Protein Drug Delivery Using a Novel Maxillofacial Technique Targeting the Visual Pathway in the Brain, the Optic Nerve, and the Retina.

Protein drugs are used for treating many diseases of the eye and the brain. The formidable blood neural barriers prevent the delivery of these drugs into the eye and the brain. Hence, there is a need for a protein drug delivery system to deliver large proteins across blood-neural barriers. Low half-life, poor penetration of epithelial barriers, low stability, and immunogenicity limit the use of non-invasive systemic routes for delivering proteins. In this pre-clinical study, the efficacy of a new maxillofacial route for administering protein drugs using a novel drug delivery system is compared with systemic administration through intra-peritoneal injection and ocular administration through topical eye drops and subconjunctival and intravitreal injections. Bevacizumab and retinoschisin proteins were administered using the maxillofacial technique along with systemic and ocular routes in wild-type male C57BL/6J mice. Liquid chromatography with tandem mass spectrometry and western blot was used to detect bevacizumab in tissue samples. Furthermore, immunohistochemistry was performed to detect the presence and localization of bevacizumab and retinoschisin in the retina and brain. The maxillofacial route of delivery could target the brain including regions involved in the visual pathway and optic nerve. The maxillofacial technique and intravitreal injection were effective in delivering the drugs into the retina. A new concept based on the glymphatic pathway, cerebrospinal fluid drug distribution, and the crossover of ipsilateral optic nerve fibers at optic chiasma is proposed to explain the presence of the drug in contralateral eye following maxillofacial administration and intravitreal injection.

SARS-CoV-2: The Road Less Traveled-From the Respiratory Mucosa to the Brain.

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.

Pulmonary Edema in COVID19-A Neural Hypothesis.

In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. We are proposing a new hypothesis that neurogenic insult may also play a major role in the pathogenesis of these manifestations. SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius (NTS) may play a role in the acute exacerbation of pulmonary edema and microvascular clotting in COVID-19 patients.

Happy Hypoxemia in COVID-19-A Neural Hypothesis.

Many COVID-19 patients are presenting with atypical clinical features. Happy hypoxemia with almost normal breathing, anosmia in the absence of rhinitis or nasal obstruction, and ageusia are some of the reported atypical clinical findings. Based on the clinical manifestations of the disease, we are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius may be the reason for happy hypoxemia in COVID-19 patients.