Blood-brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain.
OBJECTIVE
Drug delivery across the blood-brain barrier remains a significant challenge. Based on earlier findings, the authors hypothesized that parasympathetic innervation of the brain vasculature could be used to augment drug delivery to the brain.


METHODS
Using a craniotomy-cerebrospinal fluid superfusate paradigm in rats with an intravenous injection of tracer the authors demonstrated that stimulation of the postganglionic parasympathetic fibers of the sphenopalatine ganglion (SPG) increased the concentration of fluorescein isothiocyanate-dextran (4-250 kD) in the superfusate by two- to sixfold. A histological examination indicated the presence of dextran in the parenchyma. In another experiment the amount of Evans blue dye in the brain following SPG activation was similarly significantly elevated. The chemotherapeutic agents anti-HER2 monoclonal antibody and etoposide were also delivered to the brain and reached therapeutic concentrations. Brain homeostasis was not disturbed by this procedure; a measurement of nicotinamide adenine dinucleotide reduction did not show a decrease in the tissue metabolic state and brain water content did not increase significantly.


CONCLUSIONS
Sphenopalatine ganglion activation demonstrates a promising potential for clinical use in the delivery of small and large molecules to the brain.
Department of Neurology, Rambam Medical Center, Technion Faculty of Medicine, Haifa, Israel. davidy@tx.technion.ac.il
David
D
Yarnitsky
Yossi
Y
Gross
Adi
A
Lorian
Alon
A
Shalev
Itschak
I
Lamensdorf
Rinat
R
Bornstein
Shy
S
Shorer
Avraham
A
Mayevsky
Kaushik P
KP
Patel
N Joan
NJ
Abbott
William G
WG
Mayhan
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism; D002463:Cell Membrane Permeability; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003911:Dextrans / Q000008:administration & dosage / Q000493:pharmacokinetics; D004558:Electric Stimulation / Q000295:instrumentation; D004567:Electrodes, Implanted; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005726:Ganglia, Parasympathetic / Q000166:cytology / Q000378:metabolism*; D007275:Injections, Intravenous; D046911:Macromolecular Substances; D008297:Male; D009412:Nerve Fibers / Q000378:metabolism; D010159:Palate / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013101:Sphenoid Sinus / Q000166:cytology / Q000378:metabolism*
D003911:Dextrans; D046911:Macromolecular Substances; C015219:fluorescein isothiocyanate dextran; D016650:Fluorescein-5-isothiocyanate