Nerve Growth Factor Deficiency Research Articles

Brain-derived neurotrophic factor (BDNF) and other neurotrophic factors in type2 diabetes mellitus and their association with neuropathy.

Diabetes mellitus (DM) is associated with increased risk of morbidity and premature mortality due to its various complications. In an Indian study, the prevalence of diabetic peripheral neuropathy (DPN) in type 2 diabetic subjects was shown to be 29.2%. There is increasing evidence that a deficiency of nerve growth factor (NGF) in diabetes, as well as the calcitonin gene-related peptide (CGRP), may also contribute to the development of DPN. The aim of the current study was to evaluate nerve growth factor levels with neuropathy in type2 DM. Forty healthy controls and 40 patients withtype2 DM were recruited; they were asked to report to Dept. of Physiology for initial history taking, general examination and neuropathy examination. A total of 5mL of blood was collected for neurotrophic factor estimation as well as glycemic profile estimation. The brain-derived neurotrophic factor (BDNF) valueswere significantly lower in the DM group whereas the insulin levels were also quite high in DM. The hot thresholds for both the upper limb and lower limb were greater in the DM group suggesting the impending neuropathy. Similarly, the Michigan scores were also greater in the DM group. The neuropathy parameters especially the Michigan A and B and the hot thresholds were positively correlated with duration of DM and glucose profile. The neurotrophic factors especially BDNF are drastically reduced in DM patients and are negatively associated with neuropathy, and hence, BDNF can be utilized as a therapeutic target to treat and prevent neuropathy.

Low-Molecular-Weight Perorally Active Nerve Growth Factor Mimetic Reduces Manifestations of Diabetic Neuropathy in Wistar Rats.

A low-molecular-weight nerve growth factor mimetic, compound GK-2 (bis-(N-monosuccinyl- L-glutamyl-L-lysine)hexamethylenediamide) that previously demonstrated antidiabetic activity in rats with streptozotocin-induced type 2 diabetes mellitus was studied on the model of diabetic neuropathy. It was found that in 8 weeks after diabetes mellitus development, untreated diabetic rats demonstrated impaired tactile sensitivity in von Frey test, while GK-2 therapy (7.5 mg/kg orally for 28 days) restored this parameter. The decrease of tactile sensitivity in diabetic neuropathy closely correlated with the severity of hyperglycemia (r=0.76). Our findings are consistent with the concept on the role of glucose toxicity and nerve growth factor deficiency in the pathogenesis of diabetic neuropathy and attest to feasibility of further studies of nerve growth factor mimetic GK-2 as a potential treatment for diabetes and diabetic neuropathy.

Identification of amino acid residues of nerve growth factor important for neurite outgrowth in human dorsal root ganglion neurons

Nerve growth factor (NGF) is an essential neurotrophic factor for the development and maintenance of the central and the peripheral nervous system. NGF deficiency in the basal forebrain precedes degeneration of basal forebrain cholinergic neurons in Alzheimer's disease, contributing to memory decline. NGF mediates neurotrophic support via its high‐affinity receptor, the tropomyosin‐related kinase A (TrkA) receptor, and mediates mitogenic and differentiation signals via the extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2). However, the molecular mechanisms underlying the different NGF/TrkA/ERK signalling pathways are far from clear. In this study, we have investigated the role of human NGF and three NGF mutants, R100E, W99A and K95A/Q96A, their ability to activate TrkA or ERK1/2, and their ability to induce proliferation or differentiation in human foetal dorsal root ganglion (DRG) neurons or in PC12 cells. We show that the R100E mutant was significantly more potent than NGF itself to induce proliferation and differentiation, and significantly more potent in activation of ERK1/2 in DRG neurons. The W99A and K95A/Q96A mutants, on the other hand, were less effective than the wild‐type protein. An unexpected finding was the high efficacy of the K95A/Q96A mutant to activate TrkA and to induce differentiation of DRG neurons at elevated concentrations. These data demonstrate an NGF mutant with improved neurotrophic properties in primary human neuronal cells. The R100E mutant represents an interesting candidate for further drug development in Alzheimer's disease and other neurodegenerative disorders.

SAT-184 Diabetic Neuropathy as a Hematopoietic Stem Cell Disease in the Bone Marrow

Diabetic neuropathy, a major complication of diabetes mellitus, is induced at a relatively early stage after the development of diabetes, and progressively worsens throughout life. A number of pathological mechanisms for the development of neuropathy have been proposed, including ischemia, up-regulation of inflammatory cytokines, and the deficiency of nerve growth factor in peripheral nerve tissues. However, therapeutic approaches targeting these proposed mechanisms have yielded little success. We previously identified a mechanism by which aberrant bone marrow-derived cells pathologically expressing proinsulin/TNF-alpha fuse with residential neurons to impair neuronal function. Here we show that hematopoietic stem cells (HSCs) in c-kit (+), Sca-1 (+) and Lineage (-) cells, are the culprits that underlie the pathogenesis of diabetic neuropathy in both streptozotocin-induced type 1 diabetic mice and high fat diet-induced type 2 diabetic mice. Furthermore, the important role for these cells is supported by the fact that transplantation of HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion without hyperglycemia. On the other hand, transplantation of HSCs from non-diabetic mice to non-diabetic mice produces no dysfunction and no cell fusion. In conclusion, we have identified hyperglycemia-induced aberrant HSCs underlie the development of diabetic neuropathy, which may constitute a novel therapeutic target for the treatment of diabetic neuropathy.

DNMT1, a Novel Regulator Mediating mTORC1/mTORC2 Pathway-Induced NGF Expression in Schwann Cells

Schwann cells play an important role in maintaining the normal function of peripheral nerves via the secretion of nerve growth factor (NGF). The mTOR signaling pathway is known as a kind of Ser/Thr protein kinase that regulates various cell functions. DNA methyltransferase 1 (DNMT1) is an epigenetic regulator and downstream target of the mTOR pathway. In the present study, we explored the relationship between NGF expression and the mTOR pathway/DNMT1 in RSC96 cells. The results showed that both rapamycin and Torin 1 downregulated NGF expression via the inhibition of phospho-mTOR (Ser 2448) and phospho-S6K1 (Thr 389). Similarly, the silencing of RAPTOR and RICTOR decreased NGF expression by 56.7% and 52.4%, respectively, in RSC96 cells compared with the control siRNA treatment, which was accompanied by reduced phospho-S6K1 (Thr 389). The mTOR/S6K1 activator MHY1485 increased NGF expression by 28.7% and 17.1% 1day and 2day after stimulation, respectively, compared to the corresponding control group in RSC96 cells. Furthermore, DNMT1 was enhanced by 94.5% and 42.5% with mTOR pathway inhibitor (rapamycin and Torin 1, respectively) treatment for 3day compared with the control group. Additionally, the inhibition of DNMT1 with a chemical inhibitor or a specific shRNA plasmid upregulated NGF in RSC96 cells. In summary, our findings suggest that DNMT1 is the downstream target of the mTOR pathway and mediates the mTOR pathway inhibition-induced reduction in NGF expression in Schwann cells. Activation of the mTOR signaling pathway and/or inhibition of DNMT1 increased NGF expression, which may benefit patients suffering from NGF deficiencies, such as diabetic peripheral neuropathy.

Reduced NGF in Gastric Endothelial Cells Is One of the Main Causes of Impaired Angiogenesis in Aging Gastric Mucosa.

Background & AimsAging gastric mucosa has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully known. We examined whether impairment of angiogenesis in aging gastric mucosa is caused by deficiency of nerve growth factor (NGF) in gastric endothelial cells (ECs), and whether NGF therapy could reverse this impairment.MethodsIn gastric mucosal ECs (GECs) isolated from young and aging rats we examined the following: (1) in vitro angiogenesis, (2) NGF expression, and (3) the effect of NGF treatment on angiogenesis, GEC proliferation and migration, and dependence on serum response factor. In in vivo studies in young and aging rats, we examined NGF expression in gastric mucosa and the effect of NGF treatment on angiogenesis and gastric ulcer healing. To determine human relevance, we examined NGF expression in gastric mucosal biopsy specimens of aging (≥70 y) and young (≤40 y) individuals.ResultsIn cultured aging GECs, NGF expression and angiogenesis were reduced significantly by 3.0-fold and 4.1-fold vs young GECs. NGF therapy reversed impairment of angiogenesis in aging GECs, and serum response factor silencing completely abolished this response. In gastric mucosa of aging rats, NGF expression in GECs was reduced significantly vs young rats. In aging rats, local NGF treatment significantly increased angiogenesis and accelerated gastric ulcer healing. In aging human subjects, NGF expression in ECs of gastric mucosal vessels was 5.5-fold reduced vs young individuals.ConclusionsNGF deficiency in ECs is a key mechanism underlying impaired angiogenesis and delayed ulcer healing in aging gastric mucosa. Local NGF therapy can reverse these impairments.

Differential expression of cord blood neurotrophins in gestational diabetes: the impact of fetal growth abnormalities

Objective: Gestational diabetes mellitus (GDM) may induce fetal macrosomia or growth restriction and is associated with later offspring neurodevelopmental disorders. We aimed to determine whether neurotrophins brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-4 (NT-4) are differentially expressed in cord blood samples at birth in large-for-gestational-age (LGA), intrauterine-growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) offspring of diabetic mothers, as compared to AGA controls from non-diabetic mothers.Methods: BDNF, NGF and NT-4 concentrations were prospectively determined in 80 cord blood samples from LGA (n = 15), IUGR (n = 12) and AGA (n = 33) diabetic, as well as from AGA normal (controls, n = 20) singleton full-term pregnancies.Results: Fetal BDNF concentrations considerably decreased in GDM, as compared with normal pregnancies [(b = −2.836, 95%CI −5.067 to (−0.604), p = 0.013)] and were higher in females (b = 2.298, 95%CI 0.357–4.238, p = 0.021). Cord blood NGF concentrations were lower in IUGR than AGA infants (p = 0.038).Conclusions: BDNF is down-regulated in the fetus exposed to GDM, independently of the fetal growth pattern, probably representing a candidate mechanism underlying the association between maternal diabetes and later psychopathology. IUGR fetuses born to diabetic mothers present with NGF deficiency, which may contribute to their long-term neurodevelopmental sequelae. Gender-dependent differences in fetal BDNF may partly explain the higher prevalence of adverse neurodevelopmental outcomes following brain insults in male infants.

Nerve growth factor-carbon nanotube complex exerts prolonged protective effects in an in vitro model of ischemic stroke

AimsThe therapeutic potential of nerve growth factor (NGF) against the neurological disorders may be negatively affected by its short half-life. Based on the superior properties of carbon nanotubes (CNTs) for controlled drug delivery, we aimed to prepare CNT-NGF complex and evaluate its effect in an in vitro model of ischemic stroke. Materials and methodsMulti-walled CNTs (MWCNTs)-NGF complex was prepared using amino-functionalized COOH-MWCNTs and characterized by Fourier transform infrared spectroscopy and transmission electron microscopy. PC12 cells in the absence or presence of NGF (0.5, 1, 2μg/ml), acid- or amine-modified MWCNTs, or MWCNTs-NGF complex (2, 4, 8μg/ml) were exposed to 1 and 6h oxygen-glucose deprivation (OGD) followed by 24h re-oxygenation. Cytotoxicity and oxidative stress were evaluated. Key findingsOGD significantly reduced the cell viability (P<0.001). NGF dose-dependently increased the cell viability only after 1-h OGD (P<0.05), while, MWCNTs-NGF complex was effective at both 1- and 6-h OGD (P<0.05, P<0.001). NGF reduced the formation of condensed nuclei due to 1-h OGD (P<0.01, P<0.001), while, MWCNTs-NGF showed efficiency at both time points (P<0.05, P<0.01, P<0.001). OGD significantly increased malondialdehyde (MDA) content and decreased catalase (CAT) and superoxide dismutase (SOD) activities (P<0.001). After 1-h OGD, NGF reduced MDA (P<0.001) and increased CAT (P<0.05, P<0.01) and SOD (P<0.01), while, MWCNTs-NGF was effective after both 1- and 6-h OGD (MDA: P<0.01, P<0.001, CAT: P<0.001, SOD: P<0.01, P<0.001). SignificanceAminated MWCNTs-NGF complex by providing longer lasting effects for NGF might be of therapeutic significance against the disorders associated with NGF deficiency.

A comprehensive review of erectile dysfunction in men with diabetes.

Erectile dysfunction (ED) is more common in men with diabetes (DM). Dependent on the selected population, age, DM type and duration, the prevalence of diabetic ED (DED) varies from 32 to 90%. In 12-30% of men ED is the first sign of diabetes, diagnosed later. Today men with diabetes live longer than ever, and develop more late diabetic complications. Having in mind also the global ageing of the world population all this data suggests an increasing number of men with DED in the future. The main factors playing in the complex pathogenesis of DED are diabetic neuropathy (oxidative stress, polyol pathway, advanced glycation end-products, nerve growth factor deficiency, dysfunction of protein kinase C, tissue remodeling, etc.), macrovascular arterial disease (endothelial dysfunction, abnormal collagen deposition and smooth muscle degeneration, dyslipidemia, arterial hypertension, veno-occlusive dysfunction, etc.), hypogonadism, structural remodeling of the corporeal tissue, psychogenic components and adverse drug reactions. The diagnostic process is based on the results of questionnaires, neurological, vascular (Doppler) and other more rarely used investigations.Because of the complex pathogenesis of DED diabetic men represent a "difficult" treatment group. The difficulties are from the "beginning", because patients do not talk about their problem spontaneously, and doctors do not ask about it. The treatment of DED should be team work, preferably including also specialists in sexual medicine. Psychological support and counseling of the couple is necessary in most cases. The general measures include implementation of a healthier lifestyle, improved glycemic-, lipids-, and arterial pressure control, and careful re-evaluation of the concomitant medications. The specific treatment includes as first line therapy the inhibitors of phosphodiesterase type 5 (PDE-5) with lesser effectiveness compared to non-DM men. There are rare studies with selected diabetic populations and even less with head-to-head comparisons between the PDE-5 inhibitors. Men with DM have a higher prevalence of hypogonadism. Testosterone replacement therapy should be started in symptomatic men with proven hypogonadism and no contraindications. Vacuum constriction devices and intracavernous or intraurethral applications of vasoactive drugs are the second line therapy. Vascular surgery rarely comes into consideration. The penile implant is the last and effective option in men with severe DED.

Neurocardiogenic Syncope and Related Disorders of Orthostatic Intolerance

Received September 14, 2004; revision received January 31, 2005; accepted March 9, 2005. “We shall not cease from exploration and the end of all our exploring will be to arrive where we started and know the place for the first time” — —T.S. Eliot, Four Quartets Syncope, defined as transient loss of consciousness and postural tone with spontaneous recovery, has both challenged and perplexed physicians since the dawn of recorded time. The earliest written accounts come from Hippocrates, and the word syncope itself is derived from an old Greek term meaning “to cut short” or “interrupt.” Recurrent episodes of syncope may result from a large number of different disorders, all of which cause a transitory reduction in cerebral blood flow sufficient to disturb the normal functions of the brain. Over the last 2 decades, considerable attention has been given to types of syncope that occur due to a centrally mediated (or “reflex”) fall in systemic blood pressure, a condition that has been referred to as vasovagal (and later neurocardiogenic) syncope. However, research into the nature of this disorder revealed that it is but one aspect of a broad and varied group of disturbances in the normal functioning of the autonomic nervous system (ANS), each of which may result in orthostatic intolerance, hypotension, and ultimately syncope. Continued investigations into the nature of these similar yet different disorders has led to the development of a system of classification that attempts to more accurately reflect our understanding of these conditions and their interrelationships.1 The present system of classification has proven both functional and clinically relevant and includes a group of disorders that most investigators have thought to be principally autonomic in nature. Because both the cardiologist and the cardiac electrophysiologist frequently are expected to both diagnose and treat these conditions, the following …

A brief review on the pathogenesis of human diabetic neuropathy: Observations and Postulations

Diabetic neuropathy (DN), an important microvascular complication of diabetes, is one of the major causes of morbidity inpatients with diabetes. Studies have confirmed that glycaemic control and duration of diabetes are important factors for thedevelopment of DN. However, the exact mechanism of damage to peripheral nerves due to prolonged hyperglycaemicexposure is still not clear. Recent epidemiological studies have highlighted the importance of cardiovascular risk factors suchas hypertension, smoking, raised serum cholesterol, triglycerides and lipoprotein a to the development of DN. Variousmechanisms of microvascular and haemodynamic dysfunction of capillaries of nerve fibres have been postulated in thedevelopment of DN. Similarly endothelial dysfunction due to activation of protein kinase C, oxidative stress, advancedglycation end products and polyol pathway activation has been shown to be related to DN in human and experimental DN.Other possible mechanisms such as platelet dysfunction, essential fatty acid deficiency, immunological mechanisms, nervegrowth factor deficiency and presence of adhesion molecules have been described in relation to DN. However, no singletheory can explain the exact pathogenic mechanism of the development of DN. This review looks into different theories thathave been proposed and describes the inter-relationship of various factors that can lead to the development of DN. (Int JDiabetes Metab 13:135-140, 2005)

KP544, a nerve growth factor amplifier: Pharmacokinetics, safety, and efficacy in the rat

AbstractIn cultured cells, KP544 [2‐amino‐5‐(4‐chlorophenylethynyl)‐4‐(4‐trans‐hydroxycyclohexyl amino) pyrimidine] amplifies differentiation initiated by nerve growth factor (NGF) or cAMP. This report describes the pharmacokinetics, safety, and neuroprotective efficacy of KP544 in rats. After an oral dose of 10 mg/kg KP544 was 25% bioavailable with a plasma half‐life of 1.3 h and brain levels 6‐fold higher than plasma levels at 4 and 8 h post‐dose. In a safety study, daily oral dosing for 30 days at 10 and 100 mg/kg was well tolerated. The favorable pharmacokinetic and safety profiles, together with its amplification of NGF in vitro, prompted evaluation of KP544 in two models involving NGF deficiencies. In the first model, brains were lesioned with intrastriatal injections of quinolinic acid. KP544 at oral doses of 0.02 to 1.0 mg/kg/day almost completely prevented the resulting learning deficits as evaluated using a radial‐arm‐water maze. At the lowest dose, there was a slower onset of functional improvement. These effects were accompanied by reductions (16–34%) in the striatal lesion size that were greatest at the highest dose and comparable to those seen with NGF therapy. The second model involved a peripheral neuropathy induced by taxol that is associated with decreases in NGF. KP544 at oral doses of 0.1–10 mg/kg/day decreased the severity of the neuropathy as measured by caudal nerve conduction velocities (30–70% return to control values). In both models, KP544 had a large therapeutic index suggesting its potential as a new approach for treating clinical disorders involving deficiencies in NGF. Drug Dev. Res. 62:60–70, 2004. © 2004 Wiley‐Liss, Inc.

Nerve growth factor and diabetic neuropathy.

Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50–90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium.

Amyotrophic lateral sclerosis: an introduction.

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease that results in the degeneration of lower and upper motor neurones in the brain and the spinal cord. Early onset and modern therapies, including assisted ventilation, improve survival in this disease, although its cause remains uncertain. Amongst the possible causes are deficiency of nerve growth factor, deficient glutamate re-uptake, autoimmunity and mutation of superoxide dismutase 1 gene. Additional factors may be industrial pollutants and occupational exposure to chemicals associated with welding and soldering. The criteria for the diagnosis of ALS, proposed by the World Federation of Neurology, are presented together with a review of the clinical features of the disease.

NGF level in the rat sciatic nerve is decreased after long-term consumption of ethanol.

Long-term effects of ethanol consumption on endogenous nerve growth factor (NGF) level were investigated in NGF-producing target organs and tissues of the peripheral nervous system. Rats were treated with ethanol (20% v/v) for 9 months, detoxified for an additional 2 weeks and kept without ethanol for an additional month prior to sacrifice. NGF level in the NGF-producing target tissues such as iris and submandibular gland and in the trigeminal ganglion and superior cervical ganglion, where NGF-responsive perikarya are located, did not differ significantly from corresponding controls. In contrast, NGF level in the sciatic nerve was significantly reduced by 54%. This indicates that long-term ethanol consumption affects retrograde axonal transport of the neurotrophic factor NGF, suggesting that NGF deficiency may be part of the pathophysiology of peripheral neuropathy due to chronic alcoholism.

Effect of chronic autoimmune nerve growth factor deprivation on sympathetic neuroaxonal dystrophy in rats.

Nerve growth factor (NGF) deficiency has been proposed as a possible pathogenetic mechanism underlying the sympathetic autonomic neuropathy which develops in clinical and experimental diabetes and aging. To determine if long-term NGF deficiency alone would reproduce the distinctive sympathetic neuropathology of streptozocin-induced diabetes or aging in rats, nondiabetic animals were deprived of NGF for 12 months using an autoimmune paradigm. Neuroaxonal dystrophy (NAD), the neuropathologic hallmark of experimental sympathetic diabetic neuropathy and aging, was not increased in frequency in prevertebral superior mesenteric or paravertebral superior cervical ganglia in comparison to age-matched controls. Residual neurons in chronically NGF deprived sympathetic ganglia did not show significant atrophy, chromatolysis, active neuronal degeneration or intraganglionic debris. Postganglionic noradrenergic axons in ileal mesenteric nerves also failed to develop NAD in chronic autoimmune NGF-deprived rats as they would have in animals diabetic for the same duration. These results suggest that simple, isolated NGF deficiency maintained for long periods of time in nondiabetic animals is not sufficient to produce NAD in the pattern of experimental rat diabetes and aging.

Low contents of nerve growth factor in serum and submaxillary gland of diabetic mice: A possible etiological element of diabetic neuropathy

Insulin and nerve growth factor are peptides that share several chemical and functional properties. While the total or relative deficiency of insulin causes diabetes, the possible disorders due to deficiency of nerve growth factor have not been clearly defined. However, the intense biological actions of nerve growth factor in the maintenance and growth of several neural cells make feasible its participation in the physiopathology of some diseases of the peripheral nervous system. We measured the contents of nerve growth factor in serum, submaxillary gland and sciatic nerve of mice with streptozotocin-induced diabetes. Nerve growth factor in diabetic mice was diminished in serum and submaxillary gland when compared with matched controls ( P < 0.01). This finding further supports a similar observation in diabetic patients and suggests a possible etiological involvement of neural growth factor in the development of diabetic neuropathy.

Anaemia with Inappropriately Low Erythropoietin in a New Autonomic and Sensory Neuropathy Attributed to Nerve Growth Factor Deficiency

Anaemia with Inappropriately Low Erythropoietin in a New Autonomic and Sensory Neuropathy Attributed to Nerve Growth Factor Deficiency

Decreased level of nerve growth factor (NGF) and its messenger RNA in the aged rat brain

Trophic factors such as nerve growth factor (NGF) are thought to support survival, differentiation and maintenance of neurons. Recent results indicate that NGF produced in cortical and hippocampal areas is required for the function of cholinergic neurons in the basal forebrain. With the use of enzyme immunoassay and RNA blot hybridization we studied the NGF protein and NGF mRNA, respectively, in regions of the brain innervated by basal forebrain cholinergic neurons in adult and aged rats. Levels of NGF protein were decreased by 40% in hippocampus of aged (28 months) Fischer 344 rats compared with adults (6 months), whereas no alterations were observed in cerebral cortex. Moreover, a reduction by 50% in the NGF mRNA was found in samples of the aged forebrain (cerebral cortex, hippocampus, basal forebrain and hypothalamus) compared to the adult. NGF deficiencies may thus account for the loss of cholinergic neurons in the basal forebrain generally found to accompany normal aging and resulting in altered cognitive functions.