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T.R. Shantha, MD, PhD, FACA

As therapeutic agents are evolved to treat central nervous system (CNS) afflictions, the blood brain barrier (BBB) has prevented the use of many of these agents for treating neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and other CNS diseases.  The blood brain barrier (BBB) blocks the use of many of the newer engineered-discovered drugs that can protect neurons, promote nerve repair and treat CNS diseases.  This problem is partly resolved by the use of intranasal olfactory mucosa to deliver the therapeutic agents to the central nervous system bypassing through the BBB. 1-9, 13-20, 25 Such a method provides a simple, realistic, and rapid route of delivery into the CNS, bypassing through the BBB, because of the unique connections and transportation routes between the nose olfactory mucosa, olfactory nerves, olfactory bulb, subarachnoid space cerebro spinal fluid (CSF) and CNS (figures 5-7) than any other histological and anatomical structure and site. 1-9, 10, 11, 21, 22, 29 We want to explore and explain how these therapeutic or non-therapeutic agents such as brain eating amoeba, meningococcus and rabies virus and such reach the brain, bypassing through the formidable BBB.12, 24, 26  We have studied the membranes of the CNS since 1960 including olfactory mucosa, and want to discuss in the light of delivering therapeutic agents to CNS.13-16

Various formulations of therapeutic, pharmaceutical, biochemical, and biological agents or compounds have been successfully delivered to the CNS using intranasal olfactory mucosal delivery in a variety of species already. We have used insulin (unpublished, patented) to treat and improve memory in every neurodegenerative disease, including Alzheimer’s and Parkinson’s disease, as well as in healthy students to improve memory, for more than two decades. The results are amazing improvements from the disease state, and improved memory as also reported by Craft, Frey III and others 1, 11, 12, 21, 22, 25 indicating paucity of insulin in the CNS to supply much needed glucose to neurons. That is why de la Monte aptly called Alzheimer’s disease as “diabetes type III of the brain”. 10, 11 The insulin thus delivered through olfactory mucosa binds to the insulin receptors found on the neurons of CNS, resulting in rapid and additional glucose uptake needed by the neurons for proper functioning. 9, 20

Delivery of protein therapeutic agents to the CNS clearly involves extra-neuronal transport as it occurs within 30 minutes rather than hours (e.g. cephalexin).5 Our histological findings support that it passes between intercellular spaces between receptor and supporting cells of the olfactory mucosa, (figures 1-4) subsequently reaching the sub perineural epithelial and inter-axonal spaces in the 20 short olfactory nerves with CSF, (figures 4-7) afterwards it is transported to the CSF around the olfactory bulb and reaches the brain and spinal cord by CSF circulation (figure 7). A number of diverse therapeutic agents microbes and ameba have been found in CNS tissues following intranasal olfactory mucosal administration.1-8, 12, 22, 24, 25, 26, 30   Many hormones, addictive drugs such as cocaine, narcotics, naloxone, and such agents easily reach the CNS rapidly, bypassing through the BBB though the route we describe thereafter, not through the trigeminal nerve branches as hypothesized. 1, 22, 25 (figures 8, 9) The studies show that the delivery to the brain from the olfactory mucosa decreases with increasing molecular weight of the drug, this limits what we can deliver and treat. We studied the olfactory mucosa of the squirrel monkey and other species of experimental animals with brief reference to the work of our and others’ study of the olfactory mucosa. 13-16, 23, 29-31 Our intent was to show, these therapeutic agents and microorganisms take to reach the CNS, bypassing the BBB.  Our studies and other studies are incorporated here even though it is impossible to cite all of them.1-29 Recently, Dahlin successfully visualized the olfactory epithelial drug distribution and transferring pathway from the olfactory mucosa to the CNS using the model drug 3kD fluorescein dextran (FD3).

This article provides an overview of the unique anatomic, histologic, and physiologic characteristics of the nasal olfactory mucosa and its connections that allow certain intranasally applied drugs and microbes transported across the nasal respiratory mucosa and olfactory mucosa, and subsequently be transported directly into the CNS.

Read Routes of Nasal Olfactory Mucosal Transport of Therapeutic Agents, Microorganisms and Amoebae to the CNS Bypassing the Blood Brain Barrier (Drugs to treat Alzheimer’s, Parkinson’s and such delivered using olfactory mucosal route) By T.R. Shantha, MD, PhD, FACA