As therapeutic agents have evolved to
treat central nervous system (CNS) afflictions, the blood brain barrier (BBB)
has prevented the use of many of these drugs for treating neurodegenerative diseases,
such as Alzheimer’s, Parkinson’s, tumors, and other CNS diseases.1-17
The BBB blocks entry of many traditional and newly discovered drugs inside the brain
that can protect neurons; promote nerve repair; and cure, curtail, and treat
many untreatable CNS diseases. This problem is partly resolved by the use of
the intranasal olfactory mucosa to deliver therapeutic agents to the CNS
bypassing through the BBB. This simple, rapid delivery route is ideal over any
other micro-anatomical structure and site due to the unique connections and
transportation routes between the nasal olfactory mucosa, 20 olfactory nerves,
olfactory bulb, subarachnoid space cerebrospinal fluid (CSF), and CNS (Figures
1-6).13,17-24 The following will explore and explain how therapeutic
and non-therapeutic agents, such as brain-eating amoeba,24 meningococcus,
and rabies virus,20,23,24 and such can reach the brain, bypassing through
the formidable BBB based on the unique micro-anatomic and physiologic
characteristics of the nasal olfactory mucosal route and its CNS connections18
that allow transportation directly into the CNS. These findings are based on
decades of our own as well others’ studies.3-11,16,18-22
& HISTOLOGICAL ASPECTS
The olfactory mucosa is situated
within the recesses of the skull under the cribriform plate of the ethmoid bone
that forms the roof of the nose, situated 7 cm from the nostril, being
positioned partly on the nasal septum and partly on the superior turbinate (Figures
1-4).11,17,18 It is not easily accessible in humans;17 hence,
therapeutic agents need to be delivered to this narrow passage to treat CNS afflictions
as described further (Figure 1). The olfactory mucosa is made up of a mucus
layer situated on the top of the receptors cells, supporting cells between the
receptor cell, basal cells below the receptor and supporting cells, and goblet cells
extending from the lamina propria opening on the olfactory mucosa supplying the
mucosal coating to the olfactory mucosa (Figures 2-5). The lamina propria,
below the receptor and basal cells, has 20 olfactory nerve bundles with BV
(ethmoidal) and lymphatics (deep cervical) surrounded by connective tissue,
which form the epineural and perineural connective tissue around the 20
olfactory nerve trunks that are connected to olfactory bulb leptomeninges and
There are 10 to 23 cilia from each
receptor cell (extension of dendrites from receptor cells) and microvilli of
the sustentacular cells embedded in a thick viscous layer of mucus secreted
from goblet cells from the lamina propria that do not allow them to move and
may also not participate in the transport of olfactory mucosa-delivered
therapeutic agents. Based on our studies, there is a possibility that CSF
surrounding the olfactory bulb seeps from the olfactory nerve fasciculi between
these cells and emerging axons, supplying the neurotrophic factors, and at the
same time, keeping the olfactory mucosa wet (Figures 1-4). A collection of
axons form the olfactory nerves (olfactory nerves trunks or fasciculi)
surrounded by perineural epithelial cells,18-20 not by Schwann cells,2,18
creating sub-perineural epithelial and inter-axonal spaces around each nerve
fasciculus (Figures 5 & 6), which act as a highway and byway to the subarachnoid
space around the olfactory bulb and brain. Our study for decades has shown that
this perineural epithelial covering is a direct extension of pia-arachnoid
mater extension from the olfactory bulb akin to the leptomeninges that cover
the entire peripheral nervous system derived from the rest of the CNS
(including sensory and motor end organs, perisynatpic cells of the motor endplate).19,20
SPREAD & FINAL DESTINATION OF THERAPEUTIC AGENTS DELIVERED TO OLFACTORY
Without going into micro-anatomical detail,
the following are the routes taken by therapeutic agents deposited on the
olfactory mucosa through intra-neuronal and extra-neural pathways to various
centers of the CNS bypassing the BBB based on decades of our own and others’
1. A majority of therapeutic agents
deposited on the olfactory mucosa are transported between the supporting cells,
receptor cells, and dying receptor cells in the olfactory mucosa (Figures 2-4).
At any given time, about 10% of the receptor cells are dying, creating a space
(Figure 3) for transport of therapeutic agents and microorganisms to the sub-perineural
epithelial space around the 20 olfactory nerves (Figures 1-5). Therapeutic
agents (including microbes) deposited on the olfactory mucosa spread between
receptor and supporting cells, reaching the lamina propria. Due to paucity of
perineural epithelial cells covering around some of the emerging axon bundles
(Figure 2), some of it enters the BV and deep cervical lymph nodes through
lymphatics from the lamina propria.28
2. From the intercellular route of the
olfactory mucosa, most therapeutic agents are transported to sub-perineural
epithelial and inter-axonal spaces of the 20 olfactory nerves (Figures 2, 3, 5
& 6). The therapeutic agents spread around the olfactory bulb’s
subarachnoid space CSF (Figures 1 & 4) through the olfactory nerves
entering through the cribriform plate of the ethmoid bone.
3. From the olfactory bulb
subarachnoid space CSF (Figures 1, 4 & 5), therapeutic agents and microbes are
transported to the CSF in the subarachnoid space, specifically to the suprachiasmatic
and interpeduncular CSF cisterns (Figure 5) then to neuropile through the CNS
Virchow-Robin space and blood vessels’ paravascular routes.
4. From this subarachnoid space and
CSF cisterns, therapeutic agents spread to the temporal lobe, hypothalamus,
thalamus, amygdala, entorhinal cortex, hippocampus, prefrontal cortex, and such
(Figure 4 & 5). This is why we believe therapeutic agents to treat
Parkinson's, Alzheimer’s, and other neurodegenerative diseases can utilize insulin
and other adjuvant therapeutic agents13,6,17 using these main
transportation routes bypassing the BBB (Figure 3 & 5).
5. From the CSF pool around the
olfactory bulb and brain, therapeutic agents spread to the subarachnoid space around
the spinal cord due to CSF circulation and are distributed to the neuropile and
neurons of the spinal cord through the Virchow-Robin space22 and parascular
6. Therapeutic agents from CSF
delivered through olfactory nerves spread to the brain structures and neuropile
through the CSF and subarachnoid space, the Virchow-Robin space, paravascular routes,
and glymphatics deep into the brain and spinal cord to the site of pathology
7. Therapeutic agents and microbes
from Virchow-Robin spaces22 around the CNS and peripheral NS
penetrating blood vessels from the subarachnoid space are transported through
the paravascular space formed around all the blood vessels of the brain and
astroglial cells’ end-feet encasing these blood vessels (named the glymphatic space/channel/transportation
routes). It is one of the most important transportation routes regarding how
therapeutic agents from the olfactory mucosa to CSF reach deep brain neuronal structures
in the treatment of CNS diseases, including Parkinson's and Alzheimer's
diseases, evading and dodging the BBB. Brain metabolites also take the same
exit routes to systemic circulation.27
(transcellular-axoplasmic) spread results when therapeutic agents deposited in
the olfactory mucosa are endocytosed by dendritic olfactory receptor cells,
then to axoplasm of receptor cells and then into axons, olfactory nerves,
olfactory bulb, glomeruli, then through the olfactory tracts axons to mitral
and tufted cells, then to olfactory tubercle, amygdala, the prepyriform cortex,
the anterior olfactory, nucleus, and the entorhinal cortex as well as to the
hippocampus, hypothalamus, and thalamus (Figures 4 & 5). This is a very slow
spread except for neurotrophic viruses, such as rabies.20,23
9. Therapeutic agents absorbed from
the blood vessels of the olfactory and nasal mucosa reach the choroid plexus,
then therapeutic agents permeate to the ventricle, central canal of the spinal
cord, then to CSF and then to neuropile close to the ependymal lining from
systemic absorption through the respiratory and nasal mucosa. Spreading through
this route is minimal at best.
10. The olfactory mucosa is surrounded
by valveless Batson plexus of veins25 that may uptake very small
amounts of therapeutic agents from the lamina propria on turbinates and
ethmoidal air sinus walls and transport them to the cavernous sinus, other
venous sinuses, and to CSF in the subarachnoid space to be transported to
neuropile as previously described.
11. The blood vessels (probably Batson
plexus) and nerve root filaments on the medial walls of the ethmoid air sinus adjoining
the olfactory mucosal lamina propria may transport minute quantities of therapeutic
agents to CSF and then to the CNS.
12. Regarding delivery to the
olfactory, lymphatics play no role in transport of therapeutic agents to the
CNS. They only pick up the therapeutic agents and particulate matter leaked
through the olfactory nerves at the lamina propria under the basal cells from
the olfactory mucosa (Figures 2 & 4) and transport them to the deep
cervical lymphatic system.18,26
MUCOSAL TRANSPORT OF NON-THERAPEUTICS
Evidence of sub-perineural epithelial spread
(Figures 1-7) of therapeutic agents through the olfactory nerves from the
olfactory mucosa is further substantiated by the “brain-eating amoeba”24
and meningococci, transported through the olfactory nerve sub-perineural
epithelial and interaxonal space, not through trans-axoplasmic transport, which
is the route for rabies virus,20,23 and maybe other neurotrophic viruses.
Figures 1-6 are self-explanatory and detail
the structure and the possible route of transport of therapeutic agents and
microbes from the olfactory mucosa to the CNS as previously described.
NERVE BRANCH AS A ROUTE FOR TRANSPORT
Our studies showed that the only branches
exposed in the olfactory mucosal region are the anterior ethmoidal nerve, a branch
of ophthalmic division of the trigeminal nerve, and a small fasciculus branch
from the sphenopalatine ganglion, not the entire trigeminal complex as reported
and publicized.1,2,10 These small nerve fasciculi are covered with
various connective tissue layers (epineural and perineural connective tissue)
and multiple layers of perineural epithelial cells with sub-perineural
epithelial and inter-axonal potential spaces that communicate with subarachnoid
space CSF of the CNS and spinal cord (Figure 6) that has the potential to transport
therapeutic agents to the CNS CSF.18-21 It is a slow route, and
minimal to exert direct effect to cure or curtail CNS diseases. On the other
hand, the trigeminal nerve complex plays a major role in the transport of
rabies virus to the brain from the facial bites.20,23
We conclude that the olfactory mucosa,
olfactory epithelium, olfactory nerves, sub-perineural epithelial and
interaxonal spaces, olfactory bulb, olfactory bulb surrounding CSF, olfactory
and suprachiasmatic tract along with suprachiasmatic cisterns and
inter-peduncular cisterns, Virchow-Robin space, and glymphatic transport and
clearance pathway, are the main necessary highways for the direct transport of
therapeutic agents, microorganisms, viruses, and amoeba to the CNS, bypassing
the BBB. There is a constant seepage with retrograde and downward flow of CSF
from the olfactory bulb surrounding CSF to the lamina propria, lamina propria
lymphatic, BV, and olfactory mucosa itself, and vice versa. Intranasal olfactory
mucosal administration of therapeutic agents for the treatment of neurodegenerative
and many CNS diseases overcomes the limitations due to the BBB, and provides an
effective direct delivery method for a selective group of therapeutic agents to
treat the brain regions that are pathologically affected with Alzheimer’s and
Parkinson’s disease as well as other CNS diseases.
1. Thorne RG, Frey WH. Delivery of
neurotrophic factors to the central nervous system. Clin Pharmacokinet. 2001;40:907-946.
2. Illum L. Transport of drugs from
the nasal cavity to the CNS. Eur J Pharm Sci. 2000;11:1-18.
3. Mathison S, Nagilla R, Kompella UB.
Nasal route for direct delivery of solutes to the central nervous system: fact
or fiction? J Drug Target. 1998;5:415-441.
4. Thorne RG, Emory CR, Ala TA, Frey
WH. Quantitative analysis of the olfactory pathway for drug delivery to the
brain. Brain Res. 1995;692:278-282.
5. Sakane T, et.al. Transport of
cephalexin to the cerebrospinal fluid directly from the nasal cavity. J Pharm
6. Talegaonkar S, Mishra PR.
Intranasal delivery - An approach to bypass the blood brain barrier. Indian J
7. Majgainya S, Soni S, Bhat P. Novel
approach for nose-to-brain drug delivery bypassing blood brain barrier by
pressurized olfactory delivery device. J App Pharm. 2015;7(3):148-163.
8. Parvathi M. Intranasal drug
delivery to brain: An overview. Int. J Res Pharmacy Chem. IJRPC
9. De Lorenzo, AJD. The olfactory
neuron and the blood–brain barrier. Sci. 1970;70:466-467.
10. Frey WH. Bypassing the blood-brain
barrier to deliver therapeutic agents to the brain and spinal cord. Drug Deliv
11. Gopinath PG, Gopinath G, Kumar
TCA. Target site of intranasally sprayed substances and their transport across
the nasal mucosa: a new insight into the intranasal route of drug delivery.
Curr Ther Res. 1978;23,596-607.
12. Dahlin M, Bergman U, Jansson B,
Bjork E, Brittebo E. Transfer of dopamine in the olfactory pathway following
nasal administration in mice. Pharm Res. 2000;17:737-742.
13. Craft S, et al. Intranasal insulin
therapy for Alzheimer’s disease and amnestic mild cognitive impairment. Arch
Neurol. Published online September 12, 2011:1-13.
14. Reger MA, Watson GS, Frey WH II,
et al. Effects of intranasal insulin on cognition in memory-impaired older
adults: modulation by APOE genotype. Neurobiol Aging. 2006;27:451-458.
15. Teen E, Terry BM, Rivera EJ,
Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth
factor expression and signaling mechanisms in Alzheimer's disease: is this type
3 diabetes? Alzheimers Dis. 2005;7:63-80.
16. de la Monte SM, Wands JR.
Treatment of Alzheimer's disease in the US;7,833,513 B2.
17. Shantha TR. Alzheimer's disease
treatment with multiple therapeutic agents delivered to the olfactory region
through a special delivery catheter and iontophoresis. US20120323214,
US20140012182, US20150080785, WO/2015/013252A1, and WO/2009/149317A3.
18. Shantha TR, Nakajima Y.
Histological and histochemical studies on the rhesus monkey (Macaca Mulatta)
olfactory mucosa. Yerkes Regional Primate Research Center, Emory University,
Atlanta, Georgia. Z. Zellforsch. 1970;103:291-319.
19. Shantha TR, Bourne GH. Perineural
epithelium; structure and function of nervous tissues. Academic Press.
20. Shantha TR. Presented at Hanoi:
Rabies Cure: Nasal and Oral Route of Transmission of Rabies Virus and Possible
Treatment to Cure Rabies. Rabies in Asia conference in Hanoi (RIACON).
September 10, 2009. US Patent Application Publication Number: 201110020279 Al. Jan.
21. Shantha TR, Bourne. GH. The
perineural epithelium: and significance. J Nature. 1963;4893:577-579.
22. Shantha TR. Peri-vascular
(Virchow-Robin) space in the peripheral nerves and its role in spread of local anesthetics.
ASRA Congress at Tampa. Regional Anesthesia. March-April;1992.
23. Baer G, Shantha TR, Bourne GH. The
pathogenesis of street rabies virus in rats. Bulletin World Health Org. 1965;33:783-794.
24. Baig AM. Pathogenesis of amoebic
encephalitis: are the amoebae being credited to an “inside job” done by the
host immune response? Acta Trop. 2015;148:72-66.
25. Batson OV. The function of the
vertebral veins and their role in the spread of metastases. Ann Surg.
26. Jackson RT, Tigges J, Arnold W.
Subarachnoid space of the CNS, nasal mucosa and lymphatic system. Arch. Otolaryngol.
27. Nedergaard M. Garbage truck of the
brain. Science. 2013;340(6140):1529-1530.
28. Graziadei PPC. Topological
relations between olfactory neurons. Zeitschrift für Zellforschung und
Mikroskopische Anatomie. 1971;118(4):449-466.
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T.R. Shantha, MD, has been a member of the
faculty of Emory University School of Medicine, Medical College of Georgia,
Grady Memorial Hospital, Georgia Baptist Hospital, Columbus Medical Center, and
is presently a visiting professor at JJM Medical College. He has published more
than 100 research articles since 1962 in peer-reviewed reputable journals,
including Nature (7 papers), Science, NEJM, J Urology, Anesthesia, Anatomy, Exp.
Eye Research, American J of Physiology, etc. He discovered Terbutalene as a
treatment for Priapism, which is now used all over the world as the first line
of treatment in emergency rooms and by urologists. He has won numerous awards
for his academic contributions, including AMA and AAPI distinguished physician
awards. He was one of the nominees for the Nobel Prize in Physiology and
Medicine in 2007 for his and Dr. Bourne’s research work on the membranes of the
nervous system discovered at Emory University. His work is quoted in many
medical textbooks and research literature. He has more than
56 patent applications, many published and issued. He is presently working on
the treatment of Alzheimer’s and Parkinson’s disease, sleep apnea, and other