Evaluation of novel neuroprotective strategies in the treatment of retinal ganglion cell degeneration by multiscale 3D neuroimaging

Abstract 

Glaucoma is a chronic neurodegenerative disease and the leading cause of irreversible blindness worldwide. It is due to the progressive degeneration of retinal ganglion cells (RGC) by apoptosis associated with axonal degeneration and synaptic loss in dendrites and axon terminals. Currently, there are no drugs to counteract the neurodegeneration of RGCs. Thus, neuroprotection remains a major unmet need in the treatment of glaucoma.
The project aims at evaluating the potential neuroprotective effects of JNJ16259685, a mGlu1 receptor negative allosteric modulator, and of Idebenone, an antioxidant compound, alone or in combination, in an experimental model of glaucoma. As a read out, to quantitate the potential neuroprotective effects of a chronic treatment in DBA/2J mice, a genetic mouse model of glaucoma, we will analyze retina and stations of the visual pathway by X-ray phase-contrast computed tomography. X-PCI-CT is the state-of-the-art technique to achieve multiscale 3D image of biological samples at (sub)micrometric resolution and can be used to carry out unbiased quantifications of cellular and vascular structures within large nervous-tissue samples. This technique will be combined with elemental analysis by X-ray fluorescence and serial block-face scanning electron microscopy (SBF-SEM), the state-of-the-art laboratory technique to 3D image samples at nanometric resolution and analysis of markers of neuroinflammation and stereological counts of RGCs by immunohistochemistry.
The combination of the X-PCI-CT and SBF-SEM with immunohistochemistry will highly improve the
characterization of the events leading to neurodegeneration and of the potential neuroprotective effects of proposed compounds in glaucoma.