Distribution of [125I]nerve growth factor in the rat brain following a single intraventricular injection: correlation with the topographical distribution of trkA messenger RNA-expressing cells.
The present study determined the topographical distribution of [125I] nerve growth factor in rat brain at various time points following an intraventricular injection. In addition, we quantified the tissue content of nerve growth factor in various brain tissues following the injection. Autoradiographic analysis of the distribution of [125] nerve growth factor indicated that the neurotrophin is rapidly distributed within the entire ventricular system. However, penetration of nerve growth factor into the brain parenchyma was very limited. At early time points following an injection of nerve growth factor, there was an accumulation of label in the immediate vicinity of the lateral ventricle and third ventricle with predominant labeling around the septum, hypothalamus and cerebellum. By 24 h following nerve growth factor administration, there was discreet labeling of the lateral septum, medial septum, diagonal band, hypothalamus, olfactory tubercle and nucleus of the olfactory tract, and some label was present in the hippocampus and subiculum. Quantitative ELISA of nerve growth factor in brain tissues 1 h following the injection indicated a 446% and 133% increase over basal levels of nerve growth factor in the basal forebrain and hippocampus, respectively. At 24 h nerve growth factor levels measured in brain were not significantly different from endogenous basal levels as determined by ELISA, whereas there were high quantities of 125I present in the thyroid gland, suggesting that the administered [125I] nerve growth factor was rapidly degraded following the intraventricular injection. We observed a similar labeling pattern of the medial septum/diagonal band cholinergic cell body group 24 h following either an intraventricular or intrahippocampal injection of [125I] nerve growth factor. There was a good correlation between the [125I] nerve growth factor labeling pattern and the presence of trkA messenger RNA. This suggested that, at least in the septohippocampal pathway, nerve growth factor accumulated in a region which contained trkA nerve growth factor receptors. Thus, this study shows that after a single unilateral intraventricular injection of nerve growth factor into rat brain there is effective uptake by diagonal band/septal cells on both sides of the brain, and by cells whose positions correlate with the locations of cholinergic and trk A messenger RNA-expressing cells. Significant uptake was also observed in the hypothalamus and cerebellum. The very limited penetration and rapid degradation of intraventricularly administered nerve growth factor suggests that tissue penetration may be a limiting factor when attempting to influence brain neurons by exogenous neurotropic factors.
Lapchak
P A
PA
Cephalon Inc., Department of Molecular Pharmacology, West Chester, PA 19380-4245.
Araujo
D M
DM
Carswell
S
S
Hefti
F
F
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D017403:In Situ Hybridization; D007276:Injections, Intraventricular; D007457:Iodine Radioisotopes; D007700:Kinetics; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009928:Organ Specificity; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis*; D014018:Tissue Distribution
D007457:Iodine Radioisotopes; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA