Summary
A unilateral ibotenic acid lesion was placed in the nucleus basalis magnocellularis of 3- and 18-month-old rats. In the lesioned aging rats, the number of choline acetyltransferase-immunoreactive neurons of the nucleus basalis magnocellularis was markedly reduced in the ipsilateral side and to a lesser extent in the contralateral side. Twenty-one days after the lesion, the activity of choline acetyltransferase in the ipsilateral cortex was reduced by 40% in both groups of rats and by 24% in the contralateral frontal cortex of the aging rats. Intracerebroventricular administration of nerve growth factor (10 μg, twice a week) to aging lesioned rats for 3 weeks after surgery resulted in a complete recovery in the number of choline acetyltransferase-immunoreactive neurons in the nucleus basalis of both sides, and choline acetyltransferase activity in the contralateral cortex, with little effect on the ipsilateral cortex. No potentiation was seen after the concurrent administration of GM1 ganglioside and nerve growth factor. Complete recovery in cortical choline acetyltransferase activity was only observed in the lesioned rats treated with nerve growth factor for 1 week before and 3 weeks after lesioning. Nerve growth factor treatment, both after the lesion, and before and after the lesion, improved the passive avoidance performance disrupted by the lesion. In young lesioned rats daily intraperitoneal administration of GM1 (30 mg/kg) for 21 days after surgery promoted both the recovery of choline acetyltransferase activity and passive avoidance performance. In aging rats GM1, even at a dose twice as large, failed to reverse the biochemical and morphological deficits and behavioral impairment induced by the lesion. Only when GM1 administration was started 3 days before the lesion, were a complete recovery in choline acetyltransferase activity in the contralateral cortex and a partial recovery in the ipsilateral cortex obtained.
Our results indicate that nerve growth factor and, to some extent, GM1 facilitate the recovery of the cholinergic neurons after a lesion of the nucleus basalis in aging rats, but their efficacy is reduced. The lower efficacy of GM1 as compared to NGF might be due to the different routes of administration used.
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References
Alberch J, Perez-Navarro E, Arenas E, Marsal J (1991) Involvement of nerve growth factor and its receptor in the regulation of the cholinergic function in aged rats. J Neurochem 57: 1483–1487
Bartus RT, Dean III RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408–417
Bocchini V, Angeletti P (1969) The nerve growth factor: purification as a 30,000 molecular weight protein. Proc Natl Acad Sci USA 64: 787–794
Bradford MM (1976) A rapid sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254
Casamenti F, Bracco L, Bartolini L, Pepeu G (1985) Unilateral and bilateral lesion of the cholinergic forebrain nuclei. Brain Res 338: 45–57
Casamenti F, Di Patre PL, Bartolini L, Pepeu G (1988) Unilateral and bilateral nucleus basalis lesions: differences in neurochemical and behavioural recovery. Neuroscience 24: 209–215
Casamenti F, Di Patre PL, Milan F, Petrelli L, Pepeu G (1989) Effects of nerve growth factor and GM1 ganglioside on the number and size of cholinergic neurons in rats with unilateral lesion of the nucleus basalis. Neurosci Lett 103: 87–91
Casamenti F, Milan F, Pepeu G (1990) Lesions of the nucleus basalis magnocellularis in the rat: morphological, biochemical and behavioral reparative effect of nerve growth factor and ganglioside GM1. Acta Neurobiol Exp 50: 461–473
Cavicchioli L, Flanigiani TP, Vantini G, Fusco M, Polato P, Toffano G, Walsh FS, Leon A (1989) NGF amplifies expression of NGF receptor messenger RNA in forebrain cholinergic neurons of rats. Eur J Neurosci 1: 259–262
Cuello AC, Maysinger D, Garofalo L, Tagari P, Stephens PH, Pioro E, Piotte M (1987) Influence of gangliosides and nerve growth factor on the plasticity of forebrain cholinergic neurons. In: Fuxe K, Agnati LF (eds) Receptor-receptor interaction, a new intramembrane integrative mechanism. McMillan, London, pp 62–67
Cuello AC, Garofalo L, Kenigsberg RL, Maysinger D (1989) Gangliosides potentiate in vivo and in vitro effects of nerve growth factor on central cholinergic neurons. Proc Natl Acad Sci USA 86: 2056–2060
Dekker AJ, Thal LJ (1992) Effect of delayed treatment with nerve growth factor on choline acetyltransferase activity in the cortex of rats with lesions of the nucleus basalis magnocellularis: dose requirements. Brain Res 584: 55–63
Di Patre PL, Casamenti F, Cenni A, Pepeu G (1989) Interaction between nerve growth factor and GM1 monosialoganglioside in preventing cortical choline acetyltransferase and high affinity choline uptake decrease after lesion of the nucleus basalis. Brain Res 480: 219–224
Dunnett SB, Whishaw IQ, Jones GH, Bunch, ST (1987) Behavioural, biochemical and histochemical effects of different neurotoxic amino acids injected into nucleus basalis magnocellularis of rats. Neuroscience 20: 653–669
Fischer W, Wictorin K, Bjorklund A, Williams LR, Varon S, Gage FH (1987) Amelioration of cholinergic neurons atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329: 65–68
Fischer W, Bjorklund A, Chen K, Gage FH (1991) NGF improves spatial memory in aged rodents as a function of age. J Neurosci 11: 1889–1906
Fonnum F (1975) A rapid radiochemical method for the determination of choline acetyltransferase. J Neurochem 24: 407–409
Fusco M, Bentivoglio M, Vantini G, Guidolin D, Polato P, Leon A (1991) Nerve growth factor receptor-immunoreactive fibres innervate the reticular thalamic nucleus: modulation by nerve growth factor treatment in neonate, adult and aged rats. Eur J Neurosci 3: 1008–1015
Geinisman Y, Bondareff W, Tesler A (1977) Transport of [3H] fucose labelled glycoproteins in the septo-hippocampal pathway of young adult and senescent rats. Brain Res 125: 182–186
Hadjiconstantinou M, Karadsheh NS, Rattan AK, Tejwani GA, Fitkin JG, Neff NH (1992) GM1 ganglioside enhances cholinergic parameters in the brain of senescent rats. Neuroscience 46: 681–686
Haroutunian V, Kanof PD, Davis KL (1986) Partial reversal of lesion-induced deficits in cortical cholinergic markers by nerve growth factor. Brain Res 386: 397–399
Hefti F, Dravid A, Hartikka J (1984) Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with septo-hippocampal lesions. Brain Res 293: 305–311
Hefti F, Mash DC (1989) Localization of nerve growth factor receptor in the normal human brain and in Alzheimer's disease. Neurobiol Aging 10: 75–87
Hepler DJ, Wenk GL, Cribbs BL, Olton DS, Coyle, JT (1985) Memory impairments following basal forebrain lesions. Brain Res 346: 8–14
Koh S, Loy R (1988) Age-related loss of nerve growth factor sensivity in rat basal forebrain neurons. Brain Res 440: 396–401
Koliatsos VE, Applegate MD, Knusel B, Junard EO, Burton LE, Mobley WC, Hefti FF, Price DL (1991) Recombinant human nerve growth factor prevents retrograde degeneration of axotomized basal forebrain cholinergic neurons in the rats. Exp Neurol 112: 161–173
Lang W (1981) Pharmacokinetic studies with [3H]-labeled exogenous gangliosides injected intramuscularly into rat. In: Rapport, MM, Gorio, A (eds) Gangliosides in neurological and neuromuscular function. Development and repair. Raven Press, New York, pp 241–251
Levi-Montalcini R, Angeletti PU (1968) Nerve growth factor. Physiol Rev 48: 534–569
Oderfeld-Nowak B, Skup M, Ulas J, Jezierska M Gradkowska M, Zaremba M (1984) Effect of GM1 ganglioside treatment on post-lesion response of cholinergic enzymes in rat hippocampus after various partial deafferentations. J Neurosci Res 12: 409–420
Olson L, Norberg A, von Holst H, Bäckman L, Ebendal T, Alafuzoff I, Amberla K, Hartvig P, Herlitz A, Lilja A Lundqvist H, Långström B, Meyerson B, Persson A, Viitanen M, Winblad B, Seiger Å (1992) Nerve growth factor affect11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patients. J Neural Transm [P-D Sect] 4: 79–95
Page KJ, Everitt BJ, Robbins TW, Marston HM, Wilkinson LS (1991) Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA and ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: differential dependence on cholinergic neuronal loss. Neuroscience 43: 457–472
Paxinos G, Watson G (1982) The rat brain in stereo-taxic coordinates. Academic Press, New York
Pearson RCA, Neal JW, Powel TPS (1986) Hypertrophy of cholinergic neurons in the basal nucleus of the rat following damage of the controlateral nucleus. Brain Res 382: 149–152
Phillips HS, Hains JM, Laramee GR, Rosenthal A, Winslow JW (1990) Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons. Science 250: 290–294
Santucci AC, Kanof PD, Haroutunian V (1993) Cholinergic marker deficits induced by lesions of the nucleus basalis of Meynert are attenuated by nerve growth factor in young, but not in aged, F344 rats. Brain Res 609: 327–332
Schumacher JM, Short MP, Hyman BT, Breakefield XO, Isacson O (1991) Intracerebral implantation of nerve growth factor-producing fibroblasts protects striatum against neurotoxic levels of excitatory amino acids. Neuroscience 45: 561–570
Sonnino S, Ghidoni R, Galli G, Tettamanti G (1978) On the structure of a new, fucose-containing ganglioside from pig cerebellum. J Neurochem 31: 947–956
Stephens PH, Tagari PC, Garofalo L, Maysinger D, Piotte M, Cuello AC (1987) Neuronal plasticity of basal forebrain cholinergic neurons: effects of gangliosides. Neurosci Lett 80: 80–84
Svennerholm L, Gottfries CG, Blennow K, Fredman P, Karlsson I, Mansson JE, Toffano G, Wallin A (1990) Parenteral administration of GM1 ganglioside to presenile Alzheimer patients. Acta Neurol Scand 81: 48–53
Unger JW, Schmidt Y (1992) Quisqualic acid-induced lesion of the nucleus basalis of Meynert in young and aging rats: plasticity of surviving NGF receptor-positive cholinergic neurons. Exp Neurol 117: 269–277
Wainer BH, Levey AI, Mufson EJ, Mesulam M (1984) Cholinergic systems in mammalian brain identified with anti-bodies against choline acetyltransferase. Neurochem Int 6: 163–182
Wallace JE, Krauter EE, Campbell BA (1980) Motor and reflexive behavior in the aging rat. J Gerontol 35: 364–370
Will B, Hefti F (1985) Behavioural and neurochemical effects of chronic intraventricular injections of nerve growth factor in adult rats with fimbria lesions. Behav Brain Res 17: 17–24
Williams LR (1991) Exogenous nerve growth factor stimulates choline acetyltransferase activity in aging Fischer 344 male rats. Neurobiol Aging 12: 39–46
Yunshao H, Zhibin Y, Yici C (1991) Effect of nerve growth factor on the lesioned septohippocampal cholinergic system of aged rats. Brain Res 552: 159–163
Yunshao H, Zhibin Y, Yaoming G, Guobi K, Yici C (1992) Nerve growth factor promotes collateral sprouting of cholinergic fibers in the septohippocampal cholinergic system of aged rats with fimbria transection. Brain Res 586: 27–35
Zawia N, Arendash GW, Wecker L (1992) Basal forebrain cholinergic neurons in aged rat brain are more susceptible to ibotenate-induced degeneration than neurons in young adult brain. Brain Res 589: 333–337
Zupan G, Casamenti F, Scali C, Pepeu G (1993) Lesions of the nucleus basalis magnocellularis in immature rats: short- and long-term biochemical and behavioral changes. Pharmacol Biochem Behav 45: 19–25
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Casamenti, F., Scali, C., Giovannelli, L. et al. Effect of nerve growth factor and GM1 ganglioside on the recovery of cholinergic neurons after a lesion of the nucleus basalis in aging rats. J Neural Transm Gen Sect 7, 177–193 (1994). https://doi.org/10.1007/BF02253437
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DOI: https://doi.org/10.1007/BF02253437