Nerve growth factor in the psychiatric brain

Il fattore di crescita nervosa nelle patologie cerebrali psichiatriche


1Institute of Translational Pharmacology, IFT-CNR, Institute of Cell Biology and Neurobiology, IBCN-CNR, Rome, Italy
2Department of Experimental Medicine, Sapienza University of Rome, Italy
3Institute of Biochemistry and Cell Biology, IBBC-CNR, Rome, Italy
4Department of Biotechnology and Applied Clinical Sciences, University of L’Aquila, Italy
5Department of Sense Organs, Sapienza University of Rome, Italy
6Department of Anatomy and Cell Biology, Medical University, Varna, Bulgaria
7Department of Gynecology, Obstetric, and Urology, Sapienza University of Rome, Italy
8Department of Pediatrics, Medical Faculty, Sapienza University of Rome, Italy
9Centro Riferimento Alcologico Regione Lazio, ASL Roma 1, Rome, Italy

SUMMARY. The nerve growth factor (NGF) belongs to a family of proteins named neurotrophins, consisting of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. NGF regulates a large number of physiological mechanisms that result in neurotrophic, metabotrophic and/or immunotrophic effects. Neurodegenerative diseases, including Alzheimer disease, psychiatric disorders (e.g. depression and schizophrenia) and brain parasitic infection have in common the effect of changing the brain levels of neurotrophins, in particular NGF. The contribution of both NGF and its receptor TrkA in such events and the recent promising results of NGF based therapies are here presented and discussed.

KEY WORDS: NGF, Alzheimer disease, depression, brain, parasite, alcohol, neurodegeneration.

RIASSUNTO. Il fattore di crescita nervosa (NGF) appartiene a una famiglia di proteine chiamate neurotrofine, costituita dall’NGF, il fattore neurotrofico di derivazione cerebrale (BDNF), la neurotrofina-3 (NT-3), NT-4/5 e NT-6. L’NGF regola un gran numero di meccanismi fisiologici che provocano effetti neurotrofici, metabotrofici e/o immunotrofici. Le malattie neurodegenerative, tra cui la malattia di Alzheimer, il danno indotto dall’alcol, i disturbi psichiatrici (per es., depressione e schizofrenia) e l’infezione parassitaria cerebrale hanno in comune l’effetto di modificare i livelli cerebrali di neurotrofine, in particolare l’NGF. Vengono qui presentati e discussi il contributo dell’NGF e del suo recettore TrkA in tali eventi e i recenti promettenti risultati delle terapie basate sull’NGF.

PAROLE CHIAVE: NGF, malattia di Alzheimer, depression, cervello, parassita, alcol, neurodegenerazione.

Nerve growth factor (NGF), firstly isolated in 1956, is a neuropeptide regulating the survival and proliferation of selected neurons1 in central and peripheral nervous system. Actually, NGF and its comparative molecules collectively known as neurotrophins are well documented mediators of multiple biological events in health and disease2-4, varying their effects from that neurotrophic5,6 through immunotrophic7,8 to metabotrophic9,10. Thus, NGF is implicated in the pathogenesis of a large spectrum of neuronal diseases (Alzheimer’s and other neurodegenerative diseases) and non-neuronal disorders (atherosclerosis, obesity, type 2 diabetes mellitus and other cardiometabolic disorders)8,10-14. Particularly in the brain, NGF plays a key role in several diseases leading to cell death and/or neurodegeneration during development or aging15-21. NGF is synthesized as a 130 kD precursor (proNGF) that is a complex of three proteins: α-NGF, β-NGF and β-NGF the latter acting as a serine protease that cuts the subunit releasing the 26 kD mature NGF; this latter form is biologically active as a multifunctional signaling molecule8,22,23. NGF binds two types of receptors: the low-affinity NGF receptor p75 (LNGFR/p75NTR) and the tropomyosin-related kinase A (TrkA)22,24. TrkA receptor binding produces the homodimerization of the receptor and the autophosphorylation of the tyrosine residue of the cytoplasmic tail. The site of the TrkA phosphorylation is a docking site for the Shc adaptor protein that is in turn phosphorylated beginning several intracellular pathways involved in cell survival22,25. One of these involves the activation of the serine/threonine kinase Akt that develops, by the recruitment on TrkA receptor complex, the growth factor receptor bound protein 2 (Grb2) and of another docking protein, the Grb2-associated Binder1 (GAB1). This structure activates phosphatidylinositol-3 kinase (Pl3K) that, in turn, activates Akt. Inhibiting or blocking the activity of Pl3K or Akt may elicit the death of sympathetic neurons in culture even after NGF administration; instead. when both kinases are constitutively expressed, neuronal cells can survive without NGF 26,27. NGF is involved primarily in the growth, proliferation, and survival of sympathetic and sensory neurons undergoing apoptosis if NGF is missing28-30.
Another pathway of NGF mediated neuronal survival involves the mitogen-activated protein kinase (MAPK). This pathway leads to the activation of the membrane-associated G protein Ras that phosphorylates the serine/threonine kinase Raf. This phosphorylation activates the MAPK cascade regulating transcription25. Both pathways give rise to phosphorylation of the cyclic AMP response element binding protein (CREB), a transcription factor that translocates into the nucleus controlling the expression of anti-apoptotic genes. NGF plays also a delicate role in the fine regulation of learning and memory abilities during development, adult life and aging by influencing synaptic plasticity, tissue growth and attrition in crucial areas of the limbic system4,31-35. The present review amplifies and updates findings for the contribution of NGF in the pathogenesis and therapy of neuropsychiatric disorders, in which cognitive and memory disorders are prevalent36-38 (Figure 1).

Growth factors regulating the pathways involved in normal brain development have a significant role in the pathophysiology of mental disorders including those with a neurodevelopmental origin. Significant changes in growth factors’ levels were observed in patients and in animal models where altered levels of these proteins were found to induce psychiatric behavior34,39-46. During the embryonic and postnatal stages, psychophysical stressors altering the environment can modify the standard brain development opening the way in the adulthood to psychopathologies such as depression, alcohol abuse and drug dependence, schizophrenia, anomalous social behavior47-52, conditions that will require in adulthood, very important and expensive psychosocial behavioral to improve the life and abilities of patients with several mental disorders53-55. Neurotrophins, together with hypothalamic-pituitary-adrenal (HPA) axis, play a pivotal role in controlling brain plasticity and behavior, particularly in crucial periods during ontogenesis, when forming brain is extremely sensitive to external stimulations56. In rat models, stress during pregnancy increases fetal and maternal plasma corticosterone causing hypothalamic-pituitary-adrenal (HPA) axis dysregulation and a prolonged elevation of plasma glucocorticoids in response to stressing events49,50. Neurotransmitter activity and synaptic development are altered by increased activity of corticosterone and corticotrophin-releasing hormone (CRH) in the developing brain eliciting behavioral disturbances in adulthood. Indeed, rats exposed to gestational stress develop depressive-like behaviors and hyper-anxiety combined with the amygdala increase in CRH activity49,50. Quite interestingly, changes in the HPA axis described in prenatally stressed mammals were also described in humans with endogenous major depression57-59. Significantly, it has been proven that ectopic expression of Brain Derived Neurotrophic Factor (BDNF) in vivo increases CRH, whereas reduced expression of BDNF, or its receptor TrkB, decreases CRH expression and normal HPA functions60. Also during early postnatal life, nervous system development is sensitive to stressing events, and this contributes to inter-individual differences in vulnerability to psychopathologies. During the postnatal development of CNS, the neural network undergoes deep rearrangements61,62 and is particularly susceptible to external stimuli. In this period, NGF and BDNF regulates brain plasticity for a better adaptation to the environment8,63. For example, mice grown in a nest with caregiving mother show better social behaviors and skills if compared to mice raised in standard laboratory conditions. These socially enriched mice show higher levels of NGF and BDNF in the hippocampus and hypothalamus64,65. In the mouse, NGF is secreted and produced also by the submaxillary salivary glands66,67. Neurobehavioral studies have demonstrated that aggressive behavior in adult male CD-1 mice induces a remarkable release of NGF from salivary glands into the bloodstream. These findings demonstrated a link between the NGF serum concentration and the achieved status in the fighting were subordination almost double serum levels of NGF compared to dominant mice68-70. Other works have assessed the correlation between increased NGF levels and subordinate behavior6,71. In male mice, NGF chronic administration decreased aggressive behavior70. NGF release was also activated by psychosocial stress that depends on interspecific interactions while physical stressors may produce less evident effects64,65. Intermale aggressive behavior increases the synthesis of NGF in the hypothalamus72 likely because the NGF levels depends on psychological stimuli associated with anxiety, fear, hormones and neurotransmitters release to integrate the neuroendocrine response and the behavior in order to confirm the physiological homeostasis6,8,73.
Numerous human studies have shown that binge or chronic alcohol consumption as well as alcohol drinking during gestation or lactation are a central inducing-cause of brain alterations74 including mental retardation in adults, adolescents and children75-84. As for the alcohol consumption during pregnancy, the plethora of consequences in children induced by alcohol are described as Fetal Alcohol Spectrum Disorders85-88. It has been clearly shown that chronic or binge alcohol consumption as well as alcohol exposure during fetal development may significantly impair neurotrophic factors production in the brain also affecting the expression of their receptors89-96. NGF is probably the most important neurotrophin involved in ethanol-induced toxicity. Many brain studies have disclosed that NGF and its receptors are altered during prenatal/acute/chronic alcohol abuse97-102. In particular, as previously revealed97 alcohol inhibits the expression of endogenous extracellular signal-regulated kinase (ERK) and the phosphatidylinositol-3-kinase (PI3K)103-105. Furthermore, data evidenced several epigenetic roles of NGF and BDNF in regulating the serum levels of interleukin-6 (IL-6), of tumor necrosis factor-α (TNF-α) and the symptomatology of alcohol dependence106-108. In particular, it has been shown an elevation in NGF and IL-6 serum levels following alcohol consumption as well as an association between BDNF, TNF-α serum levels and the history of alcohol abuse, suggesting that changes in the methylation of neurotrophins genes may contribute to the development of alcohol dependence by affecting relevant downstream signalling cascades97,108.

Data from human and animal models suggest a function of neurotrophins also in the vulnerability to stress-related neuropsychosis109,110. Increasing literature evidences demonstrate that in psychopathological conditions the constitutive levels of neurotrophins are disrupted in both brain and plasma. In schizophrenics without neuroleptic therapy, NGF plasma levels are lower if compared to healthy subjects40. Haloperidol administration in human and mice drastically depletes NGF plasma levels111 inducing sedation. By contrast, the atypical antipsychotics olanzapine, clozapine, and risperidone induced higher levels of plasmatic NGF compared to non-medicated first-episode psychotic patients112. The crucial role played by NGF during cholinergic neurons development for regulating learning and memory could explain the vulnerability of the schizophrenic brain and the cognitive alterations observed in this disease; low levels of NGF may trigger consequent neurodevelopmental deficits. In schizophrenics, brain imaging studies evidenced modifications in selected brain areas such as prefrontal, temporal and anterior cingulum involved in affective-cognitive processes 113-116. Furthermore, the post-mortem examination of schizophrenic brains disclosed a reduction of cell proliferation in the entorhinal cortex, prefrontal region and anterior cingulate that could elucidate the onset of the disease40,114. In animal models, behavioral deficits associated with schizophrenic symptoms117 may be caused also by maternal exposure to risk factors such as alcohol drug abuse and obstetric complication118 that inhibit entorhinal and cortical neurogenesis56.
Schizophrenia is a multifactorial mental disorder elicited by social, genetic and developmental factors119,120. Disrupted-in-schizophrenia 1 (DISC1)121,122 which is expressed by neurons of the hippocampus, cerebral cortex, cerebellum and olfactory bulb in the rat brain is known to have a role in this disease123,124. The coded protein binds other proteins including fasciculation and elongation protein zeta-1(Fez1), which is involved in axonal outgrowth. DISC1-Fez1 molecular complex colocalizes in the growth cone of neurite proposing a function in the extension process also confirmed by the fact that these proteins are expressed in early ontogenic stages. In PC12 cells, neurodifferentiation following NGF stimulation was observed a drastic increase in Fez1 evidencing that NGF regulates the neurite outgrowth and extension upregulating DISC1-Fez1 complex 125. When DISC1 translocation prevents the complex being formed, neurite extension cannot occur leading to an immature brain development and supporting the hypothesis that schizophrenia is basically a neurodevelopmental disease125.
Major depression disorder (MDD) is one of most common brain disorders that implicates depression, fatigue, a decrease in concentration, scarce interest in normal daily activities and suicidal intentions126. Several neurotrophins including NGF and BDNF are involved in MDD pathogenesis127-129. MDD patients display reduced serum NGF; the same diminution was observed in hippocampus mRNA and protein expression of NGF, BDNF and their receptors in post-mortem brain examination130,131. A chemical mediator of the NGF decrease is Interferon-gamma (IFN-γ), as was demonstrated in IFN-γ knockout mice models that develop a depressive-like behavior, increased immobility and parallel reduction of NGF levels132,133.
The administration of NGF in rats reduces the expression of the cholinergic gene CHRNA5 and prokineticin receptor1 (PROKR1) mimicking the effects of fluoxetine and amitriptyline therapy. The improvement of the depression-like behavior is achieved by modulating the expression of several genes in the amygdala and hippocampus134.
Alzheimer disease (AD) is the most common type of dementia in the old age. AD is characterized by early alterations of synaptic proteins and synaptic functions with the formation of abnormal tau and amyloid proteins. After the discharge in the intracellular space of these abnormal proteins starts the massive deposition of senile plaques (SP) of the β-amyloid (Aβ) peptide and the aggregations of neurofibrillary tangles (NTF) originating from the hyperphosphorylated tau protein. According to the literature, during the progression of the disease, a serious and progressive memory deficit associated with a massive neuronal loss and a total deterioration of the brain homeostasis were observed 135-137. The basal forebrain cholinergic neurons (BFCN) innervating the hippocampus and the cerebral cortex, brain areas controlling memory and attention are quite susceptible to the AD and the first to be involved138,139.
In the pathophysiological mechanisms of AD, neurotrophic factors play a fundamental and protective role. Neurotrophins control plasticity, differentiation, pruning and survival of the BFCN and the signaling of these peptides is extremely altered in the course of the disorder140. NGF is most studied neurotrophin for its role in AD development140,141.
NGF signaling in BFCN involves three types of receptors: the high-affinity tropomyosin-related kinase A (TrkA), the low-affinity p75NTR neurotrophin receptor (p75NTR) and sortilin. NGF binding to its receptor TrkA activates the pathway signaling of cell survival, while in the presence of minor levels of NGF and/or TrkA the precursor form of NGF (pro-NGF) binds to the low-affinity p75 receptor and/or to sortilin determining an apoptotic signal leading to neurodegeneration142,143.
Indeed, NGF release by cortical and hippocampal neurons is involved in the processing of amyloid precursor protein (APP) to produce the soluble and neuroprotective APP known also to be a strong inhibitor of the enzyme β-secretase 1 (BACE1) that regulates APP amyloidogenic cleavage144. Recent studies in cellular and animal models have demonstrated the protective role of NGF against AD induced neurodegeneration. Moreover, there is strong evidence that the changes in NGF signaling is one of the earliest events in AD beginning145. In a cellular model such as the primary hippocampal neurons, NGF removal generates an Alzheimer’s like molecular condition with the development of Aβ-amyloid plaques and aggregations of neurofibrillary tangles146. Also, an antibody pointed to NGF induces similar phenotypic effects and neuronal deficits in the AD11 mouse model of AD147. The neuroprotective role of NGF observed in vivo and in vitro is exerted by the regulation of APP processing144,148.
NGF stimulation of primary cholinergic septal neurons elicits the binding of TrkA receptor to APP. This binding blocks the APP phosphorylation at the threonine 668 (T668) residue in the cytosolic tail of the protein. T668 phosphorylation is an APP post-translational modification inducing APP cleavage by the enzyme BACE1 that controls the amyloidogenic pathway of maturation144.
During the development of AD, NGF deficit is associated with an increased amyloid generation, initial synaptic alteration as observed in mild cognitive impairments and early AD. The newly generated amyloid inhibits the endocytosis of the NGF/TrkA complex and this negative feedback loop marks the AD beginning135.
In rat models of aging, increased levels of pro-NGF and p75NTR in the hippocampus and prefrontal cortex are associated with a deficit in spatial learning and memory149. An elevation in pro-NGF levels was also discovered in mild cognitive impairment and AD patients and during the examination of postmortem AD brain145. The alteration of the NGF signaling is an early event during the progression of the AD as disclosed by studies on animal and cellular models150. In animal models, as aged rats, the blocking of NGF/TrkA signaling induces a serious deficit in cholinergic function151,152. In animal models of AD, the perturbation of NGF signaling leads to a general loss of central cholinergic activities153. The effect of the imbalance in NGF/TrkA signaling leads to a pathological APP processing146. In transgenic mice lacking APP/TrkA interaction, a severe degeneration of cholinergic neurons and cognitive deficits were described154. These studies support the hypothesis of the neurotrophic model of AD development. Indeed, the reduction of NGF level and the increase in pro-NGF would activate the synaptic failure and the abnormal amyloid and tau deposition creating a neurodegenerative cascade27,155.
New pieces of evidence corroborate the relationship between NGF and APP processing based on a physical interaction between APP and NGF receptors150. The APP iuxta-membrane region containing the β and β-secretase cutting sites and matches the first 16 aa of A peptide is sufficient for the interaction with TrkA and the binding to p75NTR156. APP and TrkA proteins localize in the plasma membrane, endoplasmic reticulum (ER), Golgi and endocytic vesicles where the peptides form homodimers150.
In primary septal neurons, NGF treatment elevates APP/TrkA complexes in ER and Golgi without increasing proteins level probably because NGF disrupts this association through the control of the APP phosphorylation148,150. NGF withdrawal induces a decrease in APP/TrkA complexes and the same pattern is observed with cell death inducers such as A peptide and rapamycin. Furthermore, NGF, supporting APP/TrkA complexes, inhibits the APP/APP homodimers that are more prone to amyloidogenic processing carried out by β- and γ-secretase148,150.
The APP post-translational alterations are crucial for the physiological or amyloidogenic pathways157. The phosphorylation of the threonine residue 668 (T668) is related to amyloid production, synaptic deficits and apoptosis158,159. This phosphorylation inhibits APP/TrkA binding and elevates Aβ production in cholinergic neurons in vivo and in vitro. A recent finding has shown that NGF can reduce APP T668 level in cultured BFCN. It is also possible that the detachment of APP from TrkA is due to changes in the conformation of APP upon its phosphorylation148.
In the physiological anti-amyloidogenic pathway, binding of NGF to TrkA elicits TrkA phosphorylation and TrkA docking of the signaling adaptor SH2 containing sequence C (ShcC). Activated ShcC blocks c-Jun N-terminal kinase (JNK), a ser/thr APP kinase, preventing the APP phosphorylation at threonine residue 668 (T668). Since TrkA can bind only APP molecules not phosphorylated at T668, the NGF decrease of APP p668 levels arouses ATP-TrkA binding, and the TrkA mediated trafficking of APP to the plasma membrane and Golgi apparatus and the preferential cleavage of APP by the neuronal b-secretases ADAM10-17. Contrariwise, the reduced availability of mature NGF and/or the reduced expression levels of TrkA result in pre-apoptotic signals that stimulate JNK, increase APP pT668 and disturb APP-TrkA interaction favoring the β-secretase 1 amyloidogenic pathway 148.
Beneficial role of NGF on cholinergic neurons is carried out downregulating T668 phosphorylation, stimulating APP/TrkA binding and trafficking the complex to subcellular compartments, as Golgi complex, that is depleted of the amyloidogenic enzyme like BACE1. Tau pathology is also implicated in non-Alzheimer disorder pathophysiology (suspected non-Alzheimer disease pathophysiology - SNAP). In AD, many studies have demonstrated a synergism between tangles and plaques, with abnormal tau that enhances Aβ  toxicity and vice-versa160,161.
NGF can control the steady-state levels and the posttranslational maturation of tau that is cleavage, ubiquitination, and phosphorylation162,163. NGF withdrawal brings to tau hyperphosphorylation and to abnormal cleavage of the N terminal fragment of the protein lacking the microtubule-binding domain. The same tau fragment was also observed in animal AD models with impaired NGF signaling162,164.
Autism Spectrum Disorder (ASD) includes deficits in social communication and repetitive behavioral patterns. Genetic perturbations play a critical role in ASD with hundreds of genes associated with it. However, such aberrations do not converge in a common molecular pathway. Genetic investigations and behavioral observations show the overlapping of ASD with other psychiatric diseases, such as bipolar disorder, schizophrenia, and Attention Deficit and Hyperactivity Disorder (ADHD)165,166. Investigating differential alternative splicing (DAS) in the blood of 2-4 years old boys with a diagnosis of ASD, it was disclosed significant DAS changes in several genes of NGF receptors and signaling if compared to controls167. In another study, Lu et al. showed several NGF single-nucleotide polymorphism associated with deficits in nonverbal communication, one of the main autistic trait168.
The role of NGF in parasitic disorders is not yet clearly recognized but some information emerged from investigations on Trypanosoma cruzi and Schistosoma mansoni brain neuroinflammation.
Chagas disease or American trypanosomiasis is a tropical parasitic disorder caused by the protist Trypanosoma cruzi spread to humans and mammals by the insects “kissing bugs” of the subfamily Triatominae169,170. During the early phase of the disease, symptoms are not present or are mild with headache, fever and swollen lymph nodes. Only the 40% of people develop severe symptoms of the disorder after 30-40 years from the infection. Symptoms may include heart failure due to enlargement of heart ventricles, or enlarged esophagus or colon (megaesophagus or megacolon). This disease affects about 6,6 million people mostly in Central America and Mexico171.
Trypanosoma cruzi releases the NGF mimetic neurotrophin called PDNF (parasite-derived neurotrophic factor), a membrane-bound neuraminidase/trans-sialidase that can bind TrkA but not p75NTR5,172. Trypanosoma infection in the CNS is usually asymptomatic and neuronal examination has revealed some sort of neuroprotection and neurons preservation even near foci of inflammatory cells or parasite nest173. Neuroprotection and neuroregeneration were also discovered in animals with chronic or acute infection174-177. Signs of sprouting of sympathetic and parasympathetic nerve fibers were observed in the heart and colon with elevated levels of several neurotransmitters178,179. These findings have shown that Tripanosoma cruzi PDNF is a functional simulator of NGF that can bind TrkA, can produce TrkA autophosphorylation and can trigger Pl3K/Akt and MAPK-Erk1/2 signaling eliciting cell survival and neurite outgrowth. Quite interestingly, the inability of binding p75NTR inhibits the cell-death signaling pathway180,181. From and evolutionary and adaptive point of view, given the critical role of TrkA in neuronal maintenance, the parasitic invader utilizes TrkA to reduce tissue damage, to stimulate protective mechanisms and tissue repair maximizing host-parasite equilibrium in order to prolong parasitism. This mechanism could reveal a general and unexpected model of host-parasite interaction180.
Neuroschistosomiasis refers to the Schistosoma mansoni infection of the central nervous system and depends basically on the presence of parasite eggs in the nervous tissue and on the host immune response. After eggs deposition, the mature embryo secretes and excretes antigenic and immunogenic mediators that start the granulomatous reaction182,183. A large number of eggs and granulomas in CNS areas disrupts adjacent tissues by the inflammatory reaction and the mass effect182-186. In mice infected that manifest granulomas in several CNS areas it was found an increase in NGF levels in the cortex, hypothalamus, and brain stem with paw hyperalgesia187,188. This murine model of chronic infection suggests that the neuropathological and sensory deficits observed in human infection are associated with abnormal NGF levels and/or activity in peripheral and central nervous systems caused by the local growth of granulomas67,189-195.
NGF-based therapy
The neuroprotective action of NGF in animal models of neurodegenerative disease justified the beginning of clinical trials of NGF therapy in humans for several brain diseases including AD, schizophrenia196,197.
Encouraging results were disclosed in the basal forebrain for individuals with implanted connective cells engineered to synthesize and secrete NGF. In these studies, enhanced cell size and new neural fibers were observed. Furthermore, cells showing signs of pathology and protein clumps inside the cell body maintained a healthy size, activated prosurvival signaling and manifested stress resistance198. To potentiate the NGF expression, modified viruses containing the NGF gene were directly injected in the basal forebrain198,199. The protective role of NGF and its progressive decrease in AD is the rationale of the NGF therapy in which the administration of exogenous NGF could counteract the basal forebrain neurodegeneration200. First promising results were obtained in rodents where intracerebral NGF infusion was neuroprotective for cholinergic neuronal cells. Also in AD models like APP/PSI transgenic mouse, the less invasive treatment as ocular or nasal NGF administration decreased beta-amyloid deposition201. In AD patients, NGF phase I gene therapy has shown axonal sprouting without side effects201.
Abnormalities in NGF levels or signaling and the resulting impairments in neuroplasticity and cognitive abilities were also observed in psychiatric disorders such as bipolar disorders, schizophrenia, alcohol use disorders, major depression and autism. In schizophrenic patients treated with atypical antipsychotic drugs, NGF levels increased leading to a reduction of negative symptoms152,202. In bipolar disorders, NGF decreases during the parossistic state but may be rescued by lithium administration by potentiating NGF concentration in the frontal cortex, hippocampus, and amygdala203,204. In children with Rett syndrome, a disorder causing a delay in development and cognitive abilities resembling autism, therapies with NGF-like activity drugs may improve motor and cortical functions by also potentiating social interactions205.
Variations in the serum NGF concentrations have been associated with the pathogenesis and clinical symptoms of several psychiatric disruptions, such as: anxiety disease, mood disorders, schizophrenia, Alzheimer and others. Indeed, fluctuations in the serum levels of NGF and other growth factors are usually connected to the clinical severity and progression of mental illnesses46. Several experimental evidences clearly demonstrate that the serum analysis as biomarkers of neurotrophins, including NGF, could be quite useful to early disclose the onset of several psychiatric disorders46. The working hypothesis was based on the fact that the combined investigation of different neurotrophins could be utilized to establish whether or not such neuropeptides as biomarkers of psychiatric disorders or biomarkers of some cognitive, emotional and social deficits46. Available data in the literature19,206,207 clearly stress the point that neurotrophins and other growth factors are i) involved in the pathophysiology of psychiatric pathologies with neurodevelopmental origin; ii) in animal models selected changes in the serum presence of neurotrophins and other growth factors may elicit psychiatric-like behaviors; iii) people affected by neuropsychiatric disorders may display significant modifications in certain neurotrophins and/or other growth factors; iv) disruptions in the blood levels of neurotrophins and/or other growth factors may be associated with the severity of the brain disease, changes in the behavior, poor social abilities, and cognitive performance decline. In particular, peripheral changes in neurotrophins as NGF and/or BDNF resulted connected with functional impairments in cognitive and emotional processing whereas peripheral modifications in other growth factors as EGF, VEGF and FGF demonstrated subtle roles of these biomarkers in motor processing 46. However, as suggested by different researchers, at the present time do not exist specific and reliable biomarkers for each psychiatric disorder, but a combined screening of biomarkers appears the only alternative to improve the early diagnosis and clinical follow-up of psychiatric individuals46.
Many years of research have recognized the important trophic and homeostatic role of NGF that exerts its modulatory functions on endocrine, nervous, adipose and immune system activities. Future studies, through an extended knowledge of the molecular mechanisms of action of this small and versatile peptide, will help to develop effective brain therapeutic strategies for many clinical sectors including those involving neurodegeneration, neuroinflammation and neuroadipocrinology2,20,23,180,181.

Conflicts of interests: authors do declare no conflicts of interest.

Acknowledgements: authors do thank Sapienza Università di Roma, Italy, and IBCN-CNR, Rome, Italy.
  1. Levi-Montalcini R. The nerve growth factor 35 years later. Science 1987; 237: 1154-62.
  2. Rosso P, De Nicolò S, Carito V, et al. Ocular nerve growth factor administration modulates brain-derived neurotrophic factor signaling in prefrontal cortex of healthy and diabetic rats. CNS Neurosci Ther 2017; 23: 198-208.
  3. Tirassa P, Rosso P, Iannitelli A. Ocular nerve growth factor (NGF) and NGF eye drop application as paradigms to investigate NGF neuroprotective and reparative actions. Methods Mol Biol 2018; 1727: 19-38.
  4. Ciafrè S, Carito V, Ferraguti G, et al. Nerve growth factor in brain diseases. Biomed Rev 2018; 29: 1-16.
  5. Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 2001; 24: 1217-81.
  6. Aloe L, Alleva E, Fiore M. Stress and nerve growth factor: findings in animal models and humans. Pharmacol Biochem Behav 2002; 73: 159-66.
  7. Chaldakov GN, Fiore M, Tonchev AB, Aloe L. Neuroadipology: a novel component of neuroendocrinology. Cell Biol Int 2010; 34: 1051-3.
  8. Fiore M, Chaldakov GN, Aloe L. Nerve growth factor as a signaling molecule for nerve cells and also for the neuroendocrine-immune systems. Rev Neurosci 2009; 20: 133-45.
  9. Chaldakov GN, Fiore M, Stankulov IS, et al. Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease? Prog Brain Res 2004; 146: 279-89.
 10. Chaldakov GN, Fiore M, Ghenev PI, Stankulov IS, Aloe L. Atherosclerotic lesions: possible interactive involvement of intima, adventitia and associated adipose tissue. Int Med J 2000; 7: 43-9.
 11. Tore F, Tonchev A, Fiore M, et al. From adipose tissue protein secretion to adipopharmacology of disease. Immunol Endocr Metab Agents Med Chem 2007; 7: 149-55.
 12. Chaldakov GN, Beltowsky J, Ghenev PI, et al. Adipoparacrinology – vascular periadventitial adipose tissue (tunica adiposa) as an example. Cell Biol Int 2012; 36: 327-30.
 13. Chaldakov GN, Fiore M, Tonchev A, et al. Homo obesus: a metabotrophin-deficient species. Pharmacology and nutrition insight. Curr Pharm Des 2007; 13: 2176-9.
 14. Chaldakov GN, Fiore M, Rancˇic΄ G, et al. Rethinking vascular wall: periadventitial adipose tissue (tunica adiposa). Obesity and Metabolism 2010; 6: 46-9.
 15. Fiore M, Triaca V, Amendola T, Tirassa P, Aloe L. Brain NGF and EGF administration improves passive avoidance response and stimulates brain precursor cells in aged male mice. Physiol Behav 2002; 77: 437-43.
 16. Greco A, Ralli M, De Virgilio A, Inghilleri M, Fusconi M, de Vincentiis M. Letter to the Editor: Autoimmune pathogenic mechanisms in Huntington’s disease. Autoimmun Rev 2018; 17: 942-3.
 17. Skaper SD. Nerve growth factor: a neuroimmune crosstalk mediator for all seasons. Immunology 2017; 151: 1-15.
 18. Aygun N. Biological and genetic features of neuroblastoma and their clinical importance. Curr Pediatr Rev 2018; 14: 73-90.
 19. Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 2013; 138: 155-75.
 20. Iulita MF, Caraci F, Cuello AC. A link between nerve growth factor metabolic deregulation and amyloid-beta-driven inflammation in down syndrome. CNS Neurol Disord Drug Targets 2016; 15: 434-47.
 21. Greco A, Ralli M, Inghilleri M, De Virgilio A, Gallo A, de Vincentiis M. Letter to the Editor: Autoimmune pathogenic mechanisms in Amyotrophic Lateral Sclerosis. Autoimmun Rev 2018; 17: 530-1.
 22. Kaplan DR, Martin-Zanca D, Parada LF. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 1991; 350: 158-60.
 23. Donovan MJ, Miranda RC, Kraemer R, et al. Neurotrophin and neurotrophin receptors in vascular smooth muscle cells. Regulation of expression in response to injury. Am J Pathol 1995; 147: 309-24.
 24. Chao MV. Trophic factors: an evolutionary cul-de-sac or door into higher neuronal function? J Neurosci Res 2000; 59: 353-5.
 25. Sanes DH, Reh TA, Harris WA. Development of the nervous system. Amsterdam: Elsevier, 2005.
 26. Yano H, Chao MV. Neurotrophin receptor structure and interactions. Pharm Acta Helv 2000; 74: 253-60.
 27. Niewiadomska G, Mietelska-Porowska A, Mazurkiewicz M. The cholinergic system, nerve growth factor and the cytoskeleton. Behav Brain Res 2011; 221: 515-26.
 28. Carito V, Venditti A, Bianco A, et al. Effects of olive leaf polyphenols on male mouse brain NGF, BDNF and their receptors TrkA, TrkB and p75. Nat Prod Res 2014; 28: 1970-84.
 29. De Nicoló S, Tarani L, Ceccanti M, et al. Effects of olive polyphenols administration on nerve growth factor and brain-derived neurotrophic factor in the mouse brain. Nutrition 2013; 29: 681-7.
 30. Freeman RS, Burch RL, Crowder RJ, et al. NGF deprivation-induced gene expression: after ten years, where do we stand? Prog Brain Res 2004; 146: 111-26.
 31. Manni L, Aloe L, Fiore M. Changes in cognition induced by social isolation in the mouse are restored by electro-acupuncture. Physiol Behav 2009; 98: 537-42.
 32. Amendola T, Fiore M, Aloe L. Postnatal changes in nerve growth factor and brain derived neurotrophic factor levels in the retina, visual cortex, and geniculate nucleus in rats with retinitis pigmentosa. Neurosci Lett 2003; 345: 37-40.
 33. Fiore M, Angelucci F, Alleva E, Branchi I, Probert L, Aloe L. Learning performances, brain NGF distribution and NPY levels in transgenic mice expressing TNF-alpha. Behav Brain Res 2000; 112: 165-75.
 34. Fiore M, Talamini L, Angelucci F, Koch T, Aloe L, Korf J. Prenatal methylazoxymethanol acetate alters behavior and brain NGF levels in young rats: a possible correlation with the development of schizophrenia-like deficits. Neuropharmacology 1999; 38: 857-69.
 35. Aloe L, Properzi F, Probert L, et al. Learning abilities, NGF and BDNF brain levels in two lines of TNF-α transgenic mice, one characterized by neurological disorders, the other phenotypically normal. Brain Res 1999; 840: 125-37.
 36. Santarelli V, Marucci C, Collazzoni A, et al. Could the severity of symptoms of schizophrenia affect ability of self-appraisal of cognitive deficits in patients with schizophrenia? Lack of insight as a mediator between the two domains. Eur Arch Psychiatry Clin Neurosci 2019; Nov 13 [Epub ahead of print].
 37. Bucci P, Galderisi S, Mucci A, et al. Premorbid academic and social functioning in patients with schizophrenia and its associations with negative symptoms and cognition. Acta Psychiatr Scand 2018; 138: 253-66.
 38. Mazza M, Pollice R, Pacitti F, et al. New evidence in theory of mind deficits in subjects with chronic schizophrenia and first episode: Correlation with symptoms, neurocognition and social function. Riv Psichiatr 2012; 47: 327-36.
 39. Iannitelli A, Quartini A, Tirassa P, Bersani G. Schizophrenia and neurogenesis: a stem cell approach. Neurosci Biobehav Rev 2017; 80: 414-42.
 40. Fiore M, Angelucci F, Aloe L, Iannitelli A, Korf J. Nerve growth factor and brain-derived neurotrophic factor in schizophrenia and depression: findings in humans, and animal models. Curr Neuropharmacol 2005; 1: 109-23.
 41. Fiore M, Korf J, Antonelli A, Talamini L, Aloe L. Long-lasting effects of prenatal MAM treatment on water maze performance in rats: associations with altered brain development and neurotrophin levels. Neurotoxicol Teratol 2002; 24: 179-91.
 42. Fiore M, Aloe L, Westenbroek C, Amendola T, Antonelli A, Korf J. Bromodeoxyuridine and methylazoxymethanol exposure during brain development affects behavior in rats: consideration for a role of nerve growth factor and brain derived neurotrophic factor. Neurosci Lett 2001; 309: 113-6.
 43. Di Fausto V, Fiore M, Aloe L. Exposure in fetus of methylazoxymethanol in the rat alters brain neurotrophins’ levels and brain cells’ proliferation. Neurotoxicol Teratol 2007; 29: 273-81.
 44. Fiore M, Di Fausto V, Iannitelli A, Aloe L. Clozapine or haloperidol in rats prenatally exposed to methylazoxymethanol, a compound inducing entorhinal-hippocampal deficits, alter brain and blood neurotrophins’ concentrations. Ann Ist Super Sanita 2008; 44: 167-77.
 45. Fiore M, Korf J, Angelucci F, Talamini L, Aloe L. Prenatal exposure to methylazoxymethanol acetate in the rat alters neurotrophin levels and behavior: considerations for neurodevelopmental diseases. Physiol Behav 2000; 71: 57-67.
 46. Galvez-Contreras AY, Campos-Ordonez T, Lopez-Virgen V, Gomez-Plascencia J, Ramos-Zuniga R, Gonzalez-Perez O. Growth factors as clinical biomarkers of prognosis and diagnosis in psychiatric disorders. Cytokine Growth Factor Rev 2016; 32: 85-96.
 47. Quartini A, Pacitti F, Bersani G, Iannitelli A. From adolescent neurogenesis to schizophrenia: Opportunities, challenges and promising interventions. Biomed Rev 2017; 28: 66-73.
 48. Dell’Omo G, Fiore M, Alleva E. Strain differences in mouse response to odours of predators. Behav Processes 1994; 32: 105-15.
 49. Weinstock M. Prenatal stressors in rodents: effects on behavior. Neurobiol Stress 2017; 6: 3-13.
 50. Weinstock M. Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog Neurobiol 2001; 65: 427-51.
 51. Maccari S, Darnaudery M, Morley-Fletcher S, Zuena AR, Cinque C, Van Reeth O. Prenatal stress and long-term consequences: implications of glucocorticoid hormones. Neurosci Biobehav Rev 2003; 27: 119-27.
 52. Pike IL. Maternal stress and fetal responses: evolutionary perspectives on preterm delivery. Am J Hum Biol 2005; 17: 55-65.
 53. Sampogna G, Fiorillo A, Luciano M, et al. A randomized controlled trial on the efficacy of a psychosocial behavioral intervention to improve the lifestyle of patients with severe mental disorders: study protocol. Front Psychiatry 2018; 9: 235.
 54. Bersani G, Iannitelli A. [Legalization of cannabis: between political irresponsibility and loss of responsibility of psychiatrists]. Riv Psichiatr 2015; 50: 195-8.
 55. Mazza M, Lucci G, Pacitti F, et al. Could schizophrenic subjects improve their social cognition abilities only with observation and imitation of social situations? Neuropsychol Rehabil 2010; 20: 675-703.
 56. Alleva E, Francia N. Psychiatric vulnerability: suggestions from animal models and role of neurotrophins. Neurosci Biobehav Rev 2009; 33: 525-36.
 57. Oyola MG, Handa RJ. Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity. Stress 2017; 20: 476-94.
 58. Gaffey AE, Bergeman CS, Clark LA, Wirth MM. Aging and the HPA axis: stress and resilience in older adults. Neurosci Biobehav Rev 2016; 68: 928-45.
 59. Juruena MF. Early-life stress and HPA axis trigger recurrent adulthood depression. Epilepsy Behav 2014; 38: 148-59.
 60. Jeanneteau FD, Lambert WM, Ismaili N, et al. BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus. Proc Natl Acad Sci U S A 2012; 109: 1305-10.
 61. Guest MA, Its AR, Lin CS. Isomonodromy aspects of the tt* equations of Cecotti and Vafa I. Stokes data. Int Math Res Not 2015; 2015: 11745-84.
 62. Hua JY, Smith SJ. Neural activity and the dynamics of central nervous system development. Nat Neurosci 2004; 7: 327-32.
 63. Angelucci F, Piermaria J, Gelfo F, et al. The effects of motor rehabilitation training on clinical symptoms and serum BDNF levels in Parkinson’s disease subjects. Can J Physiol Pharmacol 2016; 94: 455-61.
 64. Branchi I, D’Andrea I, Sietzema J, et al. Early social enrichment augments adult hippocampal BDNF levels and survival of BRDU-positive cells while increasing anxiety- and “depression”-like behavior. J Neurosci Res 2006; 83: 965-73.
 65. Branchi I, D’Andrea I, Fiore M, Di Fausto V, Aloe L, Alleva E. Early social enrichment shapes social behavior and nerve growth factor and brain-derived neurotrophic factor levels in the adult mouse brain. Biol Psychiatry 2006; 60: 690-6.
 66. Aloe L, Fiore M. Submandibular glands, nerve growth factor and neuroinflammatory responses in rodents. Biomed Rev 1998; 9: 93-9.
 67. Fiore M, Moroni R, Aloe L. Removal of the submaxillary salivary glands and infection with the trematode Schistosoma mansoni alters exploratory behavior and pain thresholds in female mice. Physiol Behav 1997; 62: 399-406.
 68. Fiore M, Amendola T, Triaca V, Alleva E, Aloe L. Fighting in the aged male mouse increases the expression of TrkA and TrkB in the subventricular zone and in the hippocampus. Behav Brain Res 2005; 157: 351-62.
 69. Maestripieri D, De Simone R, Aloe L, Alleva E. Social status and nerve growth factor serum levels after agonistic encounters in mice. Physiol Behav 1990; 47: 161-4.
 70. Bigi S, Maestripieri D, Aloe L, Alleva E. NGF decreases isolation-induced aggressive behavior, while increasing adrenal volume, in adult male mice. Physiol Behav 1992; 51: 337-43.
 71. Fiore M, Amendola T, Triaca V, Tirassa P, Alleva E, Aloe L. Agonistic encounters in aged male mouse potentiate the expression of endogenous brain NGF and BDNF: possible implication for brain progenitor cells’ activation. Eur J Neurosci 2003; 17: 1455-64.
 72. Spillantini MG, Aloe L, Alleva E, Desimone R, Goedert M, Levi-Montalcini R. Nerve growth-factor messenger-Rna and protein increase in hypothalamus in a mouse model of aggression. Proc Natl Acad Sci U S A 1989; 86: 8555-9.
 73. Yanev, Stanislav, Aloe L, Fiore M, Chaldakov GN. Neurotrophic and metabotrophic potential of nerve growth factor and brain-derived neurotrophic factor: linking cardiometabolic and neuropsychiatric diseases. World J Pharmacol 2013; 2: 92.
 74. Ceccanti M, Inghilleri M, Attilia ML, et al. Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation. A pilot study. Can J Physiol Pharmacol 2015; 93: 283-90.
 75. Coriale G, Battagliese G, Pisciotta F, et al. Behavioral responses in people affected by alcohol use disorder and psychiatric comorbidity: correlations with addiction severity. Ann Ist Super Sanita 2019; 55: 131-42.
 76. Coriale G, Fiorentino D, Lauro F Di, et al. Fetal Alcohol Spectrum Disorder (FASD): neurobehavioral profile, indications for diagnosis and treatment. Riv Psichiatr 2013; 48: 359-69.
 77. Ciafrè S, Carito V, Tirassa P, et al. Ethanol consumption and innate neuroimmunity. Biomed Rev 2017; 28: 49-61.
 78. Ciafrè S, Carito V, Ferraguti G, et al. How alcohol drinking affects our genes: an epigenetic point of view. Biochem Cell Biol 2019; 7: 345-56.
 79. Ledda R, Battagliese G, Attilia F, et al. Drop-out, relapse and abstinence in a cohort of alcoholic people under detoxification. Physiol Behav 2019; 198: 67-75.
 80. Ciafrè S, Fiore M, Ceccanti M, Messina MP, Tirassa P, Carito V. Role of neuropeptide tyrosine (NPY) in ethanol addiction. Biomed Rev 2016; 27: 27-39.
 81. Ceccanti M, Iannitelli A, Fiore M. Italian Guidelines for the treatment of alcohol dependence. Riv Psichiatr 2018; 53: 105-6.
 82. Ceccanti M, Coriale G, Hamilton DA, et al. Virtual Morris task responses in individuals in an abstinence phase from alcohol. Can J Physiol Pharmacol 2018; 96: 128-36.
 83. Ceccanti M, Hamilton D, Coriale G, et al. Spatial learning in men undergoing alcohol detoxification. Physiol Behav 2015; 149: 324-30.
 84. Fein G, Torres J, Price LJ, Di Sclafani V. Cognitive performance in long-term abstinent alcoholic individuals. Alcohol Clin Exp Res 2006; 30: 1538-44.
 85. Ferraguti G, Ciolli P, Carito V, et al. Ethylglucuronide in the urine as a marker of alcohol consumption during pregnancy: comparison with four alcohol screening questionnaires. Toxicol Lett 2017; 275: 49-56.
 86. Sakata-Haga H, Fukui Y. [Effects of ethanol on the development of circadian time keeping system]. Nihon Arukoru Yakubutsu Igakkai Zasshi 2007; 42: 67-75.
 87. del Campo M, Jones KL. A review of the physical features of the fetal alcohol spectrum disorders. Eur J Med Genet 2017; 60: 55-64.
 88. Kodituwakku P, Coriale G, Fiorentino D, et al. Neurobehavioral characteristics of children with fetal alcohol spectrum disorders in communities from Italy: preliminary results. Alcohol Clin Exp Res 2006; 30: 1551-61.
 89. Aloe L, Tuveri MA, Guerra G, et al. Changes in human plasma nerve growth factor level after chronic alcohol consumption and withdrawal. Alcohol Exp Res 1996; 20: 462-5.
 90. Carito V, Ceccanti M, Cestari V, et al. Olive polyphenol effects in a mouse model of chronic ethanol addiction. Nutrition 2017; 33: 65-69.
 91. Carito V, Ceccanti M, Tarani L, Ferraguti G, Chaldakov GN, Fiore M. Neurotrophins’ modulation by olive polyphenols. Curr Med Chem 2016; 23: 3189-97.
 92. De Nicolò S, Carito V, Fiore M, Laviola G. Aberrant behavioral and neurobiologic profiles in rodents exposed to ethanol or red wine early in development. Curr Dev Disord Reports 2014; 1: 173-80.
 93. Fiore M, Mancinelli R, Aloe L, et al. Hepatocyte growth factor, vascular endothelial growth factor, glial cell-derived neurotrophic factor and nerve growth factor are differentially affected by early chronic ethanol or red wine intake. Toxicol Lett 2009; 188: 208-13.
 94. Ceccanti M, Mancinelli R, Tirassa P, et al. Early exposure to ethanol or red wine and long-lasting effects in aged mice. A study on nerve growth factor, brain-derived neurotrophic factor, hepatocyte growth factor, and vascular endothelial growth factor. Neurobiol Aging 2012; 33: 359-67.
 95. Fiore M, Laviola G, Aloe L, di Fausto V, Mancinelli R, Ceccanti M. Early exposure to ethanol but not red wine at the same alcohol concentration induces behavioral and brain neurotrophin alterations in young and adult mice. Neurotoxicology 2009; 30: 59-71.
 96. Ceccanti M, De Nicolò S, Mancinelli R, et al. NGF and BDNF long-term variations in the thyroid, testis and adrenal glands of a mouse model of fetal alcohol spectrum disorders. Ann Ist Super Sanita 2013; 49: 383-90.
 97. Carito V, Ceccanti M, Ferraguti G, Coccurello R, Ciafrè S, Tirassa P, Fiore M. NGF and BDNF alterations by prenatal alcohol exposure. Curr Neuropharmacol 2019; 17: 308-17.
 98. De Simone R, Aloe L. Influence of ethanol consumption on brain nerve growth factor and its target cells in developing and adult rodents. Ann Ist Super Sanita 1993; 29: 179-83.
 99. Angelucci F, Fiore M, Cozzari C, Aloe L. Prenatal ethanol effects on NGF level, NPY and ChAT immunoreactivity in mouse entorhinal cortex: a preliminary study. Neurotoxicol Teratol 1999; 21: 415-25.
100. Aloe L, Tirassa P. The effect of long-term alcohol intake on brain NGF-target cells of aged rats. Alcohol 1992; 9: 299-304.
101. Lhullier AC, Moreira FP, da Silva RA, et al. Increased serum neurotrophin levels related to alcohol use disorder in a young population sample. Alcohol Clin Exp Res 2015; 39: 30-5.
102. Ceccanti M, Coccurello R, Carito V, et al. Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring. Addict Biol 2016; 21: 776-87.
103. Miller MW, Mooney SM. Chronic exposure to ethanol alters neurotrophin content in the basal forebrain-cortex system in the mature rat: effects on autocrine-paracrine mechanisms. J Neurobiol 2004; 60: 490-8.
104. Mooney SM, Miller MW. Nerve growth factor neuroprotection of ethanol-induced neuronal death in rat cerebral cortex is age dependent. Neuroscience 2007; 149: 372-81.
105. Li Z, Ding M, Thiele CJ, Luo J. Ethanol inhibits brain-derived neurotrophic factor-mediated intracellular signaling and activator protein-1 activation in cerebellar granule neurons. Neuroscience 2004; 126: 149-62.
106. Carito V, Ciafrè S, Tarani L, et al. TNF-α and IL-10 modulation induced by polyphenols extracted by olive pomace in a mouse model of paw inflammation. Ann Ist Super Sanita 2015; 51: 382-6.
107. Aloe L, Fiore M. TNF-alpha expressed in the brain of transgenic mice lowers central tyroxine hydroxylase immunoreactivity and alters grooming behavior. Neurosci Lett 1997; 238: 65-8.
108. Heberlein A, Schuster R, Kleimann A, et al. Joint effects of the epigenetic alteration of neurotrophins and cytokine signaling: a possible exploratory model of affective symptoms in alcohol-dependent patients? Alcohol Alcohol 2017; 52: 277-81.
109. Bersani G, Iannitelli A, Fiore M, Angelucci F, Aloe L. Data and hypotheses on the role of nerve growth factor and other neurotrophins in psychiatric disorders. Med Hypotheses 2000; 55: 199-207.
110. Stampachiacchiere B, Marinova T, Velikova K, et al. Altered levels of nerve growth factor in the thymus of subjects with myasthenia gravis. J Neuroimmunol 2004; 146: 199-202.
111. Aloe L, Iannitelli A, Bersani G, et al. Haloperidol administration in humans lowers plasma nerve growth factor level: evidence that sedation induces opposite effects to arousal. Neuropsychobiology 1997; 36: 65-8.
112. Parikh V, Khan MM, Terry A, Mahadik SP. Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats. J Psychiatr Res 2004; 38: 521-9.
113. Parnanzone S, Serrone D, Rossetti MC, et al. Alterations of cerebral white matter structure in psychosis and their clinical correlations: a systematic review of Diffusion Tensor Imaging studies. Riv Psichiatr 2017; 52: 49-66.
114. Raedler TJ, Knable MB, Weinberger DR. Schizophrenia as a developmental disorder of the cerebral cortex. Curr Opin Neurobiol 1998; 8: 157-61.
115. Bersani G, Quartini A, Iannitelli A, et al. Corpus callosum abnormalities and potential age effect in men with schizophrenia: an MRI comparative study. Psychiatry Res 2010;183: 119-25.
116. Bersani G, Quartini A, Paolemili M, et al. Neurological soft signs and corpus callosum morphology in schizophrenia. Neurosci Lett 2011; 499: 170-4.
117. Fiore M, Dell’Omo G, Alleva E, Lipp HP. A comparison of behavioural effects of prenatally administered oxazepam in mice exposed to open-fields in the laboratory and the real world. Psychopharmacol 1995; 122: 72-7.
118. Bersani G, Quartini A, Manuali G, et al. Influence of obstetric complication severity on brain morphology in schizophrenia: an MR study. Neuroradiology 2009; 51: 363-71.
119. Rocca P, Galderisi S, Rossi A, et al. Disorganization and real-world functioning in schizophrenia: Results from the multicenter study of the Italian Network for Research on Psychoses. Schizophr Res 2018; 201: 105-12.
120. Galderisi S, Rucci P, Kirkpatrick B, et al. Interplay among psychopathologic variables, personal resources, context-related factors, and real-life functioning in individuals with schizophrenia a network analysis. JAMA Psychiatry 2018; 75: 396-404.
121. Millar JK, James K, Brandon NJ, Thomson PA. DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness. Ann Med 2004; 36: 367-78.
122. Mackie S, Millar JK, Porteous DJ. Role of DISC1 in neural development and schizophrenia. Curr Opin Neurobiol 2007; 17: 95-102.
123. Tomoda T, Hikida T, Sakurai T. Role of DISC1 in neuronal trafficking and its implication in neuropsychiatric manifestation and neurotherapeutics. Neurotherapeutics 2017; 14: 623-9.
124. Dahoun T, Trossbach SV, Brandon NJ, Korth C, Howes OD. The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review. Transl Psychiatry 2017; 7: e1015.
125. Matsuzaki S, Tohyama M. Molecular mechanism of schizophrenia with reference to disrupted-in-schizophrenia 1 (DISC1). Neurochem Int 2007; 51: 165-72.
126. Iwabuchi SJ, Peng D, Fang Y, et al. Alterations in effective connectivity anchored on the insula in major depressive disorder. Eur Neuropsychopharmacol 2014; 24: 1784-92.
127. Tanti A, Belzung C. Neurogenesis along the septo-temporal axis of the hippocampus: are depression and the action of antidepressants region-specific? Neuroscience 2013; 252: 234-52.
128. Lang UE, Borgwardt S. Molecular mechanisms of depression: perspectives on new treatment strategies. Cell Physiol Biochem 2013; 31: 761-77.
129. Tirassa P, Iannitelli A, Sornelli F, et al. Daily serum and salivary BDNF levels correlate with morning-evening personality type in women and are affected by light therapy. Riv Psichiatr 2012; 47: 527-34.
130. Wiener CD, de Mello Ferreira S, Pedrotti Moreira F, et al. Serum levels of nerve growth factor (NGF) in patients with major depression disorder and suicide risk. J Affect Disord 2015; 184: 245-8.
131. Banerjee R, Ghosh AK, Ghosh B, Bhattacharyya S, Mondal AC. Decreased mRNA and protein expression of BDNF, NGF, and their receptors in the hippocampus from suicide: an analysis in human postmortem brain. Clin Med Insights Pathol 2013; 6: 1-11.
132. Mandolesi G, Bullitta S, Fresegna D, et al. Interferon-gamma causes mood abnormalities by altering cannabinoid CB1 receptor function in the mouse striatum. Neurobiol Dis 2017; 108: 45-53.
133. Campos AC, Vaz GN, Saito VM, Teixeira AL. Further evidence for the role of interferon-gamma on anxiety- and depressive-like behaviors: involvement of hippocampal neurogenesis and NGF production. Neurosci Lett 2014; 578: 100-5.
134. McGeary JE, Gurel V, Knopik VS, Spaulding J, McMichael J. Effects of nerve growth factor (NGF), fluoxetine, and amitriptyline on gene expression profiles in rat brain. Neuropeptides 2011; 45: 317-22.
135. Xu C-J, Wang J-L, Jin W-L. The emerging therapeutic role of NGF in Alzheimer’s disease. Neurochem Res 2016; 41: 1211-8.
136. Angelucci F, Gelfo F, Fiore M, et al. The effect of neuropeptide Y on cell survival and neurotrophin expression in in-vitro models of Alzheimer’s disease. Can J Physiol Pharmacol 2014; 92: 621-30.
137. Scott SA, Mufson EJ, Weingartner JA, Skau KA, Crutcher KA. Nerve growth factor in Alzheimer’s disease: increased levels throughout the brain coupled with declines in nucleus basalis. J Neurosci 1995; 15: 6213-21.
138. Arendt T. Impairment in memory function and neurodegenerative changes in the cholinergic basal forebrain system induced by chronic intake of ethanol. Cell Anim Model Aging Dement Res 1994; 44: 173-87.
139. Arendt T, Bruckner MK, Bigl V, Marcova L. Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer’s disease. III. The basal forebrain compared with other subcortical areas. J Comp Neurol 1995; 351: 223-46.
140. Skaper SD. Neurotrophic factors: an overview. Methods Mol Biol 2018; 1727: 1-17.
141. Budni J, Bellettini-Santos T, Mina F, Garcez ML, Zugno AI. The involvement of BDNF, NGF and GDNF in aging and Alzheimer’s disease. Aging Dis 2015; 6: 331-41.
142. Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 2003; 72: 609-42.
143. Guerios SD, Wang Z-Y, Boldon K, Bushman W, Bjorling DE. Blockade of NGF and trk receptors inhibits increased peripheral mechanical sensitivity accompanying cystitis in rats. AJP Regul Integr Comp Physiol 2008; 295: R111-22.
144. Triaca V. Homage to Rita Levi-Montalcini. Molecular mechanisms of Alzheimer’s disease: NGF modulation of APP processing. Adipobiology 2013; 5: 7-18.
145. Mufson EJ, He B, Nadeem M, et al. Hippocampal proNGF signaling pathways and beta-amyloid levels in mild cognitive impairment and Alzheimer disease. J Neuropathol Exp Neurol 2012; 71: 1018-29.
146. Calissano P, Matrone C, Amadoro G. Nerve growth factor as a paradigm of neurotrophins related to Alzheimer’s disease. Dev Neurobiol 2010; 70: 372-83.
147. Ruberti F, Capsoni S, Comparini A, et al. Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen, and skeletal muscle dystrophy. J Neurosci 2000; 20: 2589-601.
148. Triaca V, Sposato V, Bolasco G, et al. NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer’s disease. Aging Cell 2016; 15: 661-72.
149. Terry AVJ, Kutiyanawalla A, Pillai A. Age-dependent alterations in nerve growth factor (NGF)-related proteins, sortilin, and learning and memory in rats. Physiol Behav 2011; 102: 149-57.
150. Canu N, Amadoro G, Triaca V, et al. The intersection of NGF/TrkA signaling and amyloid precursor protein processing in Alzheimer’s disease neuropathology. Int J Mol Sci 2017; 18: pii: E1319.
151. Yegla B, Parikh V. Effects of sustained pro NGF blockade on attentional capacities in aged rats with compromised cholinergic system. Neuroscience 2014; 261: 118-32.
152. Parikh V, Howe WM, Welchko RM, et al. Diminished trkA receptor signaling reveals cholinergic-attentional vulnerability of aging. Eur J Neurosci 2013; 37: 278-93.
153. Counts SE, Mufson EJ. The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease. J Neuropathol Exp Neurol 2005; 64: 263-72.
154. Matrone C, Di Luzio A, Meli G, et al. Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 cells. J Alzheimers Dis 2008; 13: 81-96.
155. Latina V, Caioli S, Zona C, Ciotti MT, Amadoro G, Calissano P. Impaired NGF/TrkA signaling causes early AD-Linked presynaptic dysfunction in cholinergic primary neurons. Front Cell Neurosci 2017; 11: 68.
156. O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 2011; 34: 185-204.
157. Tamayev R, Zhou D, D’Adamio L. The interactome of the amyloid beta precursor protein family members is shaped by phosphorylation of their intracellular domains. Mol Neurodegener 2009; 4: 28.
158. Lee M-S, Kao S-C, Lemere CA, et al. APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol 2003; 163: 83-95.
159. Chang K-A, Kim H-S, Ha T-Y, et al. Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration. Mol Cell Biol 2006; 26: 4327-38.
160. Bloom GS. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 2014; 71: 505-8.
161. Ribe EM, Perez M, Puig B, et al. Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis 2005; 20: 814-22.
162. Amadoro G, Corsetti V, Ciotti MT, et al. Endogenous Abeta causes cell death via early tau hyperphosphorylation. Neurobiol Aging 2011; 32: 969-90.
163. Carter C. Alzheimer’s disease: APP, Gamma Secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1, and MS4A2, and their relationships with Herpes Simplex, C. Pneumoniae, other suspect pathogens, and the immune system. Int J Alzheimers Dis 2011; 2011: 501862.
164. Corsetti V, Amadoro G, Gentile A, et al. Identification of a caspase-derived N-terminal tau fragment in cellular and animal Alzheimer’s disease models. Mol Cell Neurosci 2008; 38: 381-92.
165. Taurines R, Schwenck C, Westerwald E, Sachse M, Siniatchkin M, Freitag C. ADHD and autism: differential diagnosis or overlapping traits? A selective review. Atten Defic Hyperact Disord 2012; 4: 115-39.
166. Khanzada NS, Butler MG, Manzardo AM. GeneAnalytics pathway analysis and genetic overlap among autism spectrum disorder, bipolar disorder and schizophrenia. Int J Mol Sci 2017; 18. pii: E527.
167. Stamova BS, Tian Y, Nordahl CW, et al. Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders. Mol Autism 2013; 4: 30.
168. Lu AT-H, Yoon J, Geschwind DH, Cantor RM. QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders. Mol Psychiatry 2013; 18: 226-35.
169. Rassi AJ, Rassi A, Marcondes de Rezende J. American trypanosomiasis (Chagas disease). Infect Dis Clin North Am 2012; 26: 275-91.
170. Rassi AJ, Rassi A, Marin-Neto JA. Chagas disease. Lancet 2010; 375: 1388-402.
171. Maudlin I, Holmes PH, Miles MA (eds). The trypanosomiases. Wallingford, UK: CABI Publishing, 2004.
172. Chuenkova MV, Pereira MA. The T. cruzi trans-sialidase induces PC12 cell differentiation via MAPK/ERK pathway. Neuroreport 2001; 12: 3715-8.
173. Hoff R, Teixeira RS, Carvalho JS, Mott KE. Trypanosoma cruzi in the cerebrospinal fluid during the acute stage of Chagas’ disease. N Engl J Med 1978; 298: 604-6.
174. De Souza MM, Andrade SG, Barbosa AA, Santos RTM, Alves VAF, Andrade ZA. Trypanosoma cruzi strains and autonomic nervous system pathology in experimental Chagas disease. Mem Inst Oswaldo Cruz 1996; 91: 217-24.
175. Tafuri WL. Pathogenesis of lesions of the autonomic nervous system of the mouse in experimental acute Chagas’ disease. Light and electron microscope studies. Am J Trop Med Hyg 1970; 19: 405-17.
176. Molina HA, Cardoni RL, Rimoldi MT. The neuromuscular pathology of experimental Chagas’ disease. J Neurol Sci 1987; 81: 287-300.
177. Said G, Joskowicz M, Barreira AA, Eisen H. Neuropathy associated with experimental Chagas’ disease. Ann Neurol 1985: 18: 676-83.
178. Bocchi EA, Bestetti RB, Scanavacca MI, Cunha Neto E, Issa VS. Chronic Chagas heart disease management: from etiology to cardiomyopathy treatment. J Am Coll Cardiol 2017; 70: 1510-24.
179. Malik LH, Singh GD, Amsterdam EA. Chagas heart disease: an update. Am J Med 2015; 128: 1251.e7-9.
180. Chuenkova MV, Pereiraperrin M. Neurodegeneration and neuroregeneration in Chagas disease. Adv Parasitol 2011; 76: 195-233.
181. Chuenkova MV, Pereira Perrin M. Chagas’ disease parasite promotes neuron survival and differentiation through TrkA nerve growth factor receptor. J Neurochem 2004; 91: 385-94.
182. Palin MS, Mathew R, Towns G. Spinal neuroschistosomiasis. Br J Neurosurg 2015; 29: 582-4.
183. Carod-Artal FJ. Neuroschistosomiasis. Expert Rev Anti Infect Ther 2010; 8: 1307-18.
184. Ferrari TCA, Gazzinelli G, Correa-Oliveira R. Immune response and pathogenesis of neuroschistosomiasis mansoni. Acta Trop 2008; 108: 83-8.
185. Nascimento-Carvalho CM, Moreno-Carvalho OA. Neuroschistosomiasis due to Schistosoma mansoni: a review of pathogenesis, clinical syndromes and diagnostic approaches. Rev Inst Med Trop Sao Paulo 2005; 47: 179-84.
186. Pittella JEH. Neuroschistosomiasis. Brain Pathol 1997; 7: 649-62.
187. Varilek GW, Weinstock JV, Pantazis NJ. Isolated hepatic granulomas from mice infected with Schistosoma mansoni contain nerve growth factor. Infect Immun 1991; 59: 4443-9.
188. Aloe L, Moroni R, Mollinari C, Tirassa P. Schistosoma mansoni infection enhances the levels of NGF in the liver and hypothalamus of mice. Neuroreport 1994; 5: 1030-2.
189. Aloe L, Moroni R, Fiore M, Angelucci F. Chronic parasite infection in mice induces brain granulomas and differentially alters brain nerve growth factor levels and thermal responses in paws. Acta Neuropathol 1996; 92: 300-5.
190. Aloe L, Moroni R, Angelucci F, Fiore M. Role of TNF-α but not NGF in murine hyperalgesia induced by parasitic infection. Psychopharmacology 1997; 134: 287-92.
191. Fiore M, Carere C, Moroni R, Aloe L. Passive avoidance response in mice infected with Schistosoma mansoni. Physiol Behav 2002; 75: 449-54.
192. Fiore M, Aloe L. Neuroinflammatory implication of schistosoma mansoni infection in the mouse. Arch Physiol Biochem 2001; 109: 361-4.
193. Fiore M, Moroni R, Alleva E, Aloe L. Schistosoma mansoni: influence of infection on mouse behavior. Exp Parasitol 1996; 83: 46-54.
194. Aloe L, Fiore M. Neuroinflammatory implications of Schistosoma mansoni infection: new information from the mouse model. Parasitol Today 1998; 14: 314-8.
195. Fiore M, Alleva E, Moroni R, Aloe L. Infection with Schistosoma mansoni in mice induces changes in nociception and exploratory behavior. Physiol Behav 1998; 65: 347-53.
196. Tuszynski MH, Blesch A. Nerve growth factor: from animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer’s disease. Prog Brain Res 2004; 146: 441-9.
197. Tuszynski MH, Thal L, Pay M, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 2005; 11: 551-5.
198. Malkki H. Alzheimer disease: NGF gene therapy activates neurons in the AD patient brain. Nat Rev Neurol 2015; 11: 548.
199. Karami A, Eyjolfsdottir H, Vijayaraghavan S, et al. Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer’s disease. Alzheimers Dement 2015; 11: 1316-28.
200. Bersani G, Quartini A, Zullo D, Iannitelli A. Potential neuroprotective effect of lithium in bipolar patients evaluated by neuropsychological assessment: preliminary results. Hum Psychopharmacol 2016; 31: 19-28.
201. Tuszynski MH, Yang JH, Barba D, et al. Nerve growth factor gene therapy activation of neuronal responses in Alzheimer disease. JAMA Neurol 2015; 72: 1139-47.
202. Parikh V, Evans DR, Khan MM, Mahadik SP. Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome. Schizophr Res 2003; 60: 117-23.
203. Machado-Vieira R, Manji HK, Zarate CAJ. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord 2009; 11 Suppl 2: 92-109.
204. Quartini A, Iannitelli A, Bersani G. Lithium: from mood stabilizer to putative cognitive enhancer. Neural Regen Res 2016; 11: 1234-5.
205. Gorbachevskaya N, Bashina V, Gratchev V, Iznak A. Cerebrolysin therapy in Rett syndrome: clinical and EEG mapping study. Brain Dev 2001; 23: S90-3.
206. Du Y, Wu H-T, Qin X-Y, et al. Postmortem brain, cerebrospinal fluid, and blood neurotrophic factor levels in Alzheimer’s disease: a systematic review and meta-analysis. J Mol Neurosci 2018; 65: 289-300.
207. Mohammadi A, Rashidi E, Amooeian VG. Brain, blood, cerebrospinal fluid, and serum biomarkers in schizophrenia. Psychiatry Res 2018; 265: 25-38.