Marzo-Aprile 2009, Vol. 44, N. 2 Riv Psichiatr 2009;44(2):88-94 doi 10.1708/420.4978 Scarica il PDF (104,4 kb) Stress, anxiety and schizophrenia and neurotrophic factors: the pioneer studies with nerve growth factor titolo - split_articolo,controlla_titolo - art_titolo Stress, anxiety schizophrenia and neurotrophic factors: the pioneer studies with nerve growth factor title - controlla_titolo - art_title Stress, schizofrenia e fattori neurotrofici: gli studi pionieristici con il nerve growth factor autori - vau_aut_id LAURA GIOIOSA, ANGELA IANNITELLI, LUIGI ALOE affiliazione_autori - ignora 1Institute of Neurobiology and Molecular Medicine, Section of Neurobiology, National Research Council (CNR), Rome, Italy 2Dpt of Psychiatric Sciences and Psychological Medicine, “Sapienza” University of Rome, Polo Pontino, Italy riassunto - art_riassunto SUMMARY. The aim of this review is to highlight past and ongoing studies on neurotrophin (NT) role, in particular focusing on nerve growth factor (NGF), on behavioral response to stress, agonistic and emotional behavior, anxiety, and schizophrenia. One of the first evidences of NGF involvement in behavioral response to a social challenge was published in 1986. In male mice, agonistic encounters caused a massive NGF release into the bloodstream and in the hypothalamus. Subsequent studies revealed that this NGF release was not strictly linked to agonistic behavior, but to mice hierarchical status, with subordinates having higher NGF levels than dominants. This observation led to the hypothesis and later to the demonstration that NGF release is associated to anxiety-related behaviors. Later studies provided evidence for the involvement of NTs, including NGF, in the development of neuropsychiatric disorders. Interestingly, pharmacological treatment can reduce the effects of the maldevelopment and neuropathology due to NT imbalance during early periods of life crucial for development. Further understanding of the core pathophysiological mechanism for neurodegenerative and psychiatric disorders will eventually provide tools for amelioration of symptoms of those psychiatric disorders characterized by an NT imbalance. parolechiave - lingua - vke_key_id KEY WORDS: neurotrophins, NGF, stress, anxiety, psychiatric disorders, schizophrenia, antipsychotic drugs. abstract - art_abstract RIASSUNTO. L’obiettivo di questa rassegna è quello di presentare gli studi passati e ancora in corso sul ruolo delle neurotrofine (NT), con particolare riguardo per il fattore di crescita nervoso (NGF), sulla risposta comportamentale allo stress, sul comportamento agonistico ed emozionale, sull’ansia e la schizofrenia. Una delle prime evidenze dell’implicazione del NGF nella risposta comportamentale a una sfida sociale è stata pubblicata nel 1986. Nei topi maschi, episodi di aggressività causavano un rilascio consistente di NGF nel sangue e nell’ipotalamo. Studi successivi hanno dimostrato che questo innalzamento del NGF non era strettamente correlato al comportamento agonistico, ma allo stato gerarchico dei topi, con i topi subordinati con livelli di NGF più alti rispetto ai dominanti. Questa osservazione portò all’ipotesi e successivamente alla dimostrazione che il rilascio di NGF era associato ai comportamenti ansia-correlati. Studi eseguiti successivamente hanno fornito l’evidenza dell’implicazione delle NT, incluso il NGF, nello sviluppo dei disturbi neuropsichiatrici. Appare molto interessante il fatto che il trattamento farmacologico può ridurre gli effetti del maldevelopment e dei quadri neuropatologici dovuti allo squilibrio delle NT durante le fasi precoci della vita, cruciali per lo sviluppo. Inoltre, la comprensione del meccanismo patologico core per i disturbi neurodegenerativi e psichiatrici potrà eventualmente fornire gli strumenti per migliorare i sintomi di quei disturbi psichiatrici caratterizzati da uno squilibrio delle NT. keyword - lingua - vke_key_id PAROLE CHIAVE: neurotrofine, NGF, stress, ansia, disturbi psichiatrici, schizofrenia, antipsicotici. testo - art_testo INTRODUCTION Among neurotrophins (NTs), nerve growth factor (NGF) was the first to be identified and the best characterized member of neuroprotective molecules, collectively called neurotrophins. Besides NGF, the main factors belonging to the NT family are: brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurotrophin-6 (NT-6) and others, such as ciliary neurotrophic factor (CNTF) (1). These polypeptides can affect cell survival and activity in central nervous system (CNS). In particular, NGF is thought to play its role for survival of sympathetic and some sensory and central cholinergic neurons (2). Additionally, this molecule acts outside of the nervous system, particularly within neuroendocrine and immune system. NGF, stress and anxiety-related behavior First evidence of a link between NGF and behavior was the observation that in male mice, following agonistic episodes, NGF is released into the bloodstream from salivary glands and that its circulating levels are highly correlated with the number of agonistic episodes (3). NGF release appears to be specifically induced by agonistic encounters, which are considered a classical model of psychosocial stress in male mice (4). Remarkably, NGF circulating levels reflect not only the number of aggressive episode, but also animal hierarchical status. In pairs of fighting mice, thus, subordinates have larger NGF circulating levels relative to dominants (5). These observations were first evidence of a direct link between psychosocial stress and NGF circulating levels in an animal model. A subsequent study on emotional and physical stress carried out on young soldiers confirmed and extended to humans previous findings in mice (6). In this study blood samples were collected from Italian soldiers before and after parachute jumping in order to detect NGF variations in the bloodstream due to such a stressful event. Interestingly, not only were the NGF levels elevated due to psychological stress, but they also preceded the enhancement of cortisol and ACTH plasma levels, as a sort of early alert mechanism associated with a homeostatic adaptation. Similarly, another study on humans measuring oxytocin in pregnant and lactating women revealed that circulating NGF increase along with the pre- and post-partum oxytocin enhancement, whereas in the umbilical cord NGF levels remain at baseline level (7). Again, a possible interpretation of this outcome can be viewed in light of subjects’ anxiety state. It is, indeed, worth stressing out that subjects perceiving the delivery approaching (the parturient women) had high NGF levels. On the other hand, it is not known whether during prenatal neurogenesis a variation of circulating NT can be influenced by changes in maternal hormonal milieu. In the wake of the above-mentioned human studies, a study on alcoholic subjects yielded that chronic alcohol withdrawal, and not just the mere alcohol presence in the bloodstream, alters circulating NGF levels, indicating thus that events linked to alcohol withdrawal (such as anxiety, tremor, and hyper-excitability) are involved in NGF release into the bloodstream (8). Consistently, another human study revealed that high perceived stress and depression in caregivers are associated with elevated NGF blood levels (9). Therefore, NGF blood levels might provide an early marker of stress perception in both humans and other animals as a sort of “alerting” behavior at both cellular and organism levels. Indeed, besides trophic function, NGF seems to be involved in stress response and function of hypothalamic-pituitary-adrenocortical axis response (10), regulating hormonal and behavioral responses to both environmental and social challenging situations. The evidence that an “emotional response” induced by parachute jumping causes NGF enhancement preceding corticosteroid release (6) is consistent with this hypothesis. In many animal species, including humans, a challenging situation can be represented by the acquisition/defence of a resource, such as territory, food and/or mating partner. Emanuele, et al. (11) reported that NGF levels (and not of other NTs) are significantly elevated in the early phase of romantic love, reporting a positive correlation between romantic love intensity and circulating NGF levels. Furthermore, these researchers followed up subjects in “acute love” that maintained the relationship and interestingly observed that NGF levels were restored to baselines after 12-24 months, i.e. during the phase of “chronic love”. Overall this study provides further evidence for the role of NGF in human social chemistry. The idea that anxiety status of experimental subjects could be a file rouge linking together changes in NGF levels in both humans and mice was the starting point for several and different projects focusing on mental disorders, such as alcohol/drug addiction, anxiety, depression, schizophrenia. It is worth pointing out that an altered defence mechanism is implicated in many, if not all, the above-mentioned diseases. The notion of serum NGF should be considered as a state rather than a trait-dependent variable (12), particularly in considering early symptoms of cognitive disorders. NGF and psychiatric disorders The observation that neuronal loss or decreased neurogenesis occurs in brains of patients with a long history of depression (13) provides a connection between this syndrome and NTs. Consistently, in an animal model of depression, namely the Flinders Sensitive Line (FSL) rats, altered levels of both NGF and BDNF in several brain areas have been reported (14). Not only there is a relation between NGF and psychiatric disorders, but also a link between this molecule and drug treatment for such disorders. For instance, Iannitelli, et al. (15) reported that the therapeutic improvement with electroconvulsive therapy (ECT) in depressed patients is associated with a significant release of NTs, particularly NGF. Remarkably, in addition to an ECT direct effect on NGF levels, Bersani, et al. (16) reported a significant increase in NGF before the ECT session started (i.e., induced by the ECT waiting). Therefore, besides an enhancement of both synaptic sprouting and monoamine synthesis/turnover, NGF and ECT can promote neuroendocrine effects and regulate homeostasis (17). Taken together these observations led to the idea that antidepressant treatments exert their beneficial action by regulating synthesis and/or release of NTs (18), although there is no evidence for a defect in NTs or their receptors to cause directly a human disease affecting nervous system (19). Indeed, antidepressants generally restore normal levels of NT expression in the brain (13). For instance, lithium, the classical drug used against bipolar depression, increases NGF concentrations in hippocampus and other brain regions (20). Likewise, haloperidol can reduce NGF levels in psychotic patients (21). Besides NGF, another NT, BDNF, injected into the brain has antidepressant-like effects and it can lead to recovery of behavioral deficits in the forced swim test in an animal model of depression, namely the learned helplessness (22). Animal model of schizophrenia Epidemiological studies indicate that gestational and postnatal alterations in brain neurogenesis may increase the risk of developing behavioral and/or neuropathological deficits leading to schizophrenia during early and late post-natal life (23). This neurodevelopmental disorder is characterized by behavioral impairments in cognitive and social performances, disruption of brain cytoarchitectural and neural plasticity in limbic system, particularly in entorhinal cortex (EC) and hippocampus (24). There is also evidence that brain injury due to maternal starvation, infection, and anoxic birth can lead later in life to behavioral and brain structural deficits resembling those observed in schizophrenia (25-27). Neurotrophic factors are signaling molecules that are able to influence survival, differentiation, maintenance and connectivity of developing and adult brain nerve cells, including those that are severely damaged and, thus, underlying schizophrenic-related behaviors (28). The observations that NGF and BDNF play a crucial role during primary development of cholinergic neurons underlying learning and memory regulation (29-31) and that NGF blood levels in schizophrenic patients are lower compared to healthy controls (32) suggested a link between memory impairments and NT distribution in schizophrenic patients (33). Several animal models resemble some steps of human schizophrenia pathogenesis due to maldevelopment occurring early in life, namely asphyxia and drug-induced models. Using the former model, it has been observed that reduced BDNF levels in striatum of N 2-exposed rats couple with the risk of developing some symptoms of schizophrenia, such as social withdrawal, neophobia and stereotypy (34). Consistently, similar behavioral effects in a trans-generational drug-induced model for schizophrenia have been reported (35,36). Rats exposed to MAM during prenatal life (particularly at gestational day 12) showed impairments in learning and memory and in nociception associated to altered NGF levels in EC. Furthermore, prenatal MAM-exposure induces abnormalities in limbic system resembling some morphological and behavioral findings observed in human schizophrenia. In subsequent years, we reported changes at behavioral, cellular, biochemical and molecular levels in limbic system of adult prenatally MAM-exposed rats (28,37). Our findings suggested that dysregulation of synthesis and secretion of NTs, such as NGF and BDNF, is involved in brain and behavioral alterations (28,37). Furthermore, using the MAM model we investigated the effects of two antipsychotics, namely Clozapine and Haloperidol, on NGF and BDNF levels in both brain and bloodstream (38). Clozapine and haloperidol administration during adolescence affected both NGF and BDNF levels in both brain and bloodstream of prenatally MAM-exposed rats. Thus, this observation provided further evidence that the MAM model can be a useful tool to investigate biochemical and molecular mechanisms involved in the behavioral effects of antipsychotic drugs. The new generation of antipsychotics such as risperidone and olanzapine compared to the first generation, such as haloperidol and chlorpromazine, have neuroprotective effects in both human patients and animal models (39). Animal studies suggest that such effects are probably mediated through an enhanced expression of NTs, particularly NGF and BDNF. Thus, changes of NGF plasma concentrations in response to treatment with antipsychotics may, indeed, have a significant role in restoring brain structure and function. Treatment of psychiatric disorders with NGF The idea of studying the NGF role in psychiatric disorders originates from findings on animal models indicating that this molecule plays a crucial role in CNS development, in stress response, in integrating neuroendocrine functions, in activating agonistic behavior, as well as in mechanisms at the basis of kindling and neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. The first human studies provided evidence that NTs, particularly NGF, regulate CNS functional changes, respond to drug administration and possibly modulate the phenotypic representation of psychiatric disorders (21). Therefore, molecules known to regulate neuronal plasticity in learning and memory have been proved to be also involved in the actions of drugs used against depression and bipolar disorders. As a consequence, NGF was studied in the past and is still being studied today in preclinical and clinical contexts in relation to development and treatment of CNS pathologies (40,41). The hypothesis underlying the NT use as therapeutics assumes that these diseases result in decreased NT availability in affected brain neurons, and decreased NT receptor number on affected neurons. The exogenous NT administration can compensate such deficits. Under these conditions, the hypothesis is that NT administration would provide symptomatic treatment for the disease state rather than a cure for these nervous system disorders. To date, a growing body of efforts is being devoted to the investigation on the NGF potential use as therapeutic, since the recent development of recombinant DNA technology for the production of large amounts of active human NGF (42). There are, though, pros and cons of NGF systemic administration to take into account. Beside promoting synaptic plasticity and preventing or reversing experimental neuropathies, NGF can elicit other responses. For instance, NGF can affect sympathetic nervous system (43,44), blood pressure (45), proliferation of neurogenic tumor cells, body weight gain (46), and nociception (hyperalgesia) (47). It is, thus, conceivable that further knowledge of NGF pharmacokinetic properties will address the choice of appropriate dose regimens to optimize its potential healing actions and hopefully reduce negative side effects (48). Concerning other NTs, only recently, a number of studies linked a single nucleotide polymorphism in the BDNF gene with memory impairments, as well as altered susceptibility to neurodegenerative and/or psychiatric disorders, such as Alzheimer’s (49) and Parkinson’s diseases (50), depression (51), eating (52) and bipolar disorder (53). A common clinical symptom among these disorders is varying degrees of higher cognitive abilities. With the established role of BDNF in mediating processes related to learning and memory (54,55), this susceptibility to cognitive impairments may have broad roles in multiple disorders affecting nervous system functioning (19). As mentioned above, low BNDF levels were reported in both schizophrenic patients (32,56) and depressed patients (57,58). Recently low BDNF plasma levels have been indicated as biological marker of suicidal depression (59). Several studies reported antidepressant effects of exogenous BDNF administration into specific brain areas, particularly in the hippocampus (for a review, see reference 60). Similar effects in animal models of depression have been reported for other growth factors, such as NT-3 (61), insulin-like growth factor-I (IGF-I) (62), and vascular endothelial growth factor (VEGF) (63). Therefore, it is conceivable that drugs that selectively stimulate the NT synthesis and/or activate the NT signaling pathways could represent potential pharmacological tools in the treatment of depression- and schizophrenic-like disorders. THE EFFECT OF ANTIPSYCHOTIC DRUGS IS MEDIATED BY NEUROTROPHINS Clozapine has been reported to increase NGF levels in both blood and EC, whereas BDNF levels in EC only (38). In the hippocampus, haloperidol enhances NGF levels, while in the striatum this drug elevates both the NGF and BDNF levels (39). Given that both of these NTs are markedly involved in promoting and maintaining brain neuron plasticity clozapine or haloperidol may produce their effects modulating NGF/BDNF synthesis and release. Furthermore, in prenatally MAM-exposed rats, clozapine and haloperidol influence both TrkA and TrkB expression. Particularly, in the hippocampus clozapine increases TrkB expression, whereas haloperidol elevates TrkA/TrkB expression in EC, which is known to be a highly vulnerable structure in schizophrenic brain (56,64-66). In human post-mortem schizophrenic brains, TrkB expression appears to be reduced either with or without neuroleptic treatment (67), while in living schizophrenic patients NGF and BDNF baselines undergo through significant changes (12,32,67,68). The second-generation of antipsychotics, olanzapine, quetiapine, and clozapine enhance neurite outgrowth induced by NGF in PC12 cells (69). Chronic exposure to haloperidol, but not to the atypical antipsychotics risperidone or clozapine, alters choline acetyltransferase brain levels (65,70), an enzyme regulated by NGF (71). As already mentioned, in rat hippocampus and striatum, haloperidol administration decreased NGF or BDNF levels (39). Furthermore, a time-course study on haloperidol effects yielded elevated NGF values in hippocampus after 1 or 2 weeks of treatment (72). These findings led to the hypothesis that the MAM-exposed rat model represents a stool for investigating undesired side effects of antipsychotics and eventually neurotrophic-linked molecular events and mechanisms involved in “schizophrenia-like” diseases. CONCLUDING REMARKS In our review we highlighted the recent and ongoing studies on NTs role, particularly NGF, in psychiatric diseases. It is often difficult to extrapolate animal data to human outcomes, but findings obtained through animal studies can lead to interesting working hypothesis in the clinic. The idea of using NT administration to treat neurological diseases is based on the assumption of symptomatic treatment of impaired neurons. It has become evident that appropriate delivery of sufficient NT quantities to target neurons is a major obstacle, besides large side effects, such as epileptic activity. Development of small molecules, that can readily cross the blood-brain barrier to activate NT receptors, could represent an additional tool in understanding whether NTs, including NGF, may have a therapeutic potentiality. Indeed, Chao, et al. (19) recently hypothesize that the road of receptor activation should be actively pursued with pharmacological studies utilizing peptides and other small molecules that might serve as NT agonists or antagonists. 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