Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: comparison between intraparenchymal and intraventricular administration.
Penetration into the brain is an important consideration in the pharmacological use of neurotrophic factors for the treatment of brain neurodegeneration, e.g., in Alzheimer's disease. Furthermore, intracerebroventricular treatment with nerve growth factor (NGF) has been found to induce side effects, including aberrant sympathetic sprouting and weight loss. Such findings suggest that direct intraparenchymal application of minimal amounts of trophic factors might be therapeutically desirable. We compared the effectiveness of intrastriatal and intracerebroventricular administrations of NGF on striatal cholinergic neurons in adult rats. Daily intrastriatal administration for 1 week of > or = 50 ng of NGF resulted in an increase in mRNA levels for choline acetyltransferase (ChAT) in striatal cholinergic cells to approximately 2-fold over control. A daily intraventricular dose of 4.5 micrograms of NGF was required for a similar response. Both 5 and 50 ng of NGF/day failed to induce an effect on transmembrane protein tyrosine kinase trkA mRNA levels, but injections of 750 or 1500 ng/day of NGF up-regulated trkA mRNA expression to approximately 2-fold of control. NGF delivered intracerebroventricularly failed to induce an observable change in striatal trkA mRNA, even at a dosage of 4.5 micrograms of NGF/day. These quantitative differences in NGF actions were reflected at the level of NGF receptors. Using Western blotting procedures, we found pronounced tyrosine phosphorylation of Trk-type proteins 2 hr after intrastriatal injection of 50 ng of NGF. Maximal responses were seen with either 150 or 750 ng of NGF. For maximal activation of Trks by intraventricular NGF injection, 4.5 micrograms of NGF was required. Taken together, our results strongly favor intraparenchymal injections or infusions of NGF, and possibly other trophic factors, for therapeutical applications to maximize the effects on the targeted neuronal populations and to minimize undesirable side effects.
Venero
J L
JL
Andrus Gerontology Center, Division of Neurogerontology, University of Southern California, Los Angeles 90089-0191, USA.
Hefti
F
F
Knusel
B
B
D000818:Animals; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003574:Cytochrome c Group / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D007839:Functional Laterality; D006801:Humans; D017403:In Situ Hybridization; D007276:Injections, Intraventricular; D008845:Microinjections; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013238:Stereotaxic Techniques; D014158:Transcription, Genetic / Q000187:drug effects
D003574:Cytochrome c Group; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; D002795:Choline O-Acetyltransferase; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA