion size (14.86 +/- 7.95 mm(3); n = 5).
Conclusion: Intrathecal P-188 reduces neuronal loss after excitotoxic injury in the rat only when delivered immediately after the toxin. This observation confirms the potential of surfactant molecules as neuroprotectants but predicts that their usefulness is best realized by early and potentially ongoing treatment.