The role of neurotrophic factors in manic-, anxious- and depressive-like behaviors induced by amphetamine sensitization: Implications to the animal model of bipolar disorder.

BACKGROUND: Bipolar disorder (BD) and substance use disorders share common symptoms, such as behavioral sensitization. Amphetamine-induced behavioral sensitization can serve as an animal model of BD. Neurotrophic factors have an important role in BD pathophysiology. This study evaluated the effects of amphetamine sensitization on behavior and neurotrophic factor levels in the brains of rats. METHODS: Wistar rats received daily intraperitoneal (i.p) injections of dextroamphetamine (d-AMPH) 2 mg/kg or saline for 14 days. After seven days of withdrawal, the animals were challenged with d-AMPH (0.5 mg/kg, i.p) and locomotor behavior was assessed. In a second protocol, rats were similarly treated with d-AMPH (2 mg/kg, i.p) for 14 days. After withdrawal, without d-AMPH challenge, depressive- and anxiety-like behaviors were evaluated through forced swimming test and elevated plus maze. Levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. RESULTS: D-AMPH for 14 days augmented locomotor sensitization to a lower dose of d-AMPH (0.5 mg/kg) after the withdrawal. d-AMPH withdrawal induced depressive- and anxious-like behaviors. BDNF, NGF, and GDNF levels were decreased, while NT-3 and NT-4 levels were increased in brains after d-AMPH sensitization. LIMITATIONS: Although d-AMPH induces manic-like behavior, the mechanisms underlying these effects can also be related to phenotypes of drug abuse. CONCLUSIONS: Together, vulnerability to mania-like behavior following d-AMPH challenge and extensive neurotrophic alterations, suggest amphetamine-induced behavioral sensitization is a good model of BD pathophysiology.

Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats.

Severe thyroid hormone (TH) deficiency during critical phases of brain development results in irreversible neurological and cognitive impairments. The mechanisms accounting for this are likely multifactorial, and are not fully understood. Here we pursue the possibility that one important element is that TH affects basal and activity-dependent neurotrophin expression in brain regions important for neural processing. Graded exposure to propylthiouracil (PTU) during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. In contrast to small PTU-induced reductions in basal expression of several genes, developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes (Bdnft, Bdnfiv, Arc, and Klf9) in adulthood and was accompanied by deficits in hippocampal-based learning. These data demonstrate that mild TH insufficiency during development not only reduces expression of important neurotrophins that persists into adulthood but also severely restricts the activity-dependent induction of these genes. Considering the importance of these neurotrophins for sculpting the structural and functional synaptic architecture in the developing and the mature brain, it is likely that TH-mediated deficits in these plasticity mechanisms contribute to the cognitive deficiencies that accompany developmental TH compromise.

(±)3,4-methylenedioxymethamphetamine ("ecstasy") treatment modulates expression of neurotrophins and their receptors in multiple regions of adult rat brain.

(±)3,4-Methylenedioxymethamphetamine (MDMA), a widely used drug of abuse, rapidly reduces serotonin levels in the brain when ingested or administered in sufficient quantities, resulting in deficits in complex route-based learning, spatial learning, and reference memory. Neurotrophins are important for survival and preservation of neurons in the adult brain, including serotonergic neurons. In this study, we examined the effects of MDMA on the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their respective high-affinity receptors, tropomyosin receptor kinase (trk)B and trkC, in multiple regions of the rat brain. A serotonergic-depleting dose of MDMA (10 mg/kg × 4 at 2-hour intervals on a single day) was administered to adult Sprague-Dawley rats, and brains were examined 1, 7, or 24 hours after the last dose. Messenger RNA levels of BDNF, NT-3, trkB, and trkC were analyzed by using in situ hybridization with cRNA probes. The prefrontal cortex was particularly vulnerable to MDMA-induced alterations in that BDNF, NT-3, trkB, and trkC mRNAs were all upregulated at multiple time points. MDMA-treated animals had increased BDNF expression in the frontal, parietal, piriform, and entorhinal cortices, increased NT-3 expression in the anterior cingulate cortex, and elevated trkC in the entorhinal cortex. In the nigrostriatal system, BDNF expression was upregulated in the substantia nigra pars compacta, and trkB was elevated in the striatum in MDMA-treated animals. Both neurotrophins and trkB were differentially regulated in several regions of the hippocampal formation. These findings suggest a possible role for neurotrophin signaling in the learning and memory deficits seen following MDMA treatment.

Targeting neurotrophin-3 and its dependence receptor tyrosine kinase receptor C: a new antitumoral strategy.

INTRODUCTION: Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor that belongs to the tyrosine kinase receptor family. This family primarily consists of proto-oncogenes, and TrkC has been involved in oncogenic translocations. However, its expression in tumors is often associated with good prognosis, suggesting it actually acts as a tumor suppressor. TrkC has recently been demonstrated to be a dependence receptor, which regulates neuronal survival. Dependence receptors share the ability to trigger apoptosis in the absence of their ligand, a feature that has been suggested to confer a tumor suppressor function to these receptors. A selective advantage for a tumor cell to survive in an environment with limited ligand availability would hence be either to lose the expression of the dependence receptor, or to gain expression of its ligand. AREAS COVERED: The role of neurotrophin-3 (NT-3) and its dependence receptor TrkC in neuroblastoma, and its suitability as a therapeutic target. EXPERT OPINION: Autocrine production of NT-3 represents a selective advantage for tumor growth and dissemination, in a large fraction of aggressive neuroblastoma. Disruption of the NT-3 autocrine loop in malignant neuroblasts, triggers neuroblastoma cell death, and inhibits neuroblastoma metastasis in animal models. Thus, a novel way of targeting the tyrosine kinase receptor, is via the reactivation of its intrinsic ability to trigger cell death.

Neurotrophins: from pathophysiology to treatment in Alzheimer's disease.

Alzheimer's disease (AD) is the most common diagnosis among dementia. As increasing longevity results in larger numbers of AD patients and thus rising economic costs, there has been intense research about the pathophysiology and treatment strategies during the last years. Since neurotrophic factors are not only responsible for neuronal development but also critical for the maintenance of neurons, they represent mediators of high interest within the research of neurodegeneration. Thereby, NGF has been identified as a dynamic pattern during the time course of neurodegeneration in AD. Post mortem studies point to a lack of NGF action in early stages of AD. In contrast NGF is found in enhanced concentrations in brains with severe AD partly due to a pathologically altered axonal transport of NGF in the neurons. Therefore, pharmacological interventions strategies focus on an neurotrophin substitution in mild to moderate cases of AD. Intensive research mostly in rodents has recently led to first promising clinical trials of intracerebral neurotrophin application pointing to a growing role of neurotrophins in the establishment of new pharmacological strategies concerning AD.

Interleukin-1beta interferes with signal transduction induced by neurotrophin-3 in cortical neurons.

It was previously observed that IL-1beta interferes with BDNF-induced TrkB-mediated signal transduction and protection of cortical neurons from apoptosis evoked by deprivation from trophic support [Tong L., Balazs R., Soiampornkul R., Thangnipon W., Cotman C.W., 2007. Interleukin-1beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol. Aging]. Here we investigated whether the effect of the cytokine on neurotrophin signaling is more general. The influence of IL-1beta on NT-3 signaling was therefore studied under conditions when NT-3 primarily activated the TrkC receptor. The cytokine reduced NT-3-induced activation of MAPK/ERK and Akt, but did not interfere with Trk receptor autophosphorylation. IL-1beta reduced tyrosine phosphorylation of the docking proteins, IRS-1 and Shc, which convey receptor activation to the downstream protein kinase cascades. These are the steps that are also inhibited by IL-1beta in BDNF-induced signal transduction. The functional consequences of the effect of IL-1beta on NT-3 signaling were severe, as NT-3 protection of the trophic support-deprived cortical neurons was abrogated. In view of the role in the maintenance and plasticity of neurons of ERK, Akt and CREB, which are activated by neurotrophins, elevated IL-1beta levels in the brain in Alzheimer's disease and other neurodegenerative diseases might contribute to the decline in cognitive functions before the pathological signs of the disease develop.

Effects of the Chinese traditional prescription Xiaoyaosan decoction on chronic immobilization stress-induced changes in behavior and brain BDNF, TrkB, and NT-3 in rats.

The Xiaoyaosan (XYS) decoction, a Chinese traditional prescription containing eight commonly used herbs, has been used for treatment of mental disorders such as depression for centuries in China. However, the mechanism underlying its antidepressant activity is poorly understood. In rats with chronic immobilization stress (CIS), we examined the effects of the XYS decoction on tail suspension behavior and the levels of brain-derived neurotrophic factor (BDNF), tyroxine hydroxylase (TrkB), and neurotrophin 3 (NT-3) in the frontal cortex and hippocampus. Rats subjected to CIS exhibited decreases in weight-gain, food intake, and ambulation in the open field test; they also showed an increase in immobility in the tail suspension test. These were all attenuated by the XYS decoction. Biochemically, the XYS decoction also reversed CIS-induced decreases in BDNF and increases in TrkB and NT-3 in the frontal cortex and the hippocampal CA(1) subregion. The behavioral effects of the XYS were correlated to the biochemical actions. These results suggest that the XYS decoction produces an antidepressant-like effect, which appears to be involved by BDNF in the brain.

Chronic exposure to ethanol alters neurotrophin content in the basal forebrain-cortex system in the mature rat: effects on autocrine-paracrine mechanisms.

Neurotrophins are broadly expressed in the mammalian forebrain: notably in cerebral cortex and the basal forebrain (e.g., the septal and basal nuclei). These factors promote neuronal survival and plasticity, and have been implicated as key players in learning and memory. Chronic exposure to ethanol causes learning and memory deficits. We tested the hypothesis that ethanol affects neurotrophin expression and predicted that these changes would be consistent with alterations in retrograde or autocrine/paracrine systems. Mature rats were fed a liquid diet containing ethanol daily for 8 or 24 weeks. Weight-matched controls were pair-fed an isocaloric, isonutritive diet. Proteins from five structures (parietal and entorhinal cortices, hippocampus, and the basal and septal nuclei) were studied. ELISAs were used to determine the concentration of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). All three neurotrophins were detected in each structure examined. Ethanol treatment significantly (p < 0.05) affected neurotrophin expression in time- and space-dependent manners. NGF content was generally depressed by ethanol exposure, whereas NT-3 content increased. BDNF concentration was differentially affected by ethanol: it increased in the parietal cortex and the basal forebrain and decreased in the hippocampus. With the exception of NGF in the septohippocampal system, the ethanol-induced changes in connected structures were inconsistent with changes that would be predicted from a retrograde model. Thus, the present data (a) support the concept that neurotrophins act through a nonretrograde system (i.e., a local autocrine/paracrine system), and (b) that chronic exposure to ethanol disrupts these regulatory mechanisms.

Early postnatal corticosterone administration regulates neurotrophins and their receptors in septum and hippocampus of the rat.

The principal glucocorticoid in rats, corticosterone, interacts with neurons in the limbic system and leads to morphological and behavioral changes. Putative corticosterone-triggered mediators are neurotrophins. In the present study we investigated the effects of early postnatal corticosterone treatment in rats on neurotrophic factors of the nerve growth factor (NGF) family and their receptors. Newborn rats were treated with corticosterone-containing polymers until postnatal day 12. The mRNA and protein levels of the neurotrophins of the NGF family (NGF, BDNF, NT-3 and NT-4/5) and their receptors (trkA, trkB, trkC and p75) were quantified in septum and hippocampus using RT-PCR. In the septal region, we found an unchanged mRNA expression after corticosterone treatment, whereas in the hippocampus there was a general increase in mRNA. Particularly, the gene expression of NGF, NT-3, and the high affinity receptors trkA, trkB and trkC increased significantly. Quantification of the neurotrophin protein levels using an ELISA revealed significant treatment effects for NGF and NT-4/5 in the hippocampus. The present study of corticosterone treatment in young rats demonstrates interactions of steroid hormones with neurotrophic factors and their receptors in the septo-hippocampal system during the first two postnatal weeks.

Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli.

Neurotrophins, such as nerve growth factor (NGF) and neurotrophin-3 (NT-3), are essential for development, function, and survival of peripheral sympathetic and sensory neurons. Most eosinophilic leukocytes in the human body are localized in mucosal tissues; however, the roles of eosinophils in human diseases are not fully understood. We found that human eosinophils constitutively express messenger RNA for NGF and NT-3, synthesize and store these proteins intracellularly, and continuously replenish them. Incubation of eosinophils with a transcription inhibitor, actinomycin D, for 8 hours completely depletes intracellular NGF and NT-3. New synthesis of NGF is enhanced by Fc-receptor-mediated stimuli, such as immunoglobulin (Ig)A and IgG immune complexes; in contrast, production of NT-3 is not affected by these stimuli. Notably, supernatants of eosinophils stimulated with IgA immune complex and interleukin 5 promote neurite extension of the PC-12 pheochromocytoma cell line; this effect is abolished by pretreatment of the supernatants with anti-NGF-neutralizing antibody. By enzyme-linked immunosorbent assay, substantial amounts of NGF protein are also detected in the supernatants of stimulated eosinophils. Furthermore, in patients with seasonal allergic rhinitis, the concentrations of NGF in nasal secretions correlate with the magnitudes of eosinophilic inflammation in the airway, suggesting a potential clinical implication of eosinophil NGF. Our observations propose a new pathologic mechanism by which eosinophils may contribute to enhanced neurologic responses in patients with allergic diseases and other eosinophilic disorders. Alternatively, eosinophils may play important roles in maintenance and restoration of homeostatic functions of mucosal tissues through the pleitropic activities of NGF.

The influence of inhalative corticosteroids on circulating Nerve Growth Factor, Brain-Derived Neurotrophic Factor and Neurotrophin-3 in allergic asthmatics.

BACKGROUND: The neurotrophins Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin (NT)-3 are produced, stored and released by various immunological cells. The influence of NTs upon the function of these cells is described. Elevated plasma levels were found in inflammatory, autoimmune and allergic diseases with the highest levels in allergic asthma. A connection between bronchial hyper-responsiveness and serum levels has been reported. OBJECTIVE: Little is known about the influence of treatment with inhaled corticosteroids (ICS) on serum NT levels and their influence on the asthmatic state. METHODS: Eighty-seven volunteers were studied. Thirty-eight were stable allergic asthmatics with constant ICS doses, 29 were asthmatics not receiving anti-asthmatic treatment and 20 were age- and sex-matched healthy controls. Demographic and lung function data were evaluated. NT serum levels were determined by ELISA. RESULTS: NGF and BDNF levels were significantly increased in untreated asthmatics compared to the control and the treated group, while NT-3 demonstrated significantly higher levels in treated asthmatics compared to healthy controls. After stabilization of untreated subjects with ICS, the NT levels decreased significantly. CONCLUSIONS: These results suggest that NTs participate in allergic inflammation and asthma. Effective treatment leads to a decrease of circulating neurotrophic factors.

Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator.

The effects of a novel AMPA receptor potentiator (LY392098) on the expression of brain-derived neurotrophic factor (BDNF) were examined in primary neuron culture. The addition of either AMPA or LY392098 to cortical neurons elicited a time and concentration dependent increase in mRNA encoding BDNF. Moreover, co-addition of subeffective concentrations of AMPA (1 microM) and LY392098 (1 microM) resulted in dramatic increases in both BDNF mRNA (>25-fold) and protein ( approximately 7-fold) levels, whilst no changes in either NT-3 or NT-4 mRNA were detected. More modest ( approximately 1.5-2.5-fold) elevations in BDNF mRNA and protein expression were also produced by combinations of AMPA and LY392098 in cerebellar granule cell neurons. In contrast, AMPA and LY392098, either alone or in combination, did not elevate BDNF mRNA levels in primary astroglial cultures. Maximum elevations in BDNF mRNA and protein were produced by 6-12h of AMPA receptor activation 1-3h of AMPA receptor activation were required to elevate BDNF mRNA levels. AMPA receptor-mediated increases in BDNF mRNA and protein were abolished by the AMPA antagonist, NBQX, but were unaffected by the NMDA antagonist, MK-801. In cortical neuron cultures, activation of both L-type Ca(+2) channels and mitogen-activated protein (MAP) kinases contribute to AMPA receptor-mediated increases in BDNF mRNA. The ability of LY392098 to increase the expression of BDNF in primary neuron culture indicates this and related biarylpropylsulfonamides may be useful in the treatment of neuropsychiatric disorders.

Corticosterone inhibits generation of long-term potentiation in rat hippocampal slice: involvement of brain-derived neurotrophic factor.

In the present study, the effect of corticosterone (CORT) on the generation of long-term potentiation (LTP) and its underlying mechanism involving neurotrophin gene expression in CA1 synapses of rat hippocampal slice were examined. Our experimental results showed incubation of hippocampal slice with CORT for 3 h had no effect on either the slope or amplitude of excitatory postsynaptic potentials (EPSP) evoked in hippocampal CA1 pyramidal dentrites, indicating no marked change in basal synaptic transmission. However, when tetanic stimulation (100 pulses, 100 Hz) was delivered to the Schaffer collateral pathway, CORT application significantly attenuated the tetanus-induced increases of both EPSP slope and amplitude, demonstrating an inhibitory effect of CORT on LTP generation. In addition, CORT treatment significantly reduced both slope and amplitude ratios of the second evoked EPSP to the first one when paired-pulse facilitation (PPF) was established at different interpulse intervals from 20 to 40 ms, suggesting that a presynaptic mechanism may be involved in CORT-induced hippocampal synaptic plasticity. Reverse-transcription polymerase chain reaction (RT-PCR) analysis showed that CORT-treated hippocampal CA1 cells underwent a significant decrease in the expression of mRNA for nerve growth factor-beta (NGF-beta) and brain-derived neurotrophic factor (BDNF), but not for neurotrophin-3 (NT-3) compared with those in control. Moreover, BDNF co-applied with CORT significantly antagonized CORT-induced deficit in PPF. Taken together, the present results suggest that CORT-induced inhibition of LTP may be, at least to some extent, mediated by a presynaptic mechanism and decrease in the BDNF expression in rat hippocampal CA1 cells induced by CORT may partially account for this presynaptic mechanism.

GABA(B) receptor antagonists elevate both mRNA and protein levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) but not neurotrophin-3 (NT-3) in brain and spinal cord of rats.

In this study we show that single, physiologically-active and non-convulsive doses of the three GABA(B) receptor antagonists CGP 36742, CGP 56433A and CGP 56999A increase NGF and BDNF mRNA levels by 200-400% and protein levels by 200-250% in rat neocortex, hippocampus as well as spinal cord. In all areas examined the increase in NGF protein preceded that of BDNF. Peak levels of both neurotrophins are transient and occur between 24 and 72 h, depending on the region. In contrast, NT-3 protein concentrations in the neocortex and hippocampus were decreased significantly to 50% of control values within 48-96 h. The decrease in the spinal cord was less than 30% and did not reach significant levels. These data clearly demonstrate that GABA(B) receptor antagonists induce a specific neurotrophin expression in the central nervous system at physiologically relevant doses, as opposed to the extreme conditions of seizure paradigms. The results are in line with the concept that neuronal neurotrophin synthesis and release in brain are controlled by afferent nerve activity. GABA(B) receptor antagonists could therefore be a valuable new approach to selectively increase endogenous neurotrophin levels in the central nervous system.

Ethanol-induced alterations in neurotrophin expression in developing cerebellum: relationship to periods of temporal susceptibility.

BACKGROUND: The developing cerebellum has been shown to be profoundly affected by exposure to ethanol and to exhibit a temporal pattern of vulnerability. Cerebellar Purkinje cells are particularly susceptible to ethanol on postnatal day 4 or day 5 (P4-5), whereas this population is much less vulnerable to similar ethanol insult slightly later in the postnatal period (P7-9). The purpose of the study was to determine whether differential alterations in neurotrophic factors might be associated with this differential susceptibility. METHODS: Neonatal rats were exposed to ethanol via vapor inhalation, and enzyme-linked immunoabsorbent assays were subsequently conducted to assess cerebellar nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 protein content. These analyses were made after ethanol exposure during the period of maximal cerebellar ethanol sensitivity (postnatal days 4-5 [P4-51), during a period of much lower sensitivity (P7-8), and during the entire "brain growth spurt" (P4-10). RESULTS: These determinations revealed a significant ethanol-induced decrease in cerebellar nerve growth factor after exposure on P4-5 but not after exposure on P7-8 or P4-10. No significant changes in brain-derived neurotrophic factor or neurotrophin-3 were found with any of the exposure paradigms. CONCLUSIONS: These results suggest that alterations in nerve growth factor, which has previously been shown to support cerebellar Purkinje and granule cells, may be a mechanism contributing to the early ethanol susceptibility within these neuronar populations.

Effects of neurotrophin and neurotrophin receptor disruption on the afferent inner ear innervation.

Two neurotrophins and their two receptors appear to regulate the survival of vestibular and cochlear neurons in the developing ear. Mice lacking either brain derived neurotrophic factor (BDNF) or its associated receptor, Trk B, show a severe reduction in the number of vestibular neurons and a loss of all innervation to the semicircular canals. Mice lacking NT-3 or its receptor, Trk C, show a severe reduction of spiral neurons in the basal turn of the cochlea. Mice lacking both BDNF and NT-3 or Trk B and Trk C, reportedly lose all innervation to the inner ear. These two neurotrophins and their associated receptors are necessary for the normal afferent innervation of the inner ear.