Nerve growth factor, brain-derived neurotrophic factor, and the chronobiology of mood: a new insight into the "neurotrophic hypothesis"

The light information pathways and their relationship with the body rhythms have generated a new insight into the neurobiology and the neurobehavioral sciences, as well as into the clinical approaches to human diseases associated with disruption of circadian cycles. Light-based strategies and/or drugs acting on the circadian rhythms have widely been used in psychiatric patients characterized by mood-related disorders, but the timing and dosage use of the various treatments, although based on international guidelines, are mainly dependent on the psychiatric experiences. Further, many efforts have been made to identify biomarkers able to disclose the circadian-related aspect of diseases, and therefore serve as diagnostic, prognostic, and therapeutic tools in clinic to assess the different mood-related symptoms, including pain, fatigue, sleep disturbance, loss of interest or pleasure, appetite, psychomotor changes, and cognitive impairments. Among the endogenous factors suggested to be involved in mood regulation, the neurotrophins, nerve growth factor, and brain-derived neurotrophic factor show anatomical and functional link with the circadian system and mediate some of light-induced effects in brain. In addition, in humans, both nerve growth factor and brain-derived neurotrophic factor have showed a daily rhythm, which correlate with the morningness–eveningness dimensions, and are influenced by light, suggesting their potential role as biomarkers for chronotypes and/or chronotherapy. The evidences of the relationship between the diverse mood-related disorders, with a specific focus on depression, and neurotrophins are reviewed and discussed herein in terms of their circadian significance, and potential translation into clinical practice

Acute stimulation of vagus nerve modulates brain neurotrophins, and stimulates neuronal plasticity in the hippocampus of adult male rats

The present study was aimed at evaluating whether single intermittent acute cervical vagus nerve stimulation (ACVS), pro-vided at a frequency which exhibits a clinical efficacy, may influence brain neurotrophins and hippocampal plasticity. With this purpose, the brain of adult male rats undergoing ACVS was used to analyze the expression of Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) in brain areas known to synthetize these growth factors, and the expression the neural cell adhesion molecule (NCAM), the synaptophysin (SYP) and biosynthetic GABA (GAD67) in the hippocampus.The effects of ACVS on NGF and BDNF protein and mRNA in hippocampus, hypothalamus and cortex two hours after stimulation were shown to be dependent on the frequencies of ACVS stimulation. Prolonged (three days post stimulation) modifications of NGF and BDNF were also observed in the hippocampus of ACVS rats. An early enhancement of the plasticity markers NCAM, SYP and GAD67 was also found in ACVS hippocampus. Three days after stimulation, NCAM and GAD67 levels were still higher than controls. Immunohistochemistry confirms the stimulatory effects of ACVS on GABA showing an increase in GAD67-positive cells in the dentate gyrus and CA3 hippocampal areas. This study shows that ACVS affects brain NGF and BDNF synthesis in a frequency-dependent manner. Neurotrophins changes are associated with increased hippocampal plasticity, as demonstrated by the observed molecular and morphological modifications. These findings support the role of brain neurotrophins in the ACVS mechanism of action

Role of Neuropeptide Tyrosine (NPY) in Ethanol Addiction

Here, an overview of neurophysiological, pharmacological and genetic research on the role of neuropeptide tyrosine (NPY) in ethanol consumption and withdrawal is presented. NPY is abundantly expressed in the extended amygdala and is critically involved in the regulation of negative affective states in rats, also is involved with neurobiological responses to ethanol and other drug of abuse. Genetic, molecular and pharmacological evidences suggest that NPY is an important neurobiological substrate for the predisposition to alcoholism. Administration, as well as the withdrawal of ethanol, alters central NPY expression. Alcohol-preferring rats exhibit basal NPY deficits in central amygdala. In the latter, NPY may rescue dependence-induced increases in anxiety and alcohol drinking. Low NPY levels in some brain regions following ethanol withdrawal contribute to the increased sensitivity to seizure and the heightened levels of anxiety characteristic of withdrawal responses. Mice with deletion of NPY gene exhibit a high-anxiety, high-alcohol-drinking phenotype. Pharmacological and genetic manipulations suggest that central NPY signaling modulates ethanol consumption via Y1, Y2, and Y5 receptors. Analysis of chromosomal regions (QTLs) associated with alcohol consumption identified NPY as one of the genes that influence alcohol dependence and as a promising target for pharmacotherapeutics to combat alcohol associated disorders. Consequently, NPY is a potentially new pharmacological target for the treatment of alcohol diseases

Role of neuropeptide tyrosine (NPY) in ethanol addiction

Here, an overview of neurophysiological, pharmacological and genetic research on the role of neuropeptide tyrosine (NPY) in ethanol consumption and withdrawal is presented. NPY is abundantly expressed in the extended amygdala and is critically involved in the regulation of negative affective states in rats, also is involved with neurobiological responses to ethanol and other drug of abuse. Genetic, molecular and pharmacological evidences suggest that NPY is an important neurobiological substrate for the predisposition to alcoholism. Administration, as well as the withdrawal of ethanol, alters central NPY expression. Alcohol- preferring rats exhibit basal NPY deficits in central amygdala. In the latter, NPY may rescue dependence-induced increases in anxiety and alcohol drinking. Low NPY levels in some brain regions following ethanol withdrawal contribute to the increased sensitivity to seizure and the heightened levels of anxiety characteristic of withdrawal responses. Mice with deletion of NPY gene exhibit a high-anxiety, high-alcohol-drinking phenotype. Pharmacological and genetic manipulations suggest that central NPY signaling modulates ethanol consumption via Y1, Y2, and Y5 receptors. Analysis of chromosomal regions (QTLs) associated with alcohol consumption identified NPY as one of the genes that influence alcohol dependence and as a promising target for pharmacotherapeutics to combat alcohol associated disorders. Consequently, NPY is a potentially new pharmacological target for the treatment of alcohol diseases

Interleukin-8 and laryngeal squamous cell carcinoma

Laryngeal squamous cell carcinoma (LSCC) is the second most common neoplasm of the upper aerodigestive tract after cancer of the oral cavity. Over the past two decades, even though patients have benefited greatly from the latest advances in surgical techniques, chemotherapy and radiation therapy, the survival rate of LSCC has not improved significantly. It is reported that changes in the expression of cytokines and growth factors have implications in the malignant transformation of many cancers including head and neck squamous cell carcinoma and, more recently, LSCC. It has been hypothesized that some of these cytokines may be used as additional diagnostic markers in the sera of patients because of their excessive production by the tumor cells. This could be of great value since there are currently no reliable markers to predict either tumor development or relapse. Interleukin-8 (IL-8), a chemokine (C-X-C motif) ligand 8 (CXCL8), is now reported to play an important role in cancer invasion, angiogenesis and metastasis. Recent studies have shown an increased concentration of IL-8 in patients with LSCC and a positive association with lymph node metastasis and T classification. Interleukin-8 levels were not significantly associated with shorter overall survival and cancer progression-free survival. The investigation of the mechanisms of origin, invasion, and metastasis of the cancer is one of the emergent and most promising scientific fields in head and neck cancer, especially in LSCC. Biomarkers such as IL-8 could have a role as a screening test and as a support of the clinical decisions for appropriate therapy and postoperative care in individual patients

Involvement of substance P (SP) and its related NK1 receptor in primary Sjögren’s syndrome (pSS) pathogenesis

Primary Sjogren's Syndrome (pSS) is a systemic autoimmune disease that primarily attacks the lacrimal and salivary glands, resulting in impaired secretory function characterized by xerostomia and xerophthalmia. Patients with pSS have been shown to have impaired salivary gland innervation and altered circulating levels of neuropeptides thought to be a cause of decreased salivation, including substance P (SP). Using Western blot analysis and immunofluorescence studies, we examined the expression levels of SP and its preferred G protein-coupled TK Receptor 1 (NK1R) and apoptosis markers in biopsies of the minor salivary gland (MSG) from pSS patients compared with patients with idiopathic sicca syndrome. We confirmed a quantitative decrease in the amount of SP in the MSG of pSS patients and demonstrated a significant increase in NK1R levels compared with sicca subjects, indicating the involvement of SP fibers and NK1R in the impaired salivary secretion observed in pSS patients. Moreover, the increase in apoptosis (PARP-1 cleavage) in pSS patients was shown to be related to JNK phosphorylation. Since there is no satisfactory therapy for the treatment of secretory hypofunction in pSS patients, the SP pathway may be a new potential diagnostic tool or therapeutic target

Nerve growth factor in brain diseases

The nerve growth factor (NGF) belongs to a family of proteins termed neurotrophins, consisting of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. Today, NGF is well recognized to mediate a large number of trophobiological actions resulting in neurotrophic, immunotrophic and/or metabotrophic effects. The pathobiology of neurodegenerative diseases, including Alzheimer disease, psychiatric disorders (e.g. depression and schizophrenia) and brain parasitic infections have in common the effect of altering the brain levels of neurotrophins and in particular NGF. The involvement of NGF and its TrkA receptor in these pathologies and the recent promising results of NGF therapies are presented and discussed

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

Polyphenols from olive are known to possess antioxidant and anti-inflammatory properties. The aim of this study was to study whether or not administration of olive (Olea europaeaL.) polyphenols could have an effect on cytokines as TNF-a and IL-10 in the mouse paw following inflammation induced by carrageenan injection. TNF-a and IL-10 were measured by enzyme-linked immunosorbent assay. 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-a, our findings did not reveal differences between groups but an increase in polyphenol and carrageenan groups if compared to the carrageenan only group. No differences between groups in the serum Glutathione were found. 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-a and IL-10

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 (p75NTR, 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 p75NTR 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

Peripherally administered choleocystokinin-8 increases neurotrophins in the brain

The aim of this thesis was to test the hypothesis that the gastric hormone Cholecystokinin-8 (CCK-8) can modulate the production of Nerve Growth Factor (NGF) in the brain. NGF is the first discovered and the best characterized neurotrophic factor which plays a crucial role in the survival and development of basal forebrain cholinergic neurons (BFCN). BFCN depend on NGF also during adult life and thus NGF also is involved in the maintenance of BFNC-related functions, such as memory and learning. Since CCK-8 has been shown to stimulate the synthesis of neurotransmitters and neuropeptides in the brain and to improve memory and learning when peripherally injected, we decided to study whether NGF could be a possible brain factor mediating the central effects of CCK-8. We found that intraperitoneal injection with CCK-8 increased NGF synthesis in the brains of adult mice and rats. The CCK-8 effects are dose- and time-dependent and the strongest stimulatory effects on NGF are obtained with 8nmol/kg. The HPLC analysis and the evidence obtained in vivo confirm that CCK-8 induces an increase in biologically active form of NGF by an up-regulation of brain NGF biosynthesis. Throught NGF, CCK-8 stimulates the expression of cholinergic markers in the forebrain and counteracts the cholinergic cell degeneration in fimbria-fornix lesioned mice. The NGF response to CCK administration is abolished following pre-treatment with atropine, while pre-treatment with CCKA and CCKB receptor antagonists differentially affect the NGF levels in the hippocampus and hypothalamus. Indeed, the CCKB antagonist blocks the CCK-induced NGF synthesis in the hippocampus, while the CCKA antagonist selectively inhibits the CCK effects on hypothalamic NGF. Analysing the NGF rnRNA expression using a newly developed RT-PCR ELISA method we observed that hypothalamic but not hippocampal NGF synthesis is affected by electrical vagal stimulation. Since CCK-8 is released during vagal stimulation, this data led us to hypothesise that the vagal nerve mediates the stimulatory effects of CCK-8 on hypothalamic NGF production. A non-vagal mediated mechanism - most probably due to the activation of CCKB receptors - may be inferred for the CCK-induced NGF increase in the hippocampus. Moreover, this thesis shows that glutamate when injected intravenously in a subtoxic dose increases NGF concentrations in the hippocampus and hypothalamus. We also observed that pre-treatment with a selective NMDA receptor antagonist blocked the CCK-induced NGF synthesis in the hippocampus. These results suggest that CCK and the vagal nerve may regulate the NGF synthesis by modulating the release of excitatory amino acids. In conclusion, this thesis provides evidences that the neuroprotective action of CCK on forebrain neurons is mediated by the synthesis and release of NGF. Moreover, the data suggests that CCK exerts a stimulatory effect on neurotrophin production in brain acting via two different pathways. One pathway involves the vagal nerve and it is mainly mediated by CCKA receptors, while the other pathway is mediated through the activation of CCB receptors which are not of vagal origin