Pharmacokinetics of intrathecally applied BDNF and effects on spinal motoneurons.
Brain-derived neurotrophic factor (BDNF) is a potential drug for treatment of amyotrophic lateral sclerosis. Previous studies have demonstrated little or no penetration of the blood-brain barrier by BDNF, hence systemic application does not result in significant penetration into the spinal cord to produce direct action on motoneurons. Intrathecal (i.th) application of BDNF to sheep was investigated as a mean of topical administration. After continuous infusion a caudalcranial gradient of BDNF concentration in cerebrospinal fluid (CSF) and at the meninges was observed. BDNF did not penetrate spinal parenchyma but accumulated in spinal motoneurons probably due to axonal uptake in ventral roots and subsequent retrograde transport. Spinal motoneurons showed reduced levels of tropomyosin receptor kinase (trk) B and increased levels of c-fos at high BDNF doses in comparison to treatment with saline, even after treatment periods of several months. After bolus injection and cessation of continuous delivery multiphasic reduction of the BDNF concentration in CSF was detected. Our study demonstrates that i.th. application of BDNF is feasible, setting the stage for future clinical trials.
Dittrich
F
F
Department of Neurology, University of Würzburg, Germany.
Ochs
G
G
Grosse-Wilde
A
A
Berweiler
U
U
Yan
Q
Q
Miller
J A
JA
Toyka
K V
KV
Sendtner
M
M
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000493:pharmacokinetics*; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007278:Injections, Spinal; D009046:Motor Neurons / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012756:Sheep; D013116:Spinal Cord / Q000187:drug effects*
D019208:Brain-Derived Neurotrophic Factor; D011505:Protein-Tyrosine Kinases