NM  Vol.5 No.2 , May 2014
Intermittent vs Continuous Administration of Nerve Growth Factor to Injured Medial Septal Cholinergic Neurons in Rat Basal Forebrain
Abstract: Many medial septal neurons of the basal forebrain are dependent on nerve growth factor (NGF) from the hippocampus for survival and maintenance of a cholinergic phenotype. When deprived of their source of NGF by axotomy, medial septal neuronal cell bodies atrophy and lose their cholinergic markers. This is similar to what is observed in the basal forebrain during Alzheimer’s disease (AD). In the present study, medial septal neurons were axotomized in female rats by way of a fimbria/fornix lesion. For fourteen days following axotomy, varying NGF doses (1 - 250 μg/ml) were administered to the lateral cerebral ventricle with either mini-osmotic infusion or daily injection. The responsiveness of medial septal neurons was evaluated with choline acetyltransferase immunohistochemistry. Within the mini-osmotic pumps, NGF activity diminished greatly during the first five days of implantation, but increased dramatically in the CSF after five days of infusion. The responsiveness of medial septal neurons to NGF was dose dependent and the ED50 for NGF injection was determined to be 14.08 μg/ml compared to 27.60 μg/ml for NGF infusion. Intermittent injections at varying intervals were evaluated with 30 μg/ml NGF over a fourteen-day time period (2, 3, 6, or 12 injections). No differences occurred in the number of choline acetyltransferase neurons from rats that received weekly injections to those that received daily injections of NGF. NGF administration has been suggested as a therapy for AD. The results of these studies continue to highlight the need for NGF stability within the delivery system and AD patient CSF, the choice of delivery system, frequency of administration, and the NGF dose for maintaining basal forebrain cholinergic neurons during AD.
Cite this paper: Miller, K. , Frierdich, G. , Dillard, R. , Soriano, R. and Roufa, D. (2014) Intermittent vs Continuous Administration of Nerve Growth Factor to Injured Medial Septal Cholinergic Neurons in Rat Basal Forebrain. Neuroscience and Medicine, 5, 109-118. doi: 10.4236/nm.2014.52014.

[1]   Linke, R. and Frotscher, M. (1993) Development of the Rat Septohippocampal Projection: Tracing with DiI and Electron Microscopy of Identified Growth Cones. Journal of Comparative Neurology, 332, 69-88.

[2]   Linke, R., Pabst, T. and Frotscher, M. (1995) Development of the Hippocamposeptal Projection in the Rat. Journal of Comparative Neurology, 351, 602-616.

[3]   Pombero, A., Bueno, C., Saglietti, L., Rodenas, M., Guimera, J., Bulfone, A. and Martinez, S. (2011) Pallial Origin of Basal Forebrain Cholinergic Neurons in the Nucleus Basalis of Meynert and Horizontal Limb of the Diagonal Band Nucleus. Development, 138, 4315-4326.

[4]   Hess, C. and Blozovski, D. (1990) Intrahippocampal Injection of NGF Accelerates Spontaneous Alteration Ontogenesis and the Maturation of Septohippocampal Cholinergic Innervation in Rats. Comptes Rendus de l’Académie des Sciences—Series III, 310, 533-538.

[5]   Mobley, W.C., Rutkowski, J.L., Tennekoon, G.I., Gemski, J., Buchanan, K. and Johnston, M.V. (1986) Nerve Growth Factor Increases Choline Acetyltransferase Activity in Developing Basal Forebrain Neurons. Molecular Brain Research, 387, 53-62.

[6]   Whittemore, S.R., Friedman, P.L., Larhammar, D., Persson, H., Gonzalez-Carvajal, M. and Holets, V.R. (1988) Rat Beta-Nerve Growth Factor Sequence and Site of Synthesis in the Adult Hippocampus. Journal of Neuroscience Research, 20, 403-410.

[7]   Bandtlow, C.E., Meyer, M., Lindholm, D., Spranger, M., Heumann, R. and Thoenen, H. (1990) Regional and Cellular Codistribution of Interleukin 1 Beta and Nerve Growth Factor mRNA in the Adult Rat Brain: Possible Relationship to the Regulation of Nerve Growth Factor Synthesis. The Journal of Cell Biology, 111, 1701-1711.

[8]   Schliebs, R. and Arendt, T. (2006) The Significance of the Cholinergic System in the Brain during Aging and in Alzheimer’s Disease. Journal of Neural Transmission, 113, 1625-1644.

[9]   Schliebs, R. (2005) Basal Forebrain Cholinergic Dysfunction in Alzheimer’s Disease—Interrelationship with Beta- Amyloid, Inflammation and Neurotrophin Signaling. Neurochemical Research, 30, 895-908.

[10]   Cattaneo, A. and Calissano, P. (2012) Nerve Growth Factor and Alzheimer’s Disease: New Facts for an Old Hypothesis. Molecular Neurobiology, 46, 588-604.

[11]   Cattaneo, A., Capsoni, S. and Paoletti, F. (2008) Towards Non Invasive Nerve Growth Factor Therapies for Alzheimer’s Disease. Journal of Alzheimer’s Disease, 15, 255-283.

[12]   Rafii, M.S., Baumann, T.L., Bakay, R.A., Ostrove, J.M., Siffert, J., Fleisher, A.S., Herzog, C.D., Barba, D., Pay, M., Salmon, D.P., Chu, Y., Kordower, J.H., Bishop, K., Keator, D., Potkin, S. and Bartus, R.T. (2014) A Phase1 Study of Stereotactic Gene Delivery of AAV2-NGF for Alzheimer’s Disease. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 1-11. pii: S1552-5260(13)02838-0.

[13]   Gage, F.H., Wictorin, K., Fischer, W., Williams, L.R., Varon, S. and Bjorklund, A. (1986) Retrograde Cell Changes in Medial Septum and Diagonal Band Following Fimbria-Fornix Transection: Quantitative Temporal Analysis. Neuroscience, 19, 241-255.

[14]   O’Brien, T.S., Svendsen, C.N., Isacson, O. and Sofroniew, M.V. (1990) Loss of True Blue Labelling from the Medial Septum Following Transection of the Fimbria-Fornix: Evidence for the Death of Cholinergic and Non-Cholinergic Neurons. Brain Research, 508, 249-256.

[15]   Gilmor, M.L., Counts, S.E., Wiley, R.G. and Levey, A.I. (1998) Coordinate Expression of the Vesicular Acetylcholine Transporter and Choline Acetyltransferase Following Septohippocampal Pathway Lesions. Journal of Neurochemistry, 71, 2411-2420.

[16]   Gage, F.H., Armstrong, D.M., Williams, L.R. and Varon, S. (1988) Morphological Response of Axotomized Septal Neurons to Nerve Growth Factor. Journal of Comparative Neurology, 269, 147-155.

[17]   Gu, H., Long, D., Song, C. and Li, X. (2009) Recombinant Human NGF-Loaded Microspheres Promote Survival of Basal Forebrain Cholinergic Neurons and Improve Memory Impairments of Spatial Learning in the Rat Model of Alzheimer’s Disease with Fimbria-Fornix Lesion. Neuroscience Letters, 453, 204-209.

[18]   Kromer, L.F. (1987) Nerve Growth Factor Treatment after Brain Injury Prevents Neuronal Death. Science, 235, 214-216.

[19]   Koliatsos, V.E., Applegate, M.D., Knusel, B., Junard, E.O., Burton, L.E., Mobley, W.C., Hefti, F.F. and Price, D.L. (1991) Recombinant Human Nerve Growth Factor Prevents Retrograde Degeneration of Axotomized Basal Forebrain Cholinergic Neurons in the Rat. Experimental Neurology, 112, 161-173.

[20]   Williams, L.R., Varon, S., Peterson, G.M., Wictorin, K., Fischer, W., Bjorklund, A. and Gage, F.H. (1986) Continuous Infusion of Nerve Growth Factor Prevents Basal Forebrain Neuronal Death after Fimbria Fornix Transection. Proceedings of the National Academy of Sciences of the United States of America, 83, 9231-9235.

[21]   Emmett, C.J., Aswani, S.P., Stewart, G.R., Fairchild, D. and Johnson, R.M. (1995) Dose-Response Comparison of Recombinant Human Nerve Growth Factor and Recombinant Human Basic Fibroblast Growth Factor in the Fimbria Fornix Model of Acute Cholinergic Degeneration. Brain Research, 673, 199-207.

[22]   Williams, L.R., Jodelis, K.S. and Donald, M.R. (1989) Axotomy-Dependent Stimulation of Choline Acetyltransferase Activity by Exogenous Mouse Nerve Growth Factor in Adult Rat Basal Forebrain. Brain Research, 498, 243-256.

[23]   Williams, L.R., Inouye, G., Cummins, V. and Pelleymounter, M.A. (1996) Glial Cell Line-Derived Neurotrophic Factor Sustains Axotomized Basal Forebrain Cholinergic Neurons in Vivo: Dose-Response Comparison to Nerve Growth Factor and Brain-Derived Neurotrophic Factor. Journal of Pharmacology and Experimental Therapeutics, 277, 1140-1151.

[24]   Vahlsing, H.L., Hagg, T., Spencer, M., Conner, J.M., Manthorpe, M. and Varon, S. (1991) Dose-Dependent Responses to Nerve Growth Factor by Adult rat Cholinergic Medial Septum and Neostriatum Neurons. Brain Research, 552, 320-329.

[25]   Eriksdotter Jonhagen, M., Nordberg, A., Amberla, K., Backman, L., Ebendal, T., Meyerson, B., Olson, L., Seiger, Shigeta, M., Theodorsson, E., Viitanen, M., Winblad, B. and Wahlund, L.O. (1998) Intracerebroventricular Infusion of Nerve Growth Factor in Three Patients with Alzheimer’s Disease. Dementia and Geriatric Cognitive Disorders, 9, 246-257.

[26]   Aloe, L., Rocco, M.L., Bianchi, P. and Manni, L. (2012) Nerve Growth Factor: From the Early Discoveries to the Potential Clinical Use. Journal of Translational Medicine, 10, 239.

[27]   Olson, L., Nordberg, A., Von Holst, H., Backman, L., Ebendal, T., Alafuzoff, I., Amberla, K., Hartvig, P., Herlitz, A., Lilja, A., et al. (1992) Nerve Growth Factor Affects 11C-Nicotine Binding, Blood Flow, EEG, and Verbal Episodic Memory in an Alzheimer Patient (Case Report). Journal of Neural Transmission—Parkinson’s Disease and Dementia Section, 4, 79-95.

[28]   Allen, S.J., Robertson, A.G., Tyler, S.J., Wilcock, G.K. and Dawbarn, D. (2001) Recombinant Human Nerve Growth Factor for Clinical Trials: Protein Expression, Purification, Stability and Characterisation of Binding to Infusion Pumps, Journal of Biochemical and Biophysical Methods, 47, 239-255.