Oral Administration of NGF Synthesis Stimulators Recovers Reduced Brain NGF Content in Aged Rats and Cognitive Dysfunction in Basal – Forebrain – Lesioned Rats

Nabeshima, Toshitaka; Nitta, Atsumi; Fuji, Kazuyuki; Kameyama, Tsutomu; Hasegawa, Takaaki

doi:10.1159/000213627

Cited by 32 publications

(12 citation statements)

References 27 publications

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“…The use of old mice may have contributed to the detection of these effects, since it is known that old age increases NGF sensitivity to memory restoration [16], nerve regeneration [14], nociceptive functions and inflammatory process modulation [17]. Indeed, Ehrlich tumor growth was not modified by sialectomy in young mice.…”

Section: Discussionmentioning

confidence: 99%

Effects of Social Isolation on Ehrlich Tumor Growth and Tumor Leukocyte Infiltration in Mice: Evidence of Participation of the Submaxillary Salivary Gland

Bonamin

Barbuto²,

Malucelli³

2001

Neuroimmunomodulation

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Objective: Considering previous studies on stress and Ehrlich tumor growth from our laboratory and also known cell growth and behavior-related properties of submaxillary salivary gland products, we studied the effects of stress by social isolation, in combination or not with sialectomy (submaxillary gland ablation), on growth and leukocyte infiltration into Ehrlich adenocarcinomas. Methods: 5 × 10⁷ tumor cells/ml were inoculated into the footpads of mice and tumor growth was evaluated by measuring paw thickness on alternate days. Ten days after inoculation, tumors were harvested and processed for immunocytochemical analysis of tumor-infiltrating leukocytes (TIL) and nerve-like growth factor (NGF)/epidermal growth factor (EGF)-positive tumor cells. T and B lymphocyte, NK cell and macrophage percentages were calculated. Results: Sialectomy slightly reduced tumor growth and caused a significant increase in NK cell infiltration of tumors (p < 0.05). Social isolation caused a highly significant enhancement of both tumor growth (p ≤ 0.05) and percentage of macrophages infiltrating tumors (p < 0.05). Sialectomized isolated animals showed few significant changes in tumor growth rate (p ≤ 0.05), but presented increased percentages of NK cells, macrophages and B lymphocytes (p < 0.05). A reduction in the percentage of NGF+ tumor cells was also observed (p < 0.05). All of these effects were seen only in 8-month-old mice, but not in younger animals. Conclusion: A possible link between salivary gland factors, tumor growth and TIL patterns was considered, suggesting that growth factors may modulate tumor leukocyte infiltration as well as tumor growth rate.

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Section: Discussionmentioning

confidence: 99%

Effects of Social Isolation on Ehrlich Tumor Growth and Tumor Leukocyte Infiltration in Mice: Evidence of Participation of the Submaxillary Salivary Gland

Bonamin

Barbuto²,

Malucelli³

2001

Neuroimmunomodulation

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“…A large body of scientific evidence suggests that NGF can prevent cholinergic neuron atrophy and correct the behavioral deficits caused by experimental injury or associated with normal aging in animals [166-173]. Since recent findings indicate a defect in NGF receptor expression in CBF neurons early in the onset of AD [7,48,64,174-176], treatments aimed at facilitating NGF actions may prove highly beneficial in counteracting the cholinergic dysfunction found in AD and attenuating the rate of degeneration of CBF neurons (Table 2).…”

Section: Neuroprotective Strategies For the Treatment Of Cbf Degeneramentioning

confidence: 99%

Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications

Mufson¹,

Counts²,

Perez³

et al. 2008

Expert Review of Neurotherapeutics

525

364

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Alzheimer's disease (AD) is characterized by a progressive phenotypic downregulation of markers within cholinergic basal forebrain (CBF) neurons, frank CBF cell loss and reduced cortical choline acetyltransferase activity associated with cognitive decline. Delaying CBF neurodegeneration or minimizing its consequences is the mechanism of action for most currently available drug treatments for cognitive dysfunction in AD. Growing evidence suggests that imbalances in the expression of NGF, its precursor proNGF and the high (TrkA) and low (p75 NTR ) affinity NGF receptors are crucial factors underlying CBF dysfunction in AD. Drugs that maintain a homeostatic balance between TrkA and p75 NTR may slow the onset of AD. A NGF gene therapy trial reduced cognitive decline and stimulated cholinergic fiber growth in humans with mild AD. Drugs treating the multiple pathologies and clinical symptoms in AD (e.g., M1 cholinoceptor and/or galaninergic drugs) should be considered for a more comprehensive treatment approach for cholinergic dysfunction.

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“…A more promising strategy is to exploit the neurotrophic effects of nerve growth factor (NGF) on CBFNs by stimulating endogenous production of NGF or providing exogenous NGF directly to brain (see, e.g., Nabeshima et al, 1994;Rylett and Williams, 1994). In primary septa1 cultures, NGF stimulates ChAT activity and promotes cholinergic neuron survival (Takei et al, 1988;Downen et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Effects of intraventricular transplantation of NGF-secreting cells on cholinergic basal forebrain neurons after partial immunolesion

Rößner

Pizzo

et al. 1996

J. Neurosci. Res.

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The aim of the present study was to examine the effects of nerve growth factor on brain cholinergic function after a partial immunolesion to the rat cholinergic basal forebrain neurons (CBFNs) by 192 IgG‐saporin. Two weeks after intraventricular injections of 1.3 μg of 192 IgG‐saporin, about 50% of CBFNs were lost which was associated with 40–60% reductions of choline acetyltransferase (ChAT) and high‐affinity choline uptake (HACU) activities throughout the basal forebrain cholinergic system. Two groups of lesioned animals received intraventricular transplantations of mouse 3T3 fibroblasts retrovirally transfected with either the rat NGF gene (3T3NGF+) or the retrovirus alone (3T3NGF−) and were sacrificed eight weeks later. In vivo production of NGF by 3T3NGF+ cells was confirmed by NGF immunohistochemistry on the grafts and NGF immunoassay on cerebrospinal fluid (CSF) samples. Both ChAT and HACU activities returned to normal control levels in the basal forebrain and cortex after 3T3NGF+ transplants, whereas no recovery was observed in 3T3NGF− transplanted animals. There was a 25% increase in the size of remaining CBFNs and an increased staining intensity for NGF immunoreactivity in these cells after NGF treatments. Acetylcholinesterase (AChE) histochemistry revealed that the optical density of AChE‐positive fibers in the cerebral cortex and hippocampus were reduced by about 60% in immunolesioned rats which were completely restored by 3T3NGF+ grafts. In addition, decreases in growth‐associated protein (GAP)‐43 immunoreactivity after immunolesion and increases in synaptophysin immunoreactivity after 3T3NGF+ grafts were observed in the hippocampus. Our results further confirm the notion that transfected NGF‐secreting cells are useful in long‐term in vivo NGF treatment and NGF can upregulate CBFN function. They also highly suggest that NGF induces terminal sprouting from remaining CBFNs. © 1996 Wiley‐Liss, Inc.

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Oral Administration of NGF Synthesis Stimulators Recovers Reduced Brain NGF Content in Aged Rats and Cognitive Dysfunction in Basal – Forebrain – Lesioned Rats

Cited by 32 publications

References 27 publications

Effects of Social Isolation on Ehrlich Tumor Growth and Tumor Leukocyte Infiltration in Mice: Evidence of Participation of the Submaxillary Salivary Gland

Effects of Social Isolation on Ehrlich Tumor Growth and Tumor Leukocyte Infiltration in Mice: Evidence of Participation of the Submaxillary Salivary Gland

Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications

Effects of intraventricular transplantation of NGF-secreting cells on cholinergic basal forebrain neurons after partial immunolesion

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