Intracranial Inoculation Is More Potent Than Intranasal Inoculation for Inducing Optic Neuritis in the Mouse Hepatitis Virus-Induced Model of Multiple Sclerosis

Singh, Manmeet; Khan, Reas S.; Dine, Kimberly; Das Sarma, Jayasri; Shindler, Kenneth S.

The precise mechanisms mediating spread of a virus or a drug from the nose to various CNS regions are not fully elucidated. At least three steps are necessary following intranasal administration (1) crossing the epithelial barrier in the nasal cavity, (2) transport from nasal mucosa to site of brain entry, likely across the cribiform plate, (3) transport from the site of brain entry to other anatomical regions. Alternatively, they may be absorbed into the systemic circulation and gain secondary access to the CNS through the blood brain barrier. The speed at which proteins were reported to reach the eye and optic nerve, 30 min after intranasal administration (Khan et al., 2017) , suggests hematogenous spread is very unlikely, and that intraaxonal transport is even more unlikely. It was hypothesized that perhaps some pathway of local diffusion or lymphatic pathway may allow rapid protein diffusion over the relatively short distance from absorption through the cribiform plate to optic nerve (Khan et al., 2017) . For RSA59, prior intracranial studies demonstrate that the virus can use axonal transport machinery to spread intraneuronally (Das Sarma et al., 2009) , thus it is likely that a similar mechanism would be used after intranasal administration and entry into the olfactory nerve. The path from there to optic nerve is not direct, and thus may require much higher titers of virus to occur at a pathologic level, or may not be possible at all. These hypothesized mechanisms may explain why we were not able to see viral staining day 1 post infection whereas the drug ST266 and other small molecules can be found in optic nerve as early as 30 min post intranasal inoculation (Dhuria et al., 2010; Khan et al., 2017) .