Protective effects of nicotinamide in a mouse model of glaucoma DBA/2 studied by second-harmonic generation...

Glaucoma is a blinding disease where the retinal ganglion cells and their axons degenerate. Degradation of axonal microtubules is thought to play a critical role in the pathogenesis, but the mechanism is unknown. Here we investigate whether microtubule disruption in glaucoma can be alleviated by metabolic rescue. The morphology and integrity of microtubules of the retinal nerve fibers were evaluated by second-harmonic generation microscopy in a mouse model of glaucoma, DBA/2, which received a dietary supplement of nicotinamide to reduce metabolic stress. It was compared with control DBA/2, which did not receive nicotinamide, and non-glaucomatous DBA/2-Gpnmb+. We found that morphology but not microtubules are significantly protected by nicotinamide. Furthermore, from co-registered images of second-harmonic generation and immunofluorescence, it was determined that microtubule deficit was not due to a shortage of tubulins. Microtubule deficit colocalized with the sectors in which the retinal ganglion cells were disconnected from the brain, indicating that microtubule disruption is associated with axonal transport deficit in glaucoma. Together, our data suggests significant role axonal microtubules play in glaucomatous degeneration, offering a new opportunity for neuroprotection.