Abstract Body: Background
Patients chronically exposed to air pollution suffer myelin damage and neuroinflammation that can inhibit axonal regeneration. Our group has demonstrated that diesel exhaust particulate (DEP) inhalation increases expression of axonal outgrowth inhibitors in mice. The objective of this study was to examine how pharmacologically targeting the Nogo-66 receptor (NgR1) through a novel intranasal route can mitigate this effect.

Methods
Female and male 8-week-old C57BL/6 mice were exposed to 6 weeks of inhaled Filtered Air (FA) and DEP (NIST SRM 2975) at 100μg/m3. Within a week of the exposure ending, we began 30 days of nasal administration of either NEP1-40, an NgR1 antagonist inhibiting peptide, or a scrambled peptide control. There were four groups: NEP 1-40+Filter (NF), NEP 1-40+DEP (ND), Scrambled NEP 1-40+Filter (SF), Scrambled NEP 1-40+DEP (SD). Mice were humanely euthanized. We confirmed intranasal absorption of NEP 1-40 and scrambled peptide with fluorescence analysis of the cortex. Corpus callosum levels of Oligodendrocyte myelin glycoprotein (OMgp), Chondroitin sulfate proteoglycans (CSPGs), Nogo-A membrane protein, Nogo Receptor 1 (NgR1), Paired immunoglobulin-like receptor B (PirB), Aquaporin 4-(AQP4), and degraded myelin basic protein (dMBP) were assayed via immunofluorescence.

Results
In fluorescence analysis of peptide absorption in the cortex, there was no difference between the FA and DEP groups within the active peptide and scrambled peptide arms. In the scrambled peptide arm, DEP exposed mice (SD) had higher levels of NgR1 (p<0.01) compared to the FA (SF) group, with no difference observed in the active peptide arm between DEP (ND) and FA (NF). The SD group had higher levels of OMgp compared to the SF group (p=0.05), with no difference in the active peptide arm. There was a trend towards an increase in PirB in the SD group compared to the SF group (p=0.06), with no difference in the active peptide arm (Figure 1). No significant effects were observed in Nogo-A, CSPG, AQP4, and dMBP between groups.

Conclusion
Nasal administration of NEP 1-40 successfully penetrated into the brain. NEP1-40 peptide administration mitigated expression of axonal outgrowth inhibitor OMgp and axonal outgrowth inhibitor receptors NgR1 and PirB compared to scrambled peptide administration. This suggests that intranasally targeting the NgR1 pathway may be a viable pharmacologic mechanism of facilitating neuronal recovery in patients exposed to air pollution.