Intranasal delivery of human beta-amyloid peptide in rats: effective brain targeting.
(1) Intranasal administration is a non-invasive and effective way for the delivery of drugs to brain that circumvents the blood-brain barrier. The aims of the study were to test a nasal delivery system for human beta-amyloid (A beta) peptides, to measure the delivery of the peptides to brain regions, and to test their biological activity in rats. (2) A beta(1-42), in the form of a mixture of oligomers, protofibrils, and fibrils was dissolved in a nasal formulation containing hydrophobic, hydrophylic, and mucoadhesive components. The peptide solution was administered intranasally to rats as a single dose or in repeated doses. (3) Nasally injected A beta labeled with the blue fluorescent dye amino-methyl coumarinyl acetic acid (AMCA) could be detected by fluorescent microscopy in the olfactory bulb and frontal cortex. The concentration of the peptide was quantified by fluorescent spectroscopy, and a significant amount of AMCA-A beta peptide could be detected in the olfactory bulb. Unlabeled A beta also reached the olfactory bulb and frontal cortex of rats as evidenced by intense immunostaining. (4) In behavioral experiments, nasal A beta treatment did not affect anxiety levels (open-field test) and short-term memory (Y-maze test), but significantly impaired long-term spatial memory in the Morris water maze. The treatments did not result in A beta immunization. (5) The tested intranasal delivery system could successfully target a bioactive peptide into the central nervous system and provides a basis for developing a non-invasive and cost effective, new model to study amyloid-induced dysfunctions in the brain.
Sipos
Eszter
E
Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
Kurunczi
Anita
A
Fehér
András
A
Penke
Zsuzsa
Z
Fülöp
Lívia
L
Kasza
Agnes
A
Horváth
János
J
Horvát
Sándor
S
Veszelka
Szilvia
S
Balogh
Gábor
G
Kürti
Levente
L
Eros
István
I
Szabó-Révész
Piroska
P
Párducz
Arpád
A
Penke
Botond
B
Deli
Mária A
MA
D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling / Q000379:methods
D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)