Kinesin-1 and degenerative changes in optic nerve axons in NMDA-induced neurotoxicity

Abstract

We examined the histologic findings of optic nerve axons and changes in kinesin-1, which is involved in axonal flow, in N-methyl- d-aspartate (NMDA)-induced neurotoxicity in rats. Substantial degenerative changes visualized as black profiles and pale large axons were observed 72 h after NMDA injection, but those degenerative changes were not apparent in axons 12 and 24 h after injection. Morphometric analysis showed a significant, approximately 40% reduction in the number of axons 72 h after NMDA injection. Immunohistochemical study showed that there was a recognizable loss of neurofilament-immunopositive dots, but myelin basic protein immunostaining was unchanged 72 h after NMDA injection. Western blot analysis showed early elevation of kinesin-1 (KIF5B) protein levels in the retina 24 and 72 h after NMDA injection. Conversely, significant decreases in KIF5B protein levels in the optic nerve were seen during the same time course. Immunohistochemical study also showed that there was a reduction in KIF5B immunoreactivity in axons, but neurofilament immunostaining was unchanged 24 h after NMDA injection. These findings suggest that the intravitreal injection of NMDA causes neurofilament loss without myelin alteration in the early stage. The depletion of kinesin-1 precedes axonal degeneration of the optic nerve in NMDA-induced neurotoxicity.