Drug targeting to the brain: transfer of picolinic acid along the olfactory pathways.
Picolinic acid (PA) protects against quinolinic acid- and kainic acid-induced neurotoxicity in the brain. To study the uptake of PA to the brain, we administered [3H]PA via a unilateral nasal instillation or iv injection to mice. Autoradiography demonstrated a rapid uptake of radioactivity in the olfactory nerve layer and in the ipsilateral olfactory bulb (OB) following nasal instillation of [3H]PA. After 4 h, there was a high level of radioactivity in the central parts of the ipsilateral OB and olfactory peduncle. Moreover, iv injection of [3H]PA demonstrated a selective uptake and retention of radioactivity in the OB. Gas chromatography-mass spectrometry (GC-MS) demonstrated the presence of PA and PA-glycine conjugate in the OB. In mice with reduced peripheral olfactory innervations there was a decreased uptake of [3H]PA in the OB as compared to controls suggesting that an intact olfactory neuroepithelium is a prerequisite for an uptake of PA to the OB. There is an increased interest in brain targeting of drugs with limited ability to pass the blood-brain barrier. The present results demonstrate that PA fulfils structural requirements for a transfer along the olfactory pathways to the brain.
Bergström
U
U
Department of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, PO Box 573, SE-751 23 Uppsala, Sweden.
Franzén
A
A
Eriksson
C
C
Lindh
C
C
Brittebo
E B
EB
D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D007275:Injections, Intravenous; D051379:Mice; D009833:Olfactory Pathways / Q000187:drug effects / Q000378:metabolism*; D010848:Picolinic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics
D010848:Picolinic Acids; C030614:picolinic acid