Neurological manifestations have been reported in COVID-19; however, the route used by SARS-CoV-2 to enter the brain is still under debate. Recent studies have focused on the olfactory route. SARS-CoV-2 viral proteins were also detected in the glossopharyngeal and vagal nerves originating from the lower brainstem and in isolated cells of the brainstem. Our proof of concept in vivo real-time imaging study of mice using an indocyanine green dye indicated that the neurovascular component of the connective tissue of the respiratory mucosa can also provide an alternate route to the brain.

The blood neural barriers are formidable barriers that prevent delivery of drugs into the eye and the brain. Currently, large biologics are used for treating many diseases of the eye and the brain. But the blood retinal barrier and the blood brain barrier prevent entry of these useful drugs into the eye and the brain respectively. Hence, there is a need for a drug delivery technique to bypass these natural barriers. Bevacizumab (Avastin) is a full length humanized monoclonal antibody with a molecular weight of 149kda. It binds to circulating vascular endothelial growth factor A and prevents interaction with vascular endothelial growth receptors. This results in blocking endothelial response and tumor vascularization. Bevacizumab is used to prevent choroidal neovascularization in age related macular degeneration and to prevent retinal neovascularization in diabetic retinopathy. It is also used for treating certain types of brain cancer. But it crosses neither the blood retinal barrier nor the blood brain barrier. This in vivo mouse study assessed the delivery of a commercial formulation of bevacizumab into the retina of mice using different ocular techniques like topical drops, subconjunctival injection, intravitreal injection and a novel maxillofacial technique. The objective was to assess whether the novel maxillofacial drug delivery technique could deliver drugs into the retina and to compare the efficacy of the maxillofacial technique with the mentioned ocular techniques. The distribution of bevacizumab was further compared with retinoschisin which is a small protein with a molecular weight of 24kda. Intravitreal injection and maxillofacial technique were effective in delivering drugs into the retina. In addition, the maxillofacial technique could target the brain including regions involved in the visual pathway and the optic nerve. The glymphatic pathway could also be targeted for drug delivery. Drug was also detected in the contralateral optic nerve and retina. Based on our study findings, we propose a new concept to explain the presence of the drug in the contralateral eye. We propose that after maxillofacial drug delivery, early distribution of the drug can occur in the CSF at the optic chiasma from the brain via the glymphatic system. In the case of the intravitreal injection, the drug from the experimental eye may be cleared through the glymphatic pathway of the ipsilateral optic nerve into the CSF surrounding the nerve. The crossover of the ipsilateral optic nerve fibers at the optic chiasma can result in further distribution of the drug in the CSF at the optic chiasma. From the region of the optic chiasma, the drug can distribute into the CSF surrounding the contralateral optic nerve. The drug can be then distributed into the contralateral optic nerve through the glymphatic pathway and be delivered into the contralateral eye. The drug can be further cleared into the aqueous of the contralateral eye through the anterior clearance pathway.

Objective Retinoschisis and Norrie disease are X-linked recessive retinal disorders caused by mutations in RS1 and NDP genes respectively. Both are likely to be monogenic and no locus heterogeneity has been reported. However, there are reports showing overlapping features of Norrie disease and retinoschisis in a NDP knock-out mouse model and also the involvement of both the genes in retinoschisis patients. Yet, the exact molecular relationships between the two disorders have still not been understood. The study investigated the association between retinoschisin (RS1) and norrin (NDP) using in vitro and in silico approaches. Specific protein–protein interaction between RS1 and NDP was analyzed in human retina by co-immunoprecipitation assay and MALDI-TOF mass spectrometry. STRING database was used to explore the functional relationship. Result Co-immunoprecipitation demonstrated lack of a direct interaction between RS1 and NDP and was further substantiated by mass spectrometry. However, STRING revealed a potential indirect functional association between the two proteins. Progressively, our analyses indicate that FZD4 protein interactome via PLIN2 as well as the MAP kinase signaling pathway to be a likely link bridging the functional relationship between retinoschisis and Norrie disease.

Objective: Retinoschisis and Norrie disease are X-linked recessive retinal disorders caused by mutations in RS1 and NDP genes respectively. Both are likely to be monogenic and no locus heterogeneity has been reported. However, there are reports showing overlapping features of Norrie disease and retinoschisis in a NDP knock-out mouse model and also the involvement of both the genes in retinoschisis patients. Yet, the exact molecular relationships between the two disorders have still not been understood. The study investigated the association between retinoschisin (RS1) and norrin (NDP) using in vitro and in silico approaches. Specific protein-protein interaction between RS1 and NDP was analyzed in human retina by co-immunoprecipitation assay and MALDI-TOF mass spectrometry. STRING database was used to explore the functional relationship. Result: Co-immunoprecipitation demonstrated lack of a direct interaction between RS1 and NDP and was further substantiated by mass spectrometry. However, STRING revealed a potential indirect functional association between the two proteins. Progressively, our analyses indicate that FZD4 protein interactome via PLIN2 as well as the MAP kinase signaling pathway to be a likely link bridging the functional relationship between retinoschisis and Norrie disease.