The present work assessed the effects of intracerebroventricular injections (2x5 mg/2.5 ml) of recombined human nerve growth factor (rhNGF) at postnatal days 2 and 3 upon the development of spatial learning capacities in rats. The treated rats were trained at the age of 22 days to escape onto an invisible platform at a fixed position in space in a Morris navigation task. For half of the subjects, the training position was also cued, a procedure aimed at facilitating escape and reducing attention to the distant spatial cues. At the age of 2 months all the rats were retrained in the same task. Treatment effects were found in both immature and adult rats. The injection of NGF induced a slight alteration of the immature rats' performance. In contrast, a marked impairment of spatial abilities was shown in the 2-month-old rats. The most consistent effects were a significant increase in the escape latency and a decrease bias towards the training platform area during probe trials. The reduction of spatial memory was particularly marked if the subjects had been trained in a cued condition. Taken together, these experiments reveal that an acute pharmacological treatment that leads to transient modifications during early development might induce a behavioural change long after treatment. Thus, the development and the maintenance of an accurate spatial representation are tightly related to the development of brain structures that could be altered by precocious NGF administrations.

The present work assessed the effects of intracerebroventricular injections of rh recombined human nerve growth factor (rh NGF) (5 μg/2.5 μl) at postnatal days 12 and 13 upon the development of spatial learning capacities. The treated rats were trained at the age of 22 days to escape onto an invisible platform at a fixed position in space in a Morris navigation task. For half of the subjects, the training position was also cued, a procedure aimed at facilitating escape and at reducing attention to the distant spatial cues. Later, at the age of 6 months, all the rats were trained in a radial-arm maze task. Treatment effects were found in both immature and adult rats. The injection of NGF improved the performance in the Morris navigation task in both training conditions. There was a significant reduction in the escape latency and an increased bias toward the training platform quadrant during probe trials. The most consistent effect was the precocious development of an adult-like spatial memory. In the radial-arm maze, the NGF-treated rats made significantly fewer reentries than vehicle rats and this effect was particularly marked in the treated female rats. Taken together, these experiments reveal that the development and the maintenance of an accurate spatial representation are tightly related to the development of brain structures facilitated by the action of NGF. Moreover, these experiments demonstrate that an acute pharmacological treatment that leads to a transient modification in the choline acetyltransferase activity can induce a behavioral change long after the treatment.

Annals of the New York Academy of SciencesVolume 825, Issue 1 p. 366-379 Poly(ADP-Ribose) Polymerase (PARP) Revisited A New Role for an Old Enzyme: PARP Involvement in Neurodegeneration and PARP Inhibitors as Possible Neuroprotective Agents C. COSI, Corresponding Author C. COSI FIDIA Research Laboratories Abano Terme Padova 35031, Italy Pierre Fabre Research Center Castres 81106, FraneAddress correspondence to Dr. Cristina Cosi, Division of Neurobiology II, Pierre Fabre Res. Ctr. Castres 81106, France. Tel: (33) 5 63 71 42 86; fax: (33) 5 63 71 43 63.Search for more papers by this authorH. SUZUKI, H. SUZUKI Institute of Biological Chemistry University of Verona Verona 37134, ItalySearch for more papers by this authorS. D. SKAPER, S. D. SKAPER FIDIA Research Laboratories Abano Terme Padova 35031, ItalySearch for more papers by this authorD. MILANI, D. MILANI FIDIA Research Laboratories Abano Terme Padova 35031, ItalySearch for more papers by this authorL. FACCI, L. FACCI FIDIA Research Laboratories Abano Terme Padova 35031, ItalySearch for more papers by this authorM. MENEGAZZI, M. MENEGAZZI Institute of Biological Chemistry University of Verona Verona 37134, ItalySearch for more papers by this authorG. VANTINI, G. VANTINI FIDIA Research Laboratories Abano Terme Padova 35031, ItalySearch for more papers by this authorY. KANAI, Y. KANAI Department of Molecular Oncology University of Tokyo Minato-ku Tokyo 108, JapanSearch for more papers by this authorA. DEGRYSE, A. DEGRYSE Pierre Fabre Research Center Castres 81106, FraneSearch for more papers by this authorF. COLPAERT, F. COLPAERT Pierre Fabre Research Center Castres 81106, FraneSearch for more papers by this authorW. KOEK, W. KOEK Pierre Fabre Research Center Castres 81106, FraneSearch for more papers by this authorM. R. MARIEN, M. R. MARIEN Pierre Fabre Research Center Castres 81106, FraneSearch for more papers by this author C. COSI, Corresponding Author C. COSI FIDIA Research Laboratories Abano Terme Padova 35031, Italy Pierre Fabre Research Center Castres 81106, FraneAddress correspondence to Dr. Cristina Cosi, Division of Neurobiology II, Pierre Fabre Res. Ctr. Castres 81106, France. Tel: (33) 5 63 71 42 86; fax: (33) 5 63 71 43 63.Search for more papers by this authorH. SUZUKI, H. SUZUKI Institute of Biological Chemistry University of Verona Verona 37134, ItalySearch for more papers by this authorS. D. SKAPER, S. D. SKAPER FIDIA Research Laboratories Abano Terme Padova 35031, ItalySearch for more papers by this authorD. MILANI, D. MILANI FIDIA Research Laboratories Abano Terme Padova 35031, ItalySearch for more papers by this authorL. FACCI, L. FACCI FIDIA Research Laboratories Abano Terme Padova 35031, ItalySearch for more papers by this authorM. MENEGAZZI, M. MENEGAZZI Institute of Biological Chemistry University of Verona Verona 37134, ItalySearch for more papers by this authorG. VANTINI, G. VANTINI FIDIA Research Laboratories Abano Terme Padova 35031, ItalySearch for more papers by this authorY. KANAI, Y. KANAI Department of Molecular Oncology University of Tokyo Minato-ku Tokyo 108, JapanSearch for more papers by this authorA. DEGRYSE, A. DEGRYSE Pierre Fabre Research Center Castres 81106, FraneSearch for more papers by this authorF. COLPAERT, F. COLPAERT Pierre Fabre Research Center Castres 81106, FraneSearch for more papers by this authorW. KOEK, W. KOEK Pierre Fabre Research Center Castres 81106, FraneSearch for more papers by this authorM. R. MARIEN, M. R. MARIEN Pierre Fabre Research Center Castres 81106, FraneSearch for more papers by this author First published: 17 December 2006 https://doi.org/10.1111/j.1749-6632.1997.tb48447.xCitations: 8Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1 Banasik, M. H. Komura, M. Shimoya & K. Ueda. 1992. Specific inhibitors of poly (ADP-ribose) synthetase & mono(ADP-ribose) transferase. J. Biol. Chem. 267: 1569–1575. 2 Chambon, P., J. D. Meil, J. Doly, M. T. Strosser & P. Mandel. 1966. 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Citing Literature Volume825, Issue1Neuroprotective Agents: Third International ConferenceOctober 1997Pages 366-379 ReferencesRelatedInformation

The spatio-temporal organization of spike discharges was studied in rat auditory thalamus (i.e., medial geniculate body and auditory sector of thalamic reticular nucleus) following a 2-week continuous intracerebroventricular administration of nerve growth factor (NGF). Recording of extracellular single-unit activity indicated that, in medial geniculate body, NGF induced a significant increase of the mean firing rate. In thalamic reticular nucleus, where units tend to discharge in bursts, NGF increased the average burst size (number of spikes) and the intraburst frequency without affecting the firing rate. Following white noise acoustical stimulation, in medial geniculate body, more onset excitation and a lower signal-to-noise ratio were observed in NGF-treated rats than in controls. Conversely, in thalamic reticular nucleus, NGF-treated animals showed more inhibitory responses than controls. In addition, within the medial geniculate body, functional interactions between pairs of units simultaneously recorded from different electrodes were greatly increased by the nerve growth factor treatment. These data indicate that modifications of temporal pattern of discharges in selected brain regions are among the effects induced by the intracerebroventricular administration of nerve growth factor.

Glutamate neurotoxicity is correlated with an increase of cytosolic free Ca2+. In some cell systems, activation of Ca2+ dependent endonucleases or formation of free radicals can damage DNA and activate the chromatin bound enzyme poly(ADP‐ribose) polymerase (pADPRP). We have investigated whether pADPRP may be involved in glutamate neurotoxicity in vitro. Cerebellar granule cells at 12 days in culture when treated with a toxic dose of glutamate (100 μM) showed a rapid and transient increase of poly ADP‐ribose immunoreactivity. Cellular immunostaining was heterogeneous and returned to control levels after washout of glutamate. In the same cell preparations glutamate elicited a marked increase in enzyme protein immunoreactivity which persisted at later times. Non‐toxic doses of glutamate did not affect immunostaining. In another set of experiments, pADPRP mRNA was increased 30 min after glutamate. In order to investigate the role of pADPRP in glutamate‐mediated neurotoxicity, structurally different inhibitors of pADPRP (3‐aminobenzamide, benzamide, 3‐aminophthalhydrazide) and their inactive analogues (benzoic acid and phthalimide) were tested in this model. Addition of the inhibitors to cultures 60 min before and during the 30 min of glutamate treatment prevented neuronal death by 60–100%, assessed 24 hr later. Glutamate‐induced Ca2+ influx was not affected. Inactive analogues failed to afford neuroprotection. These data indicate that not only is pADPRP activated by the early, possibly Ca2+ ‐mediated mechanisms initiated by glutamate, but that it might also actively contribute to the subsequent neuronal death. © 1994 Wiley‐Liss, Inc.

The suggested potential for therapeutic use of nerve growth factor (NGF) in the treatment of toxic and degenerative disorders of the nervous system indicates a need to determine its pharmacokinetics. To this end, murine NGF was administered to adult rats and multiple blood samples were withdrawn at intervals. NGF levels, determined in plasma samples by a two-site enzyme immunoassay, were used to determine the pharmacokinetics of NGF. These studies demonstrate that murine NGF has a distribution half-life of about 5.4 min and an elimination half-life of 2.3 h following intravenous injection. When administered by subcutaneous (sc) injection, the elimination half-life is prolonged to 4.5 h. Administration of NGF by sc continuous infusion, using mini-osmotic pumps, provides stable, dose-related levels of circulating NGF within few days from pump implantation. Upon removal of the pump, NGF levels show a rapid decay (t1/2 about 1.5 h) followed by a slow elimination phase (t1/2 about 150 h). These pharmacokinetic parameters might serve for selection of an appropriate administration route and dose regimen that would optimize schedule-dependent expression of NGF therapeutic activity.

The distribution of Fos, the protein product of the immediate early gene c-fos, was studied with immunocytochemistry in the adult male rat brain after nerve growth factor (NGF) administration. NGF was injected in the lateral cerebral ventricle through a previously implanted cannula. The total number of Fos-immunoreactive (ir) neurons in the brain was 2-3 times higher after NGF administration than in control animals (untreated or injected with cytochrome c). With respect to control rats, in the NGF-treated cases Fos-ir cells were more numerous in the anterior olfactory nucleus, in the medial prefrontal and anterior cingulate cortices, in the basal forebrain, in the preoptic and ventromedial nuclei of the hypothalamus, as well as anterior hypothalamic area, in the thalamic midline nuclei, and in some brainstem structures, such as the parabrachial nucleus. The relative quantitative increase of Fos-ir neurons varied in the different structures. In addition, Fos-ir neurons were evident after NGF administration in areas devoid of immunopositive cells in control animals. These included: frontoparietal and occipital cortical fields, the hypothalamic arcuate nucleus, and many brainstem structures, such as the dorsal nucleus of the lateral lemniscus, posterodorsal tegmental, medial and lateral vestibular, ventral cochlear, and prepositus hypoglossal nuclei. These findings demonstrate that the intracerebroventricular administration of NGF can induce c-fos expression in neurons in vivo. The distribution of Fos-ir neurons indicates that NGF can induce activation of functionally and chemically heterogeneous neuronal subsets in the brain.

A large body of experimental data suggests that neurotrophic molecules and/or substances that facilitate their action could be pharmaceutical agents for neurodegenerative pathologies. In particular, it has been demonstrated that nerve growth factor (NGF) exerts a physiological role for forebrain cholinergic neurons, while brain‐derived neurotrophic factor (BDNF) seems to play a relevant role in rescuing dopaminergic neurons following damage. In addition, gangliosides are reported to potentiate neurotrophic factor effects in vitro as well as in vivo. In this study we examined the effects of the monosialoganglioside GM1 in different experimental models. The responsiveness of forebrain cholinergic neurons following NGF ± GM1 was evaluated by assessing choline acetyltransferase (ChAT) activity in hippocampus, septal area and striatum of behaviorally impaired 24‐month‐old rats. NGF was intracerebroventricularly (i.c.v.) infused for 2 weeks while GM1 was given systemically for 3 weeks, starting from the beginning of NGF infusion. Moreover, the possible protective effects of GM1 were assessed following exposure of cultured cerebellar granule cells and dopaminergic mesencephalic neurons to different doses of 6‐OH‐DOPA, a metabolite of the dopamine pathway which has excitotoxic properties and has been hypothesized to participate in the pathology of Parkinson's disease. GM1 treatment to aged rats was seen to potentiate the NGF‐induced increase of ChAT activity in the striatum ipsilateral to the NGF infusion. Moreover, in the striatum contralateral to the NGF infusion, GM1 increased ChAT activity above the control values, whereas NGF treatment alone did not affect enzymatic activity. GM1 treatment of cerebellar granule cells and mesencephalic neurons counteracted the dose‐and time‐dependent neurotoxidty of 6‐OH‐DOPA. These data support the notion that GM1 might prove useful in treating those pathological conditions where trophic factor deficits and/or cxcitotoxin‐related toxicity play an important role.

Eva, C.; Fusco, M.*; Brusa, R.; Gamalero, S. Ricci; Vantini, G.*; Genazzani, E. Author Information

The present study provides evidence that the adult mammalian retina is highly sensitive to the excitotoxic action of NMDA. In particular, we have investigated the effects of a single intravitreal injection of different doses of N-methyl-D-aspartate (NMDA) (2-200 nmoles) on the adult rat retina. Morphological evaluation of transverse sections of retinae demonstrated a dose-dependent loss of cells in the ganglion cell layer (GCL) and a reduction in the thickness of the inner plexiform layer. No obvious alterations were noted in the more distal retinal layers. Quantitative analyses of Nissl-stained whole-mounted retinae revealed that administration of 20 nmoles of NMDA resulted in a 70% loss of cells with a soma diameter greater than 8 microns (presumed retinal ganglion cells); a 20% loss of cells with a soma diameter smaller than 8 microns (presumed displaced amacrine cells) was also observed. In addition, NMDA produced a dose-dependent decrease of retinal choline acetyltransferase (ChAT) activity, suggesting that NMDA affects cholinergic amacrine cells as well. MK-801, a non-competitive NMDA antagonist, completely prevented the NMDA-induced loss of cells in the GCL and blocked, in a dose-dependent manner, the NMDA-induced decrease of ChAT activity. The excitotoxic action of NMDA observed in these experiments is thus likely mediated through the NMDA receptor subtype. This "in vivo" model may be utilized to identify potential drugs that antagonize or limit the deleterious effects consequent to NMDA receptor overstimulation in the central nervous system.

The cellular localization of the nerve growth factor-like immunoreactivity (NGF-LIR) has been studied in the intact adult rat brain at the level of the hippocampus and the septum. Immunolabelling for NGF combined with counterstaining with cresyl violet and double immunostaining technique, which allowed simultaneous localization of NGF-LIR and that of astroglial marker-GFAP, were used. The data indicate neuronal localization of NGF-like immunoreactivity and a lack of colocalization of NGF-LIR with the immunoreactivity of GFAP in the hippocampus. These data are consistent with in situ hybridization results for NGF and immunocytochemical results for pro-NGF localization obtained by others. At the septal level, apart from neuronal localization of NGF-LIR, single NGF-like immunoreactive astrocytes have been observed. This suggests that, although to a very small extent, in vivo intact brain astrocytes may, just as astrocytes growing in vitro, synthesize NGF-like molecules. This finding may be of importance in better understanding the trophic support for NGF responsive cholinergic neurones in the brain.

Until recently nerve growth factor (NGF) was the only widely characterized neurotrophic factor which had been shown both in vitro and in vivo to be essential for the survival of selected populations of neurons during development and to be important for maintenance of the differentiated phenotype of mature neurons. The recent cloning of new members of the NGF family, namely brain-derived neurotrophic factor neurotrophin-3 (NT-3), NT-4 and NT-5, has greatly expanded our knowledge of the structural properties and neurotrophic activities of these proteins. Elucidation of their developmental and topographical expression and associated receptors in both the central nervous system and peripheral nervous system is proceeding at a brisk pace, leading to proposals for a potential pharmacological use of these proteins. This possibility will ultimately rely upon a more complete understanding of the roles of these trophic factors in human nervous system physiology and pathology.

The cellular localization of the nerve growth factor-like immunoreactivity (NGF-LIR) has been studied in the septum and hippocampus of the rat brain 7 days following partial electrolytic lesion (2 mA, 30 s) of the septohippocampal pathways or after single intraventricular administration of 15 U of interleukin-1 beta (IL-1 beta). A double immunostaining technique which allowed a simultaneous localization of NGF-LIR and that of astroglia marker glial fibrillary acidic protein was used. Our data show that after both treatments, apart from neuronal localization of NGF-LIR typical for normal brain, many astrocytes both in the septum and hippocampus became NGF-like immunoreactive. Besides, NGF-LIR often formed a "halo" reaction around astrocytes. These results support the notion that activated in vivo brain astrocytes may, just as astrocytes growing in vitro, synthesize and secrete NGF-like molecules. Our findings may be of importance in considerations concerning trophic support to the cholinergic neurons of the basal forebrain nuclei whose impaired function is essentially responsible for some cognitive deficits in neurodegenerative diseases such as Alzheimer disease.