Direct transport of VEGF from the nasal cavity to brain.
The aim of the present study was to assess the potential of delivering VEGF directly into the central nervous system (CNS) following intranasal administration. Adult Sprague-Dawley rats were randomized into two groups, given [(125)I]-VEGF intranasally or intravenously. VEGF was intranasally administered in both nares alternately, the single dose is 10 microl with time interval of 2 min for about 18.5 min. The intravenous (IV) group was treated with 100 microl [(125)I]-VEGF intravenously. Thirty minutes after administration, rats were killed following blood sample collections, then the brains were removed, and olfactory bulb, striatum corpora, cortex, thalamus, pons, cerebella, medulla, hippocampus, cervical cord and other tissues were collected, weighted, under auto gamma counting and autoradiography analysis. Cisternal sampling of cerebrospinal fluid (CSF) was performed in an additional group of animals. Both gamma counting and high resolution phosphor imaging of tissue sections showed that intranasal administration of [(125)I]-VEGF resulted in substantial delivery throughout the CNS. The highest CNS tissue concentration following IN delivery was found in the trigeminal nerve, followed by the optic nerve, olfactory bulbs, olfactory tubercle, striatum, medulla, frontal cortex, midbrain, pons, appendix cerebri, thalamus, hippocampus, cerebellum. Intranasal administration of [(125)I]-VEGF also targeted the deep cervical lymph nodes. CSF did not contain [(125)I]-VEGF following intranasal administration. Intravenous [(125)I]-VEGF resulted in blood and peripheral tissue exposure higher concentrations than that intranasal administration, but CNS concentrations were significantly lower. The results suggest intranasally delivered VEGF can bypass the blood-brain barrier via olfactory- and trigeminal-associated extracellular pathways to directly entry into the CNS. Intranasal administration of VEGF may provide an effective way for the treatments of CNS diseases.
Yang
Ji-Ping
JP
Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province, China.
Liu
Huai-Jun
HJ
Cheng
Song-Ming
SM
Wang
Zhao-Lu
ZL
Cheng
Xi
X
Yu
Hui-Xin
HX
Liu
Xin-Feng
XF
D000281:Administration, Intranasal; D000344:Afferent Pathways / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D009296:Nasal Cavity / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D009832:Olfactory Nerve / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014276:Trigeminal Nerve / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*
D007457:Iodine Radioisotopes; D042461:Vascular Endothelial Growth Factor A