Distribution of intracerebral ventricularly administered neurotrophins in rat brain and its correlation with trk receptor expression.
To assess the potential effectiveness by which injected neurotrophins can diffuse throughout the brain, we used autoradiographic and immunohistochemical techniques to examine the brain distributions of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) after a single injection into the lateral cerebral ventricle (ICV) in rats. As described previously, ICV-injected NGF labeled cholinergic neurons in the basal forebrain. Injection of BDNF resulted in few or no labeled neurons in the basal forebrain or in the substantia nigra. However, very intense labeling was associated with the ventricular walls and immediate parenchyma. The distribution of NT-3 after ICV injection was intermediate between that of NGF and BDNF. In the basal forebrain, similar neurotrophin distributions were observed in neonate versus adult animals. Our in situ hybridization analysis has shown that mRNA encoding the BDNF receptor(s) (trkB) is highly expressed by ependymal cells as well as by many neurons and glia. On the other hand, expression of the high-affinity NGF receptor (trkA) is restricted to cholinergic neurons in basal forebrain and striatum. In addition, staining with antisera specific for the trkA or trkB receptors demonstrated that their expression patterns closely reflect their mRNA distributions. Taken together, these data suggest that the presence of the trkB receptor on the ependymal layer of the ventricle and its expression throughout the brain parenchyma represents a significant impediment to the adequate diffusion of ICV-injected BDNF into the brain for delivery to target neurons.
Yan
Q
Q
Department of Neurobiology, Amgen, Inc., Amgen Center, Thousand Oaks, California 91320.
Matheson
C
C
Sun
J
J
Radeke
M J
MJ
Feinstein
S C
SC
Miller
J A
JA
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020933:Neurotrophin 3; D016548:Prosencephalon / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000096:biosynthesis*; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis*; D020801:Receptor, Ciliary Neurotrophic Factor; D020917:Receptor, trkA; D017978:Receptors, Growth Factor / Q000032:analysis / Q000096:biosynthesis*; D017475:Receptors, Nerve Growth Factor / Q000032:analysis / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013378:Substantia Nigra / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA