ProNGF processing in adult rat tissues and bioactivity of NGF prodomain peptides.

The neurotrophin nerve growth factor (NGF) and its precursor proNGF are both bioactive and exert similar or opposite actions depending on the cell target and its milieu. The balance between NGF and proNGF is crucial for cell and tissue homeostasis and it is considered an indicator of pathological conditions. Proteolytical cleavage of proNGF to the mature form results in different fragments, whose function and/or bioactivity is still unclear. The present study was conducted to investigate the distribution of proNGF fragments derived from endogenous cleavage in brain and peripheral tissues of adult rats in the healthy condition and following inflammatory lipopolysaccharide (LPS) challenge. Different anti-proNGF antibodies were tested and the presence of short peptides corresponding to the prodomain sequence (pdNGFpep) was identified. Processing of proNGF was found to be tissue-specific and accumulation of pdNGFpeps was found in inflamed tissues, mainly in testis, intestine and heart, suggesting a possible correlation between organ functions and a response to insults and/or injury. The bioactivity of pdNGFpep was also demonstrated in vitro by using primary hippocampal neurons. Our study supports a biological function for the NGF precursor prodomain and indicates that short peptides from residues 1-60, differing from the 70-110 sequence, induce apoptosis, thereby opening the way for identification of new molecular targets to study pathological conditions.

Involvement of Substance P (SP) and Its Related NK1 Receptor in Primary Sjögren's Syndrome (pSS) Pathogenesis.

Primary Sjögren'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.

Psycho-Cognitive Profile and NGF and BDNF Levels in Tears and Serum: A Pilot Study in Patients with Graves' Disease.

Nerve Growth Factor (NGF) and Brain derived Neurotrophic Factor (BDNF) mature/precursor imbalance in tears and serum is suggested as a risk factor and symptomatology aggravation in ophthalmology and neuropsychiatric disturbances. Cognitive and mood alterations are reported by patients with Graves' Orbitopathy (GO), indicating neurotrophin alterations might be involved. To address this question, the expression levels of NGF and BDNF and their precursors in serum and tears of GO patients were analyzed and correlated with the ophthalmological and psycho-cognitive symptoms. Hamilton Rating Scale for Anxiety (HAM-A) and Depression (HAM-D), Temperament and Character Inventory (TCI), and Cambridge Neuropsychological Test Automated Battery (CANTAB) test were used as a score. NGF and BDNF levels were measured using ELISA and Western Blot and statistically analyzed for psychiatric/ocular variable trend association. GO patients show memorization time and level of distraction increase, together with high irritability and impulsiveness. HAM-A and CANTAB variables association, and some TCI dimensions are also found. NGF and BDNF expression correlates with ophthalmological symptoms only in tears, while mature/precursor NGF and BDNF correlate with the specific psycho-cognitive variables both in tears and serum. Our study is the first to show that changes in NGF and BDNF processing in tears and serum might profile ocular and cognitive alterations in patients.

NGF Prevents Loss of TrkA/VEGFR2 Cells, and VEGF Isoform Dysregulation in the Retina of Adult Diabetic Rats.

Among the factors involved in diabetic retinopathy (DR), nerve growth factor (NGF) and vascular endothelial growth factor A (VEGFA) have been shown to affect both neuronal survival and vascular function, suggesting that their crosstalk might influence DR outcomes. To address this question, the administration of eye drops containing NGF (ed-NGF) to adult Sprague Dawley rats receiving streptozotocin (STZ) intraperitoneal injection was used as an experimental paradigm to investigate NGF modulation of VEGFA and its receptor VEGFR2 expression. We show that ed-NGF treatment prevents the histological and vascular alterations in STZ retina, VEGFR2 expression decreased in GCL and INL, and preserved the co-expression of VEGFR2 and NGF-tropomyosin-related kinase A (TrkA) receptor in retinal ganglion cells (RGCs). The WB analysis confirmed the NGF effect on VEGFR2 expression and activation, and showed a recovery of VEGF isoform dysregulation by suppressing STZ-induced VEGFA121 expression. Reduction in inflammatory and pro-apoptotic intracellular signals were also found in STZ+NGF retina. These findings suggest that ed-NGF administration might favor neuroretina protection, and in turn counteract the vascular impairment by regulating VEGFR2 and/or VEGFA isoform expression during the early stages of the disease. The possibility that an increase in the NGF availability might contribute to the switch from the proangiogenic/apoptotic to the neuroprotective action of VEGF is discussed.

Pilot Investigation on p75ICD Expression in Laryngeal Squamous Cell Carcinoma.

We investigated the p75 Neurotrophin Receptor (p75NTR) expression and cleavage product p75NTR Intracellular Domain (p75ICD) as potential oncogenic and metastatic markers in human Laryngeal Squamous Cell Carcinoma (LSCC). p75NTR is highly expressed in Cancer Stem Cells (CSCs) of the laryngeal epithelia and it has been proposed as a marker for stemness, cell migration, and chemo-resistance in different squamous carcinomas. To investigate the clinical significance of p75NTR cleavage products in solid tumors, full-length and cleaved p75NTR expression was analyzed in laryngeal primary tumors from different-stage LSCC patients, diagnosed at the Policlinico Umberto I Hospital. Molecular and histological techniques were used to detect the expressions of p75NTR and p75ICD, and ATP Binding Cassette Subfamily G Member 2 (ABCG2), a CSC marker. We found regulated p75NTR cleavage during squamous epithelial tumor progression and tissue invasion. Our preliminary investigation suggests p75ICD expression and localization as possible features of tumorigenesis and metastaticity. Its co-localization with ABCG2 in squamous cells in the parenchyma invaded by the tumor formation allows us to hypothesize p75NTR and p75ICD roles in tumor invasion and CSC spreading in LSCC patients. These data might represent a starting point for a comprehensive analysis of p75NTR cleavage and of its clinical relevance as a potential molecular LSCC signature, possibly helping diagnosis, and improving prognosis and personalized therapy.

Behavioral dysregulations by chronic alcohol abuse. Motivational enhancement therapy and cognitive behavioral therapy outcomes.

Patients with alcohol use disorder (AUD) do not manifest homogeneous clinical symptoms. Various studies described both cognitive impairments and psychiatric disorders among people with AUD. This disorder is one of the most frequent mental disorders in developed countries, due to excessive alcohol consumption. Alcohol is toxic as it increases the production of reactive oxygen species (ROS) and can cause dependence. This causes negative effects on brain development and cognitive functions that affect the individual's work, health, and social life. Current pharmacology treatment for alcohol addiction is based on direct action against the neurotransmitters involved in alcohol dependence. AUD patients without comorbid psychiatric disorders or severe cognitive deficits are defined as "pure alcoholics". To date, poor is known about effective treatments for this typology of AUD patients. Psychotherapy is largely used in resolving many psychiatric disorders, including substance use disorders. Motivational enhancement therapy (MET) and cognitive-behavioral therapy (CBT) are two psychotherapies used to achieve and maintain abstinence in patients affected by substance use disorders. This short review aims to describe two CBT and MET and to present the advantages and disadvantages of these two psychotherapies in the treatment of AUD.

Markers of Neuroinflammation in the Serum of Prepubertal Children with Fetal Alcohol Spectrum Disorders.

BACKGROUND: Fetal Alcohol Spectrum Disorders (FASD) are the manifestation of the damage caused by alcohol consumption during pregnancy. Children with Fetal Alcohol Syndrome (FAS), the extreme FASD manifestation, show both facial dysmorphology and mental retardation. Alcohol consumed during gestational age prejudices brain development by reducing, among others, the synthesis and release of neurotrophic factors and neuroinflammatory markers. Alcohol drinking also induces oxidative stress. HYPOTHESIS/OBJECTIVE: The present study aimed to investigate the potential association between neurotrophins, neuroinflammation, and oxidative stress in 12 prepubertal male and female FASD children diagnosed as FAS or partial FAS (pFAS). METHODS: Accordingly, we analyzed, in the serum, the level of BDNF and NGF and the oxidative stress, as Free Oxygen Radicals Test (FORT) and Free Oxygen Radicals Defense (FORD). Moreover, serum levels of inflammatory mediators (IL-1α, IL-2, IL-6, IL-10, IL-12, MCP-1, TGF-ß, and TNF-α) involved in neuroinflammatory and oxidative processes have been investigated. RESULTS: We demonstrated low serum levels of NGF and BDNF in pre-pubertal FASD children with respect to healthy controls. These changes were associated with higher serum presence of TNF- α and IL-1α. Quite interestingly, an elevation in the FORD was also found despite normal FORT levels. Moreover, we found a potentiation of IL-1α, IL-2, IL-10, and IL-1α1 in the analyzed female compared to male children. CONCLUSION: The present investigation shows an imbalance in the peripheral neuroimmune pathways that could be used in children as early biomarkers of the deficits observed in FASD.

Gender differences in ultradian serum levels of NGF and BDNF correlate with psychophysical traits in healthy humans.

We aimed at investigating the gender and/or ultradian pattern of serum levels of the Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF). Blood samples were collected at the 8.00, 13.00 and 20.00 hours of the day in healthy men and women, and the neurotrophins concentration was measured in the serum by ELISA. A further aim of the study was to evaluate whether or not the NGF/BDNF variations might be related to specific physiological or psychological traits as mood, feeling good and feeling rested, sexual desire and energy. Heart rate and blood pressure were also monitored at the same hours in each enrolled subject. The anxiety (STAI-T and STAI-S score) and sleeping quality were once evaluated in the morning too. We found that serum BDNF increases in men and decreases in women from morning to evening, while NGF shows a similar ultradian profile between men and women, but with higher concentrations in women. Both neurotrophins also show gender-related associations with psychophysiological variables. High NGF levels correlated with a high score for all the psychological variables in men, but with a low score in women. An inverse correlation was found between BDNF and energy and sexual desire in women, while no correlations were found in men. These data disclose that the condition of well-being (or activity/arousal status) is featured by an increasing NGF profile in men and a negative BDNF/NGF trend in women. The clinical relevance of the present data is discussed.

NGF Eye Administration Recovers the TrkB and Glutamate/GABA Marker Deficit in the Adult Visual Cortex Following Optic Nerve Crush.

Eye-drop recombinant human nerve growth factor (ed-rhNGF) has proved to recover the retina and optic nerve damage in animal models, including the unilateral optic nerve crush (ONC), and to improve visual acuity in humans. These data, associated with evidence that ed-rhNGF stimulates the brain derived neurotrophic factor (BDNF) in retina and cortex, suggests that NGF might exert retino-fugal effects by affecting BDNF and its receptor TrkB. To address these questions, their expression and relationship with the GABAergic and glutamatergic transmission markers, GAD65 and GAD67, vesicular inhibitory amino acid transporter (VGAT), and vesicular glutamate transporters 1 and 2 (VGLUT-1 and VGLUT-2) were investigated in adult ONC rats contralateral and ipsilateral visual cortex (VCx). Ed-rhNGF recovers the ONC-induced alteration of GABAergic and glutamatergic markers in contralateral VCx, induces an upregulation of TrkB, which is positively correlated with BDNF precursor (proBDNF) decrease in both VCx sides, and strongly enhances TrkB+ cell soma and neuronal endings surrounded by GAD65 immuno-reactive afferents. These findings contribute to enlarging the knowledge on the mechanism of actions and cellular targets of exogenously administrated NGF, and suggest that ed-rhNGF might act by potentiating the activity-dependent TrkB expression in GAD+ cells in VCx following retina damage and/or ONC.

Vagus nerve stimulation and Neurotrophins: a biological psychiatric perspective.

Since 2004, vagus nerve stimulation (VNS) has been used in treatment-resistant or treatment-intolerant depressive episodes. Today, VNS is suggested as possible therapy for a larger spectrum of psychiatric disorders, including schizophrenia, obsessive compulsive disorders, and panic disorders. Despite a large body of literature supports the application of VNS in patients' treatment, the exact mechanism of action of VNS remains not fully understood. In the present study, the major knowledges on the brain areas and neuronal pathways regulating neuroimmune and autonomic response subserving VNS effects are reviewed. Furthermore, the involvement of the neurotrophins (NTs) Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF) in vagus nerve (VN) physiology and stimulation is revised. The data on brain NGF/BDNF synthesis and in turn on the activity-dependent plasticity, connectivity rearrangement and neurogenesis, are presented and discussed as potential biomarkers for optimizing stimulatory parameters for VNS. A vagus nerve-neurotrophin interaction model in the brain is finally proposed as a working hypothesis for future studies addressed to understand pathophysiology of psychiatric disturbance.

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.

Role of neurotrophins in pregnancy, delivery and postpartum.

Neurotrophins (NTs) are a family of polypeptides whose functions have been extensively studied in the past two decades. In particular, Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) play a major role in the development, nutrition and growth of the central and peripheral nervous system and in the pathogenesis of neurodegenerative, cardiometabolic and (auto)immune diseases. However, NGF and BDNF have subtle functions for follicular development, implantation, and placentation. This short narrative review summarizes the existing evidence, published between 2000 and 2019, about the role of NTs in many different conditions that might affect women during and after pregnancy such as preeclampsia, gestational diabetes, obesity, depression, anxiety, smoking and alcohol abuse. Literature suggests that the dysregulation of synthesis and release of NTs may lead to decisive effects on both maternal and fetal health. Some piece of evidences was found about a possible association between NGF/BDNF and breastfeeding. Additional studies on human models are necessary to further characterize the role of NTs in life-changing experiences like labor and delivery.

Cancer stem cells-driven tumor growth and immune escape: the Janus face of neurotrophins.

Cancer Stem Cells (CSCs) are self-renewing cancer cells responsible for expansion of the malignant mass in a dynamic process shaping the tumor microenvironment. CSCs may hijack the host immune surveillance resulting in typically aggressive tumors with poor prognosis.In this review, we focus on neurotrophic control of cellular substrates and molecular mechanisms involved in CSC-driven tumor growth as well as in host immune surveillance. Neurotrophins have been demonstrated to be key tumor promoting signaling platforms. Particularly, Nerve Growth Factor (NGF) and its specific receptor Tropomyosin related kinase A (TrkA) have been implicated in initiation and progression of many aggressive cancers. On the other hand, an active NGF pathway has been recently proven to be critical to oncogenic inflammation control and in promoting immune response against cancer, pinpointing possible pro-tumoral effects of NGF/TrkA-inhibitory therapy.A better understanding of the molecular mechanisms involved in the control of tumor growth/immunoediting is essential to identify new predictive and prognostic intervention and to design more effective therapies. Fine and timely modulation of CSCs-driven tumor growth and of peripheral lymph nodes activation by the immune system will possibly open the way to precision medicine in neurotrophic therapy and improve patient's prognosis in both TrkA- dependent and independent cancers.

VEGF inhibition alters neurotrophin signalling pathways and induces caspase-3 activation and autophagy in rabbit retina.

This study sought to evaluate the prospective role exerted by vascular endothelial growth factor (VEGF) in the modulation of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) signalling pathways in the rabbit retina. To reach this aim, the anti-VEGF agents aflibercept and ranibizumab were used as a pharmacological approach to evaluate the putative consequences elicited by VEGF inhibition on neurotrophin signalling. VEGF inhibition determined a marked imbalance in proneurotrophin expression, a significant reduction in TrkA and TrkB phosphorylation states and a decrease in the pan-neurotrophin receptor p75. Importantly, VEGF blockade also caused a strong increase in cleaved caspase-3, beclin-1 and lipidated LC3. The effects were more pronounced in the aflibercept group when compared with ranibizumab-treated rabbits, particularly 1 week after injection. This study demonstrates that VEGF exerts pivotal physiological roles in regulating NGF and BDNF pathways in the retina, as its inhibition by anti-VEGF agents deeply impacts neurotrophin homeostasis. These events are accompanied by a sustained induction of apoptotic and autophagic markers, suggesting that anti-VEGF-dependent impairments in neurotrophin signalling could be responsible for the activation of retinal cell death pathways.

Statins and the Brain: More than Lipid Lowering Agents?

BACKGROUND: Statins represent a class of medications widely prescribed to efficiently treat dyslipidemia. These drugs inhibit 3-ßhydroxy 3ß-methylglutaryl Coenzyme A reductase (HMGR), the rate-limiting enzyme of mevalonate (MVA) pathway. Besides cholesterol, MVA pathway leads to the production of several other compounds, which are essential in the regulation of a plethora of biological activities, including in the central nervous system. For these reasons, statins are able to induce pleiotropic actions, and acquire increased interest as potential and novel modulators in brain processes, especially during pathological conditions. OBJECTIVE: The purpose of this review is to summarize and examine the current knowledge about pharmacokinetic and pharmacodynamic properties of statins in the brain. In addition, effects of statin on brain diseases are discussed providing the most up-to-date information. METHODS: Relevant scientific information was identified from PubMed database using the following keywords: statins and brain, central nervous system, neurological diseases, neurodegeneration, brain tumors, mood, stroke. RESULTS: 315 scientific articles were selected and analyzed for the writing of this review article. Several papers highlighted that statin treatment is effective in preventing or ameliorating the symptomatology of a number of brain pathologies. However, other studies failed to demonstrate a neuroprotective effect. CONCLUSION: Even though considerable research studies suggest pivotal functional outcomes induced by statin therapy, additional investigation is required to better determine the pharmacological effectiveness of statins in the brain, and support their clinical use in the management of different neuropathologies.

Nerve Growth Factor Role on Retinal Ganglion Cell Survival and Axon Regrowth: Effects of Ocular Administration in Experimental Model of Optic Nerve Injury.

Retinal ganglion cell (RGC) degeneration occurs within 2 weeks following optic nerve crush (ONC) as a consequence of reduced retro-transport of growth factors including nerve growth factor (NGF). The hypothesis that intravitreal (ivt) and eye drop (ed) administration of recombinant human NGF (rhNGF) might counteract ONC in adult rats is explored in this study. We found that both ivt- and ed-rhNGF reduced RGC loss and stimulated axonal regrowth. Chiefly, survival and regenerative effects of rhNGF were associated with a reduction of cells co-expressing Nogo-A/p75NTR at crush site borders, which contribute to glia scar formation following nerve injury, and induce further degeneration. We also found that ocular application of rhNGF reduced p75NTR and proNGF and enhanced phosphorylation of TrkA and its intracellular signals at retina level. Nogo-R and Rock2 expression was also normalized by ed-rhNGF treatment in both ONC and contralateral retina. Our findings that ocular applied NGF reaches and exerts biological actions on posterior segment of the eye give a further insight into the neurotrophin diffusion/transport through eye structures and/or their trafficking in optic nerve. In addition, the use of a highly purified NGF form in injury condition in which proNGF/p75NTR binding is favored indicates that increased availability of mature NGF restores the balance between TrkA and p75NGF, thus resulting in RGC survival and axonal growth. In conclusion, ocular applied NGF is confirmed as a good experimental paradigm to study mechanisms of neurodegeneration and regeneration, disclose biomarkers, and time windows for efficacy treatment following cell or nerve injury.

In vivo antivascular endothelial growth factor treatment induces corneal endothelium apoptosis in rabbits through changes in p75NTR-proNGF pathway.

Intravitreal injection (IVT) of antivascular endothelial growth factor (anti-VEGF) agents is widely used for the treatment of retinal vascular diseases. Recently, the injection of anti-VEGF agents in the ocular anterior chamber has been proposed for the treatment of neovascular glaucoma and potential side effects on the corneal structures have been investigated with contrasting results. Increasing evidence has demonstrated that VEGF inhibition is associated with cellular apoptotic changes and that this effect may be mediated by alterations in nerve growth factor (NGF) pathway. In this study, we demonstrated that anterior chamber injection (IC), but not IVT injection of two different anti-VEGF agents, aflibercept and ranibizumab, affects rabbit corneal endothelium in terms of survival and apoptosis and is associated with changes in endothelial expression of NGF precursor (proNGF) and p75 neurotrophin receptor (p75NTR) receptor. We observed an increase in corneal endothelial cell incorporation of trypan blue and expression of cleaved-caspase 3 (c-Casp3), p75NTR, and RhoA after IC injection of both anti-VEGF drugs when compared with the vehicle. Our results showed that apoptosis induction by aflibercept was more pronounced when compared with that of ranibizumab. Aflibercept also mediated a significant increase in endothelial expression of proNGF when compared with the vehicle. In line with these data, IC administration of both anti-VEGF agents induced the activation of apoptotic signals in endothelial cells, including an increase in c-Casp3, decrease in Bad Ser 112 phosphorylation, and unbalance of AKT phosphorylation. These results demonstrated that administration of anti-VEGF in the anterior chamber of rabbit affects endothelial cell survival by inducing apoptosis through alteration of NGF pathway.

Ocular Nerve Growth Factor (NGF) and NGF Eye Drop Application as Paradigms to Investigate NGF Neuroprotective and Reparative Actions.

The eye is a central nervous system structure that is uniquely accessible to local treatment. Through the ocular surface, it is possible to access the retina, optic nerve, and brain. Animal models of retina degeneration or optic nerve crush could thus serve as tools to investigate whether and how factors, which are anterogradely or retrogradely transported through the optic nerve, might contribute to activate neuroprotection and eventually regeneration. Among these factors, nerve growth factor (NGF) plays a crucial role during development of the visual system, as well as during the entire life span, and in pathological conditions. The ability of NGF to exert survival and trophic actions on the retina and brain cells when applied intraocularly and topically as eye drops is critically reviewed here, together with the effects of ocular neurotrophins on neuronal pathways influencing body rhythm, cognitions, and behavioral functions. The latest data from animal models and humans are presented, and the mechanism of action of ocularly administered NGF is discussed. NGF eye drops are proposed as an experimental strategy to investigate the role and cellular targets of neurotrophins in the mechanism(s) underlying neurodegeneration/regeneration and their involvement in the regulation of neurological and behavioral dysfunctions.

Ocular Nerve Growth Factor Administration Modulates Brain-derived Neurotrophic Factor Signaling in Prefrontal Cortex of Healthy and Diabetic Rats.

AIMS: Nerve growth factor (NGF) eyedrops (ed-NGF) activate brain neurons, stimulate growth factors, including brain-derived neurotrophic factor (BDNF), and exert neuroprotection in the forebrain of streptozotocin-induced diabetic rats (STZ rats). In this study, the effects of ed-NGF on BDNF signaling in the prefrontal cortex (PFC) were explored in healthy and STZ-diabetic rats, in which cortical neuronal and axonal loss, and altered circulating BDNF associated with depressive phenotype are also described. METHODS: STZ and healthy (CTR) adult rats received ed-NGF twice a day for 2 weeks. Depressive phenotype was identified by force swimming test (FST). Proteins extracted from PFC were processed for ELISA and Western blot analyses to measure the expression of BDNF, proBDNF, and their receptors and intracellular signals. RESULTS: ed-NGF treatment modulates BDNF pathway in PFC and normalizes the STZ-induced BDNF alterations by stimulating TRK-mediated survival mechanism. A decreased latency in FST was also found in STZ rats, while no change was observed comparing CTR + NGF and STZ + NGF with CTR. CONCLUSION: The present data confirm the capacity of ed-NGF treatment to affect brain neurons and lead to brain damage recovery by activating protective and remodeling pathways triggered by BDNF. We suggest that the ed-NGF-induced changes in BDNF signaling might influence the manifestation of depressive phenotype in diabetic rats.

Time-Dependent Nerve Growth Factor Signaling Changes in the Rat Retina During Optic Nerve Crush-Induced Degeneration of Retinal Ganglion Cells.

Nerve growth factor (NGF) is suggested to be neuroprotective after nerve injury; however, retinal ganglion cells (RGC) degenerate following optic-nerve crush (ONC), even in the presence of increased levels of endogenous NGF. To further investigate this apparently paradoxical condition, a time-course study was performed to evaluate the effects of unilateral ONC on NGF expression and signaling in the adult retina. Visually evoked potential and immunofluorescence staining were used to assess axonal damage and RGC loss. The levels of NGF, proNGF, p75NTR, TrkA and GFAP and the activation of several intracellular pathways were analyzed at 1, 3, 7 and 14 days after crush (dac) by ELISA/Western Blot and PathScan intracellular signaling array. The progressive RGC loss and nerve impairment featured an early and sustained activation of apoptotic pathways; and GFAP and p75NTR enhancement. In contrast, ONC-induced reduction of TrkA, and increased proNGF were observed only at 7 and 14 dac. We propose that proNGF and p75NTR contribute to exacerbate retinal degeneration by further stimulating apoptosis during the second week after injury, and thus hamper the neuroprotective effect of the endogenous NGF. These findings might aid in identifying effective treatment windows for NGF-based strategies to counteract retinal and/or optic-nerve degeneration.