Trackins (Trk-Targeting Drugs): A Novel Therapy for Different Diseases.

Many routes may lead to the transition from a healthy to a diseased phenotype. However, there are not so many routes to travel in the opposite direction; that is, therapy for different diseases. The following pressing question thus remains: what are the pathogenic routes and how can be they counteracted for therapeutic purposes? Human cells contain >500 protein kinases and nearly 200 protein phosphatases, acting on thousands of proteins, including cell growth factors. We herein discuss neurotrophins with pathogenic or metabotrophic abilities, particularly brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), pro-NGF, neurotrophin-3 (NT-3), and their receptor Trk (tyrosine receptor kinase; pronounced "track"). Indeed, we introduced the word trackins, standing for Trk-targeting drugs, that play an agonistic or antagonistic role in the function of TrkBBDNF, TrkCNT-3, TrkANGF, and TrkApro-NGF receptors. Based on our own published results, supported by those of other authors, we aim to update and enlarge our trackins concept, focusing on (1) agonistic trackins as possible drugs for (1a) neurotrophin-deficiency cardiometabolic disorders (hypertension, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, obesity, diabetic erectile dysfunction and atrial fibrillation) and (1b) neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and multiple sclerosis), and (2) antagonistic trackins, particularly TrkANGF inhibitors for prostate and breast cancer, pain, and arrhythmogenic right-ventricular dysplasia. Altogether, the druggability of TrkANGF, TrkApro-NGF, TrkBBDNF, and TrkCNT-3 receptors via trackins requires a further translational pursuit. This could provide rewards for our patients.

Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant.

BACKGROUND: Obesity is a major health burden. Preadipocytes proliferate and differentiate in mature adipocytes in the adipogenic process, which could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, blocks adipogenesis. Mutants of SIRT6 (N308K/A313S) were recently linked to the in the long lifespan Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level. METHODS: We analyzed the role of SIRT6 wild-type (WT) or SIRT6 centenarian-associated mutant (N308K/A313S) overexpression in adipogenesis, by creating stably transduced preadipocyte cell lines using lentivirus on the 3T3-L1 model. Histone post-translational modifications (PTM: acetylation, methylation) and transcriptomic changes were analyzed by mass spectrometry (LC-MS/MS) and RNA-Seq, respectively, in 3T3-L1 adipocytes. In addition, the adipogenic process and related signaling pathways were investigated by bioinformatics and biochemical approaches. RESULTS: Overexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner. CONCLUSIONS: SIRT6 N308K/A313S overexpression in mature adipocytes ameliorated glucose sensitivity and impacted sympathetic innervation signaling. These findings highlight the importance of targeting SIRT6 enzymatic activities to regulate the co-morbidities associated with obesity.

Deficiency of histone variant macroH2A1.1 is associated with sexually dimorphic obesity in mice.

Obesity has a major socio-economic health impact. There are profound sex differences in adipose tissue deposition and obesity-related conditions. The underlying mechanisms driving sexual dimorphism in obesity and its associated metabolic disorders remain unclear. Histone variant macroH2A1.1 is a candidate epigenetic mechanism linking environmental and dietary factors to obesity. Here, we used a mouse model genetically depleted of macroH2A1.1 to investigate its potential epigenetic role in sex dimorphic obesity, metabolic disturbances and gut dysbiosis. Whole body macroH2A1 knockout (KO) mice, generated with the Cre/loxP technology, and their control littermates were fed a high fat diet containing 60% of energy derived from fat. The diet was administered for three months starting from 10 to 12 weeks of age. We evaluated the progression in body weight, the food intake, and the tolerance to glucose by means of a glucose tolerance test. Gut microbiota composition, visceral adipose and liver tissue morphology were assessed. In addition, adipogenic gene expression patterns were evaluated in the visceral adipose tissue. Female KO mice for macroH2A1.1 had a more pronounced weight gain induced by high fat diet compared to their littermates, while the increase in body weight in male mice was similar in the two genotypes. Food intake was generally increased upon KO and decreased by high fat diet in both sexes, with the exception of KO females fed a high fat diet that displayed the same food intake of their littermates. In glucose tolerance tests, glucose levels were significantly elevated upon high fat diet in female KO compared to a standard diet, while this effect was absent in male KO. There were no differences in hepatic histology. Upon a high fat diet, in female adipocyte cross-sectional area was larger in KO compared to littermates: activation of proadipogenic genes (ACACB, AGT, ANGPT2, FASN, RETN, SLC2A4) and downregulation of antiadipogenic genes (AXIN1, E2F1, EGR2, JUN, SIRT1, SIRT2, UCP1, CCND1, CDKN1A, CDKN1B, EGR2) was detected. Gut microbiota profiling showed increase in Firmicutes and a decrease in Bacteroidetes in females, but not males, macroH2A1.1 KO mice. MacroH2A1.1 KO mice display sexual dimorphism in high fat diet-induced obesity and in gut dysbiosis, and may represent a useful model to investigate epigenetic and metabolic differences associated to the development of obesity-associated pathological conditions in males and females.

GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/ß-catenin and ALK5/SMAD2/3 pathways.

OBJECTIVE: GDF11 is a member of the TGF-ß superfamily that was recently implicated as potential "rejuvenating" factor, which can ameliorate metabolic disorders. The main objective of the presented study was to closely characterize the role of GDF11 signaling in the glucose homeostasis and in the differentiation of white adipose tissue. METHODS: We performed microscopy imaging, biochemical and transcriptomic analyses of adipose tissues of 9 weeks old ob/ob mice and murine and human pre-adipocyte cell lines. RESULTS: Our in vivo experiments employing GDF11 treatment in ob/ob mice showed improved glucose/insulin homeostasis, decreased weight gain and white adipocyte size. Furthermore, GDF11 treatment inhibited adipogenesis in pre-adipocytes by ALK5-SMAD2/3 activation in cooperation with the WNT/ß-catenin pathway, whose inhibition resulted in adipogenic differentiation. Lastly, we observed significantly elevated levels of the adipokine hormone adiponectin and increased glucose uptake by mature adipocytes upon GDF11 exposure. CONCLUSION: We show evidence that link GDF11 to adipogenic differentiation, glucose, and insulin homeostasis, which are pointing towards potential beneficial effects of GDF11-based "anti-obesity" therapy.

Cardio- and Neurometabolic Adipobiology: Consequences and Implications for Therapy.

Studies over the past 30 years have revealed that adipose tissue is the major endocrine and paracrine organ of the human body. Arguably, adiopobiology has taken its reasonable place in studying obesity and related cardiometabolic diseases (CMDs), including Alzheimer's disease (AD), which is viewed herein as a neurometabolic disorder. The pathogenesis and therapy of these diseases are multiplex at basic, clinical and translational levels. Our present goal is to describe new developments in cardiometabolic and neurometabolic adipobiology. Accordingly, we focus on adipose- and/or skeletal muscle-derived signaling proteins (adipsin, adiponectin, nerve growth factor, brain-derived neuroptrophic factor, neurotrophin-3, irisin, sirtuins, Klotho, neprilysin, follistatin-like protein-1, meteorin-like (metrnl), as well as growth differentiation factor 11) as examples of metabotrophic factors (MTFs) implicated in the pathogenesis and therapy of obesity and related CMDs. We argue that these pathologies are MTF-deficient diseases. In 1993 the "vascular hypothesis of AD" was published and in the present review we propose the "vasculometabolic hypothesis of AD." We discuss how MTFs could bridge CMDs and neurodegenerative diseases, such as AD. Greater insights on how to manage the MTF network would provide benefits to the quality of human life.

Alcohol Drinking, Apolipoprotein Polymorphisms and the Risk of Cardiovascular Diseases.

Lipoprotein disorders are a major risk factor for atherosclerotic neuro-cardiovascular disease (ACVD) and are heavily influenced by lifestyle, including alcohol drinking. Moderate drinkers have a lower ACVD risk than abstainers due to their higher levels of high-density lipoprotein (HDL) cholesterol, an important protective factor against ACVD. On the contrary, heavy drinking increases ACVD risk. According to an extensive literature body, ethanol intoxication modifies lipid serum profile and induces endothelial dysfunction. Single nucleotide polymorphisms may influence the relationship between alcohol drinking, HDL cholesterol level, and atherosclerotic risk. The risk of ACVD in heavy drinkers seems enhanced in patients with apolipoprotein E4 allele, interleukin- 6-174 polymorphism, and cholesteryl ester transfer protein TaqIB polymorphism. Apolipoprotein E4 is a known risk factor for ACVD, while apolipoprotein E2 has mixed effects. Therefore, even if a "protective role" may be attributed to moderate drinking, this effect cannot be extended to everyone.

Nerve Growth Factor in Alcohol Use Disorders.

The nerve growth factor (NGF) belongs to the family of neurotrophic factors. Initially discovered as a signaling molecule involved in the survival, protection, differentiation, and proliferation of sympathetic and peripheral sensory neurons, it also participates in the regulation of the immune system and endocrine system. NGF biological activity is due to the binding of two classes of receptors: the tropomyosin-related kinase A (TrkA) and the low-affinity NGF pan-neurotrophin receptor p75. Alcohol Use Disorders (AUD) are one of the most frequent mental disorders in developed countries, characterized by heavy drinking, despite the negative effects of alcohol on brain development and cognitive functions that cause individual's work, medical, legal, educational, and social life problems. In addition, alcohol consumption during pregnancy disrupts the development of the fetal brain causing a wide range of neurobehavioral outcomes collectively known as fetal alcohol spectrum disorders (FASD). The rationale of this review is to describe crucial findings on the role of NGF in humans and animals, when exposed to prenatal, chronic alcohol consumption, and on binge drinking.

Nerve Growth Factor, Stress and Diseases.

Stress is a constant threat for homeostasis and is represented by different extrinsic and intrinsic stimuli (stressors, Hans Selye's "noxious agents"), such as aggressive behavior, fear, diseases, physical activity, drugs, surgical injury, and environmental and physiological changes. Our organisms respond to stress by activating the adaptive stress system to activate compensatory responses for restoring homeostasis. Nerve Growth Factor (NGF) was discovered as a signaling molecule involved in survival, protection, differentiation, and proliferation of sympathetic and peripheral sensory neurons. NGF mediates stress with an important role in translating environmental stimuli into physiological and pathological feedbacks since NGF levels undergo important variations after exposure to stressful events. Psychological stress, lifestyle stress, and oxidative stress are well known to increase the risk of mental disorders such as schizophrenia, major depressive disorders, bipolar disorder, alcohol use disorders and metabolic disorders such as metabolic syndrome. This review reports recent works describing the activity of NGF in mental and metabolic disorders related to stress.

Nerve growth factor in the psychiatric brain.

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.

How alcohol drinking affects our genes: an epigenetic point of view.

This work highlights recent studies in epigenetic mechanisms that play a role in alcoholism, which is a complex multifactorial disorder. There is a large body of evidence showing that alcohol can modify gene expression through epigenetic processes, namely DNA methylation and nucleosomal remodeling via histone modifications. In that regard, chronic exposure to ethanol modifies DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol-mediated chromatin remodeling in the brain promotes the transition from use to abuse and addiction. Unravelling the multiplex pattern of molecular modifications induced by ethanol could support the development of new therapies for alcoholism and drug addiction targeting epigenetic processes.

Colchicine, a microtubule-disassembling drug, in the therapy of cardiovascular diseases.

Colchicum autumnale, from which colchicine has been isolated more than 100 years ago, has been used as a treatment for pain and swelling for thousands of years. It is one of the few drugs known from that time period whose use has survived to modernity. Over the past decades, advances in the knowledge of (i) cytoskeletal microtubules (МТ), and (ii) anti-inflammatory and anti-fibrotic effects of colchicine, a classical MT-disassembling (tubulin-targeting) agent, have led to potential new uses for this very old drug extended beyond acute gouty arthritis and familial Mediterranean fever. Here, in brief, I present the Bulgarian contribution to possible potential of colchicine in the therapy of cardiovascular diseases that has emerged in the early 1970s in the Laboratory of Electron Microscopy, Medical Institute, Varna, Bulgaria, studying the secretory function of vascular smooth muscle cells. From this time onward, low-dose colchicine (0.5-1.0 mg/daily) was increasingly administered orally for therapy of cardiovascular diseases such as acute coronary syndromes, postoperative atrial fibrillation (in cardiac surgery), pericarditis, cardiac hypertrophy-associated heart failure, restenosis after angioplasty, and systemic necrotizing vasculitis. Thus, colchicine might be a new tool in the present therapeutic armamentarium for cardiovascular diseases. It is simply an example of MT-disassembling drugs. Further studies will definitely be required before gaining real confidence in this kind of antitubulin pharmacology and therapy. This may lead to developing new and more specific antitubulins for cardiovascular diseases.

Virtual Morris task responses in individuals in an abstinence phase from alcohol.

The present study was aimed at examining spatial learning and memory, in 33 men and 12 women with alcohol use disorder (AUD) undergoing ethanol detoxification, by using a virtual Morris task. As controls, we recruited 29 men and 10 women among episodic drinkers without a history of alcohol addiction or alcohol-related diseases. Elevated latency to the first movement in all trials was observed only in AUD persons; furthermore, control women had longer latencies compared with control men. Increased time spent to reach the hidden platform in the learning phase was found for women of both groups compared with men, in particular during trial 3. As predicted, AUD persons (more evident in men) spent less time in the target quadrant during the probe trial; however, AUD women had longer latencies to reach the platform in the visible condition during trials 6 and 7 that resulted in a greater distance moved. As for the probe trial, men of both groups showed increased virtual locomotion compared with the women of both groups. The present investigation confirms and extends previous studies showing (i) different gender responses in spatial learning tasks, (ii) some alterations due to alcohol addiction in virtual spatial learning, and (iii) differences between AUD men and AUD women in spatial-behaviour-related paradigms.

Neurotrophins' Modulation by Olive Polyphenols.

BACKGROUND: Polyphenols are probably the most known and investigated molecules of nutritional interest as micronutrients present in abundance in our diet. Some of the most important food sources of polyphenols in the Mediterranean diet are olives and olive oil. A growing body of evidence from animal models to clinical studies indicates that polyphenol compounds may have neuroprotective effects in several pathologies of the nervous system through the control of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction. OBJECTIVE: Based on the most recent scientific literature, dietary intake of polyphenols attenuates oxidative stress and reduces risk for related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and Huntington's disease. Also at the peripheral level, they act as antioxidant, defending tissues against oxidative damage and scavenging free radicals. RESULTS: Recent findings in animal models and humans show that polyphenols may have a role in regulating neurotrophins levels, in particular nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF), suggesting that polyphenols may also induce their protective effects through the potentiation of neurotrophins action. NGF and BDNF, primarily known as biological mediators stimulating neuron growth, proliferation, survival and differentiation are recently studied also as metabotrophic factors, acting on glucose and energy metabolism, pancreatic beta cells and cardiovascular homeostasis. CONCLUSION: In this context, a better understanding of the effects of polyphenols on neurotrophins and their receptors (TrkA, TrkB, p75NTR) could certainly generate interest for drug discovery and also for the potential dietary prevention of several neurological and cardiometabolic diseases.

Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring.

Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offspring. However, the role of paternal alcohol exposure (PAE) on offspring EtOH sensitivity and neurotrophins has not received much attention. The present study examined whether PAE may disrupt nerve growth factor (NGF) and/or brain-derived neurotrophic factor (BDNF) and affect EtOH preference/rewarding properties in the male offspring. CD1 sire mice were chronically addicted for EtOH or administered with sucrose. Their male offsprings when adult were assessed for EtOH preference by a conditioned place preference paradigm. NGF and BDNF, their receptors (p75(NTR) , TrkA and TrkB), dopamine active transporter (DAT), dopamine receptors D1 and D2, pro-NGF and pro-BDNF were also evaluated in brain areas. PAE affected NGF levels in frontal cortex, striatum, olfactory lobes, hippocampus and hypothalamus. BDNF alterations in frontal cortex, striatum and olfactory lobes were found. PAE induced a higher susceptibility to the EtOH rewarding effects mostly evident at the lower concentration (0.5 g/kg) that was ineffective in non-PAE offsprings. Moreover, higher ethanol concentrations (1.5 g/kg) produced an aversive response in PAE animals and a significant preference in non-PAE offspring. PAE affected also TrkA in the hippocampus and p75(NTR) in the frontal cortex. DAT was affected in the olfactory lobes in PAE animals treated with 0.5 g/kg of ethanol while no differences were found on D1/D2 receptors and for pro-NGF or pro-BDNF. In conclusion, this study shows that: PAE affects NGF and BDNF expression in the mouse brain; PAE may induce ethanol intake preference in the male offspring.

Spatial learning in men undergoing alcohol detoxification.

Alcohol dependence is a major public health problem worldwide. Brain and behavioral disruptions including changes in cognitive abilities are common features of alcohol addiction. Thus, the present study was aimed to investigate spatial learning and memory in 29 alcoholic men undergoing alcohol detoxification by using a virtual Morris maze task. As age-matched controls we recruited 29 men among occasional drinkers without history of alcohol dependence and/or alcohol related diseases and with a negative blood alcohol level at the time of testing. We found that the responses to the virtual Morris maze are impaired in men undergoing alcohol detoxification. Notably they showed increased latencies in the first movement during the trials, increased latencies in retrieving the hidden platform and increased latencies in reaching the visible platform. These findings were associated with reduced swimming time in the target quadrant of the pool where the platform had been during the 4 hidden platform trials of the learning phase compared to controls. Such increasing latency responses may suggest motor control, attentional and motivational deficits due to alcohol detoxification.

TNF-α and IL-10 modulation induced by polyphenols extracted by olive pomace in a mouse model of paw inflammation.

BACKGROUND: Polyphenols from olive are known to possess antioxidant and anti-inflammatory properties. AIM: The aim of this study was to study whether or not 10 consecutive days i.p. administration of a blend of olive (Olea europaea L.) polyphenols (10 mg/kg) containing mostly hydroxytyrosol could have an effect on cytokines playing important roles in inflammatory processes as TNF-α and IL-10. MATERIALS AND METHODS: Inflammation was induced in the mouse paw by 2 carrageenan injections (50 µl vol, 5 mg/kg each). TNF-α and IL-10 were measured by enzyme-linked immunosorbent assay. RESULTS: Carrageenan decreased IL-10 in the paws, however, this reduction appeared to be less evident in mice treated with carrageenan but administered with polyphenols. As for TNF-α, our findings did not reveal differences between groups but an increase in the polyphenol and carrageenan group if compared to the carrageenan only group. As for antioxidant polyphenols' properties, no differences between groups in the serum glutathione were found. CONCLUSIONS: Altogether, this investigation shows that olive polyphenols in the mouse may modulate the levels of cytokines having a role in the process of inflammation as TNF-α and IL-10.

Effects of olive leaf polyphenols on male mouse brain NGF, BDNF and their receptors TrkA, TrkB and p75.

In this study, we evaluated, in the mouse, the effects of 20 mg/kg i.p. daily administration for 15 consecutive days of a blend of polyphenols, containing mostly oleuropein, extracted from the olive leaves (Olea europaea) on brain nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and on the expression of their receptors, TrkA, TrkB and p75. Polyphenols decreased the levels of reduced glutathione (GSH) and increased the levels of NGF and BDNF in the serum. In the brain, we found decreased levels of NGF and BDNF in the hippocampus and striatum but elevated levels of NGF in the olfactory lobes and hypothalamus and again BDNF potentiation in the olfactory lobes. No changes in TrkA, TrkB and p75 expression were observed. In conclusion, olive polyphenols may not only elicit an activation of the rodent olfactory system by increasing the levels of NGF and BDNF but also be stressing for the animal by reducing both the levels of hippocampal NGF/BDNF and serum GSH and increasing serum levels of NGF and BDNF.

Triactome: neuro-immune-adipose interactions. Implication in vascular biology.

Understanding how the precise interactions of nerves, immune cells, and adipose tissue account for cardiovascular and metabolic biology is a central aim of biomedical research at present. A long standing paradigm holds that the vascular wall is composed of three concentric tissue coats (tunicae): intima, media, and adventitia. However, large- and medium-sized arteries, where usually atherosclerotic lesions develop, are consistently surrounded by periadventitial adipose tissue (PAAT), we recently designated tunica adiposa (in brief, adiposa like intima, media, and adventitia). Today, atherosclerosis is considered an immune-mediated inflammatory disease featured by endothelial dysfunction/intimal thickening, medial atrophy, and adventitial lesions associated with adipose dysfunction, whereas hypertension is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell hypertrophy/hyperplasia. PAAT expansion is associated with increased infiltration of immune cells, both adipocytes and immunocytes secreting pro-inflammatory and anti-inflammatory (metabotrophic) signaling proteins collectively dubbed adipokines. However, the role of vascular nerves and their interactions with immune cells and paracrine adipose tissue is not yet evaluated in such an integrated way. The present review attempts to briefly highlight the findings in basic and translational sciences in this area focusing on neuro-immune-adipose interactions, herein referred to as triactome. Triactome-targeted pharmacology may provide a novel therapeutic approach in cardiovascular disease.

NGF and BDNF long-term variations in the thyroid, testis and adrenal glands of a mouse model of fetal alcohol spectrum disorders.

OBJECTIVES: Fetal Alcohol Spectrum Disorders (FASD) due to prenatal ethanol consumption may induce long-lasting changes to the newborns affecting also the endocrine system and the nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) signaling. Thus the aim of this study was to investigate in the thyroid, testis and adrenal glands of a FASD mouse model the long-lasting effects of ethanol exposure during pregnancy and lactation on NGF and BDNF and their main receptors, TrkA and TrkB, including their phosphorylated patterns. METHODS: We used aged male CD-1 mice early exposed to ethanol solution or red wine at same ethanol concentration (11% vol). RESULTS: We found elevations in NGF and BDNF in the thyroid of aged mice exposed to ethanol solution only but not in the red wine group. In the testis NGF resulted to be increased only in the ethanol solution group. In the adrenal glands data showed an elevation in NGF in both the ethanol solution group and red wine. No changes in TrkA, TrkB, phospho-TrkA and phospho-TrkB were revealed in all tissues examined. CONCLUSIONS: Early administration of ethanol may induce long-lasting changes in the mouse thyroid, testis and adrenal glands at NGF and BDNF levels.

Effects of olive polyphenols administration on nerve growth factor and brain-derived neurotrophic factor in the mouse brain.

OBJECTIVE: Polyphenols are chemicals derived from plants known to possess antioxidant and anti-inflammatory properties. High intake of fruit and vegetables is believed to be beneficial to human health. Various studies have suggested that dietary polyphenols may protect against cancer and cardiometabolic and neurodegenerative diseases. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are neurotrophins that play key roles in brain cell development, growth, and survival. The aim of this study was to investigate whether or not administration of olive (Olea europaea L.) polyphenols could have an effect on NGF and BDNF content and the expression of their receptors, TrkA and TrkB, respectively, in the mouse brain. METHODS: NGF and BDNF were measured by enzyme-linked immunosorbent assay. TrkA and TrkB were measured by Western blotting. RESULTS: We found NGF and BDNF elevation in the hippocampus and olfactory bulbs and a decrease in the frontal cortex and striatum. These data were associated with potentiated expression of TrkA and TrkB in the hippocampus and olfactory bulbs but no differences between groups in the striatum and frontal cortex. Polyphenols did not affect some behavioral mouse parameters associated with stressing situations. CONCLUSIONS: Altogether, this study shows that olive polyphenols in the mouse may increase the levels of NGF and BDNF in crucial areas of the limbic system and olfactory bulbs, which play a key role in learning and memory processes and in the proliferation and migration of endogenous progenitor cells present in the rodent brain.