Sara De Nicolò

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.

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.

Vascular and neuronal protection induced by the ocular administration of nerve growth factor in diabetic-induced rat encephalopathy.

Based on our previous findings on the efficacy of ocular applied nerve growth factor as eye drops (oNGF) to act in brain and counteract neuronal damage, we hypothesized that oNGF treatment might revert neuronal atrophy occurring in diabetic brain also by controlling neurotrophin system changes. The major NGF brain target areas, such as the septum and the hippocampus, were used as an experimental paradigma to test this hypothesis.

Ocular nerve growth factor administration counteracts the impairment of neural precursor cell viability and differentiation in the brain subventricular area of rats with streptozotocin-induced diabetes.

The ocular administration of nerve growth factor (NGF) as eye drops (oNGF) has been shown to exert protective effects in forebrain‐injured animal models, including adult diabetes induced by a single injection of streptozotocin (STZ) (60 mg/kg body weight). This type 1 diabetes model was used in this study to investigate whether oNGF might extend its actions on neuronal precursors localised in the subventricular zone (SVZ). NGF or saline was administrated as eye drops twice daily for 2 weeks in rats with STZ‐induced diabetes and healthy control rats. The expression of mature and precursor NGF and the NGF receptors, tropomyosin‐related kinase A and neurotrophin receptor p75, and the levels of DNA fragmentation were analysed by ELISA and western blotting. Incorporation of bromodeoxyuridine was used to trace newly formed cells. Nestin, polysialylated neuronal cell adhesion molecule (PSA‐NCAM), doublecortin (DCX) and glial fibrillary acidic protein antibodies were used to identify the SVZ cells by confocal microscopy. It was found that oNGF counteracts the STZ‐induced cell death and the alteration of mature/pro‐NGF expression in the SVZ. It also affects the survival and differentiation of SVZ progenitors. In particular, oNGF counteracts the reduction in the number of cells expressing PSA‐NCAM/DCX (neuroblast type A cells) and the related reductions in the number and distribution of nestin/DCX‐positive cells (C‐type cells), or glia‐committed cells (type B cells), observed in the SVZ of diabetic rats. These findings show that oNGF treatment counteracts the effect of type 1 diabetes on neuronal precursors in the SVZ, and further support the neuroprotective and reparative role of oNGF in the brain.

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.

Ocular nerve growth factor administration (oNGF) affects disease severity and inflammatory response in the brain of rats with experimental allergic encephalitis (EAE).

The rat acute experimental autoimmune encephalomyelitis (EAE) model was used to investigate the effects of ocularly administered nerve growth factor (oNGF) on disease development and brain inflammation. It was found that oNGF affects clinical scores. However, EAE rats receiving oNGF treatment showed reduced expression of pro-inflammatory cytokines and chemokines in the cerebellum and the hippocampus, but not in the frontal cortex. These data confirm the ability of oNGF to counteract the effects of EAE in the brain and suggest a role for oNGF in the regulation of local inflammatory responses observed in the acute phase of EAE.

Serum BDNF and NGF Modulation by Olive Polyphenols in Alcoholics duringWithdrawal

Many studies have suggested possible relationships between the neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) and alcohol addiction. Previous reports demonstrated severe changes in these neurotrophins in the serum of alcohol dependent patients and during withdrawal. Alcohol dependence syndromes during consumption and/or withdrawal are also characterized by elevated oxidative stress. Polyphenols, including olive polyphenols, are natural compounds known to possess marked antioxidant properties. Thus, this study was carried out in order to verify the effects of a blend of olive polyphenols supplementation containing mostly hydroxytyrosol (50 mg/day for 15 consecutive days) in alcoholic men during withdrawal on serum BDNF and NGF. As controls a group of alcohol dependent patients received sucrose tablets as placebo. BDNF and NGF were measured by ELISA on day 1, 3, 7 and 15 of the detoxification period. Some parameters of oxidative stress were analyzed too as free oxygen radicals defense (FORD) and free oxygen radicals test (FORT). No differences in oxidative status due to polyphenols were found. However, withdrawal elicited a mild increase in BDNF over two weeks that was counteracted on day 3 by polyphenols. As for NGF no effects of polyphenols supplementation were discovered to antagonize the expected NGF serum elevation during withdrawal. In conclusion the present data may indicate that monitoring serum BDNF and/or NGF in alcoholics undergoing detoxification could contribute to characterize alcohol dependence profiles to improve recovery processes throughout also antioxidant compounds.

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.

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

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.

Aberrant Behavioral and Neurobiologic Profiles in Rodents Exposed to Ethanol or Red Wine Early in Development

Alcohol intake by women before planning a pregnancy, during pregnancy, and/or during lactation induces brain, behavioral, and physical abnormalities in the fetus, which are known as fetal alcohol spectrum disorders. Thanks to the availability of animal models, some cellular and biochemical processes affecting offspring exposed to ethanol during early development have been extensively investigated. Ethanol effects may be mitigated or increased if offspring also are exposed to either positive or adverse conditions during early life. These environmental conditions may have an impact on neuronal and behavioral development and may increase the risk of developing neuropsychiatric symptoms. Indeed, brain development largely is modifiable by experiences, and neuroplasticity is particularly evident during early phases of life. Molecular mediators for brain development and synaptic plasticity are neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor. Early ethanol exposure not only affects the fetal brain directly, but it also leads to long-lasting consequences that emerge during adulthood and aging. Although the mechanisms responsible for these abnormalities in the fetus are unclear, it is hypothesized that ethanol might damage the central nervous system through oxidative stress processes by increasing free-radical production and decreasing cellular antioxidant ability. Ethanol’s effects on animal models have been investigated in detail; however, only few studies have investigated the consequences of early wine consumption. Wine contains several concentrations of ethanol and is consumed largely by Mediterranean populations. We recently compared the consequences of early exposure to ethanol or red wine (at the same ethanol concentration) administered during different stages of development in animal models. Our studies show a series of behavioral and neurologic abnormalities in juvenile, adult, and aged offspring of mice exposed to ethanol. A much smaller number of changes (if any) were evidenced as a consequence of early exposure to red wine. Antioxidant compounds measurable in red wine may have mitigated the toxicity associated with ethanol in the fetus. These “protective” mechanisms in mice pre- and postnatally exposed to red wine, compared with the ethanol group, remain unknown. As a whole, our data should not be interpreted as encouraging women to consume red wine before or during pregnancy and/or lactation. Indeed, in these cases, alcohol intake absolutely must be avoided.