B. Marchetti | University of Catania (original) (raw)

Papers by B. Marchetti

Research paper thumbnail of Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)

Proceedings of the National Academy of Sciences, 2004

Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging ast... more Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration ( B f )of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma mem...

Research paper thumbnail of A Wnt1 regulated Frizzled-1/β-Cateninsignaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection

Molecular Neurodegeneration, 2011

Background Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitu... more Background Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. Results In vitro experiments identi...

Research paper thumbnail of Uncovering novel actors in astrocyte-neuron crosstalk in Parkinson's disease: the Wnt/β-catenin signaling cascade as the common final pathway for neuroprotection and self-repair

European Journal of Neuroscience, 2013

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss... more Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neuronal cell bodies in the substantia nigra pars compacta and gliosis. The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are ill-defined, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD pathophysiology, playing both protective and destructive roles. Here, the contribution of reactive astrocytes and their ability to modulate DAergic neurodegeneration, neuroprotection and neurorepair in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model of PD will be discussed in the light of novel emerging evidence implicating wingless-type mouse mammary tumor virus integration site (Wnt)/b-catenin signaling as a strong candidate in MPTP-induced nigrostriatal DAergic plasticity. In this work, we highlight an intrinsic Wnt1/frizzled-1/b-catenin tone that critically contributes to the survival and protection of adult midbrain DAergic neurons, with potential implications for drug design or drug action in PD. The dynamic interplay between astrocyte-derived factors and neurogenic signals in MPTP-induced nigrostriatal DAergic neurotoxicity and repair will be summarized, together with recent findings showing a critical role of glia-neural stem/progenitor cell (NPC) interactions aimed at overcoming neurodegeneration and inducing neurorestoration. Understanding the intrinsic plasticity of nigrostriatal DAergic neurons and deciphering the signals facilitating the crosstalk between astrocytes, microglia, DAergic neurons and NPCs may have major implications for the role of stem cell technology in PD, and for identifying potential therapeutic targets to induce endogenous neurorepair.

Research paper thumbnail of 64 Adrenal steroids stimulate the growth of dimethylbenzanthracene (DMBA)- induced rat mammary tumors

Journal of Steroid Biochemistry

Aging influences the hypothalamic-pituitary-testicular axis in a complex fashion. Although the pr... more Aging influences the hypothalamic-pituitary-testicular axis in a complex fashion. Although the primary lesion is essentially at the testicular level, the delayed pituitary response to GnRH suggests the existence of discrete change in hypothalamopituitary function. We studied peak frequency of LH and T secretion in young and elderly males. Blood samples were taken every 20 minutes for 24 hrs in 20 young (<60 yrs) and 13 elderly 070 yrs) monks living together in a monastery. Mean T was significantly lower in the elderly (402+181 ng/dl) than in the young monks (535+134), while the opposite was true for LH (2.8FZ.l ng/ml and 1.7tO.3 respectively) (P<Tj.OS). Peak frequency, analysed by pulsar, of T and LH was significantly higher in 20-40 yrs old monks (n=lO) than in elderly monks (

Research paper thumbnail of Further characterization of the direct inhibitory effect of LHRH agonists at the testicular level in the rat

Journal of Steroid Biochemistry

To further clarify the relative importance of the pituitary and gonadal sites of LHRH action, int... more To further clarify the relative importance of the pituitary and gonadal sites of LHRH action, intact and hypophysectomized adult male rats were treated with hCG for 7 days, in the presence or absence of simultaneous treatment with increasing doses of the LHRH agonist [D-Ser(TBU)6des-Gly-NH2(10)]LHRH ethylamide, Buserelin (0.025, 0.25, 2.5 or 25 micrograms/rat, twice daily). Daily treatment of intact adult rats with hCG (25 IU) markedly increased ventral prostate and seminal vesicle weight, while a dose-dependent inhibition of the effect was observed following combined administration of Buserelin. In hypophysectomized rats, treatment with hCG resulted in a partial restoration of ventral prostate and seminal vesicle weight, while combined treatment with a high dose of the LHRH agonist (25 micrograms, twice daily) partially (P less than 0.05) inhibited the stimulatory effect of hCG. LH/hCG receptors were almost completely inhibited after hCG injection alone and a further decrease was observed in the presence of simultaneous LHRH agonist treatment. The hCG-induced stimulation of GH/PRL receptors was counteracted by Buserelin treatment in hypophysectomized animals. The present data demonstrate that although LHRH-induced LH release has been shown to play a major role in the loss of testicular functions induced by low doses of LHRH agonists in the rat, a direct inhibitory action of LHRH agonists can be exerted at the testicular level at high doses of the peptide.

Research paper thumbnail of Neurochemical, immunological and pharmacological assessments in a transgenic mouse model of the endocrine changes in depression

Aging Clinical and Experimental Research, 1997

Research paper thumbnail of Insulin-like Growth Factor-I Effects on ADP-Ribosylation Processes and Interactions with Glucocorticoids During Maturation and Differentiation of Astroglial Cells in Primary Culture

IGFs in the Nervous System, 1998

Nervous system function depends upon the extensive and intimate coupling between neuronal cells a... more Nervous system function depends upon the extensive and intimate coupling between neuronal cells and glial cells [1, 2]. We have recently shown [3, 4] that during differentiation in vitro, astroglial cells in primary culture release polypeptide growth factors that exert dramatic effects on the differentiation of an immortalized hypothalamic LH-RH neuronal (Gt1-1 subclone) cell line [3–6]. The growth factors (GFs) have emerged as crucial intercellular signaling agents that coordinate the developmental and adult physiological processes of both astrocytes and neurons [6–8]. Insulin-like growth factors I and II (IGF-I and IGF-II) are peptide growth factors structurally related to insulin. IGF-I, IGF-II and fibroblast growth factors (FGFs) are synthesized by developing astroglial cells and exert autocrine and paracrine mitogenic actions [6–9]. Primary astroglial cells possess IGF receptors and synthesize IGFs and IGF binding proteins [9,10]. Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), IGF-I and insulin are potent mitogens capable of inducing cell division in various cell types and in particular in cultured cells from the central nervous system (CNS) [6–8, 11–13]. The effects of bFGF on the morphology of cultured astrocytes prepared from various areas of newborn rat brain, and on their expression of glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) have also been described [14]. Furthermore, EGF acts as a neurotrophic agent preferential for dopaminergic neurons in rat embryonic mesencephalic cultures [12], and enhances the proliferation of cultured astrocytes from rat brain [7,15].

Research paper thumbnail of Control of luteinizing hormone receptor levels and activity in the anterior pituitary gland and gonads

Research paper thumbnail of Vulnerability to Parkinson's Disease: Towards an Unifying Theory of Disease Etiology

Encyclopedia of Environmental Health, 2011

Parkinson's disease (PD) is the most common neurodegenerative disorder affecting approximatel... more Parkinson's disease (PD) is the most common neurodegenerative disorder affecting approximately 1% of the population over age 65. It is characterized by the selective loss of dopamine-containing neurons in a restricted region of the midbrain called the substantia nigra pars compacta (SNpc). Several genes that cause certain forms of inherited PD ( 90%) appear to be sporadic and are likely to represent an interplay between genetic and environmental influences. More men than women develop PD; aging and menopause in women (estrogen deficiency) are the recognized risk factors. Polymorphisms in candidate genes involved in dopamine metabolism, mitochondrial function, lipoprotein metabolism, inflammation, and xenobiotic detoxification have been described. In addition, living in rural areas and pesticides exposure, head injury, and infectious diseases during childhood have also been suggested to increase risk; whereas smoking and consumption of coffee, dietary factors, exercising, social interactions, and use of certain nonsteroidal anti-inflammatory drugs reportedly reduce the incidence of PD. Neuropathological studies and animal models highlight neuroinflammation and the astroglial cell compartment as key players in these processes. The overall information points toward glia and its mediators as the final common pathway of gene×environment interactions directing toward neurodegeneration or neuroprotection and neurorepair.

Research paper thumbnail of Immortalized hypothalamic luteinizing hormone-releasing hormone (LHRH) neurons induce a functional switch in the growth factor responsiveness of astroglia: involvement of basic fibroblast growth factor

International Journal of Developmental Neuroscience, 2000

Recent evidence indicates that astroglial-derived growth factors (GFs) participate in the develop... more Recent evidence indicates that astroglial-derived growth factors (GFs) participate in the development of luteinizing hormone-releasing hormone (LHRH) neurons, but it is still unknown whether LHRH neurons may exert a reciprocal modulation of glial cell function. Using immortalized hypothalamic LHRH (GT 1-1) neurons in co-culture with glial cells, we have recently shown that basic fibroblast growth factor (bFGF) plays a prominent role in the glial-induced acquisition of the mature LHRH phenotype by GT 1-1 cells. We have resorted to this model and combined biochemical and morphological approaches to study whether the response of glial cells to a number of GFs (including bFGF, insulin-like growth factor I, IGF-I, epidermal growth factor, EGF and insulin) expressed during LHRH neuron differentiation, is modulated by co-culture with pure LHRH neurons. Pre-treatment of hypothalamic astrocytes with an inactive ('priming') dose of bFGF for 12 h powerfully increased astroglia proliferative response to IGF-I (10 ng/ml), EGF (10 g/ml) and insulin (10 mg/ml), inducing a 65-100% increase in the [ 3 H]thymidine incorporation compared to untreated cultures. When astroglial cells and developing GT 1-1 neurons were co-cultured for 5 days in vitro (DIV), the [ 3 H]thymidine incorporation was significantly higher than in astroglial cells cultured without neurons. Application of the different GFs to the co-culture for either 12 or 24 h further stimulated DNA synthesis to various extent according to the GF applied and the time of application. Localization of the proliferating cells by dual immunohistochemical staining, followed by cell counting and bromodeoxiuridine (BrdU) labeling index calculation, revealed that the incorporation of BrdU was restricted to the nuclei of LHRH-immunopositive neurons. Such changes were accompanied by extensive morphological alterations of astroglial and LHRH fiber networks, whereas neutralization of bFGF activity in GT 1-1 neuron-glial co-cultures by a bFGF-antibody, dramatically counteracted the observed effects. The functional switch of astroglia proliferative response to GFs coupled to the potent morphological and functional modifications of developing glia and pure LHRH neurons observed in vitro, support a bidirectional interaction between immortalized LHRH neurons and astroglial cells and identify bFGF as a key player in this crosstalk.

Research paper thumbnail of A potential role for catecholamines in the development and progression of carcinogen-induced mammary tumors: Hormonal control of β-adrenergic receptors and correlation with tumor growth

The Journal of Steroid Biochemistry and Molecular Biology, 1991

ABSTRACT

Research paper thumbnail of Aging-Induced Nrf2-ARE Pathway Disruption in the Subventricular Zone Drives Neurogenic Impairment in Parkinsonian Mice via PI3K-Wnt/ -Catenin Dysregulation

Journal of Neuroscience, 2013

Research paper thumbnail of Wnt/β-catenin signaling is required to rescue midbrain dopaminergic progenitors and promote neurorepair in ageing mouse model of Parkinson's disease

STEM CELLS, 2014

Wnt/β-catenin signaling is required for specification and neurogenesis of midbrain dopaminergic (... more Wnt/β-catenin signaling is required for specification and neurogenesis of midbrain dopaminergic (mDA) neurons, the pivotal neuronal population that degenerates in Parkinson’s disease (PD), and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wnt/β-catenin signaling plays a vital role in adult neurogenesis but whether it might engage DA neurogenesis/neurorepair in the affected PD brain is yet unresolved. Recently, the adult midbrain aqueduct periventricular regions (Aq-PVRs) were shown to harbor multipotent clonogenic neural stem/progenitor cells (mNPCs) with DA potential in vitro, but restrictive mechanisms in vivo are believed to limit their DA regenerative capacity. Using in vitro mNPC culture systems we herein demonstrate that aging is one most critical factor restricting mNPC neurogenic potential via dysregulation of Wnt/β-catenin signaling. Coculture paradigms between young/aged (Y/A) mNPCs and Y/A astrocytes identified glial age and a decline of glial-...

Research paper thumbnail of Neuroendocrine-immune (NEI) circuitry from neuron-glial interactions to function: Focus on gender and HPA-HPG interactions on early programming of the NEI system

Immunology and Cell Biology, 2001

Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a... more Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life. Signals generated by the hypothalamic-pituitary-gonadal axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids), and by the hypothalamic-pituitary-adrenocortical axis (glucocorticoids (GC)), are major players coordinating the development of immune system function. Conversely, products generated by immune system activation exert a powerful and long-lasting regulation on neuroendocrine axes activity. The neuroendocrine-immune system is very sensitive to preperinatal experiences, including hormonal manipulations and immune challenges, which may influence the future predisposition to several disease entities. We review our work on the ongoing mutual regulation of neuroendocrine and immune cell activities, both at a cellular and molecular level. In the central nervous system, one chief compartment is represented by the astroglial cell and its mediators. Hence, neuron-glial signalling cascades dictate major changes in response to hormonal manipulations and pro-inflammatory triggers. The interplay between LHRH, sex steroids, GC and pro-inflammatory mediators in some physiological and pathological states, together with the potential clinical implications of these findings, are summarized. The overall study highlights the plasticity of this intersystem cross-talk for pharmacological targeting with drugs acting at the neuroendocrine-immune interface.

Research paper thumbnail of Plasticity of Subventricular Zone Neuroprogenitors in MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine) Mouse Model of Parkinson's Disease Involves Cross Talk between Inflammatory and Wnt/β-Catenin Signaling Pathways: Functional Consequences for Neuroprotection and Repair

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 8, 2012

In Parkinson's disease (PD), neurogenesis is impaired in the subventricular zone (SVZ) of po... more In Parkinson's disease (PD), neurogenesis is impaired in the subventricular zone (SVZ) of postmortem human PD brains, in primate nonhuman and rodent models of PD. The vital role of Wingless-type MMTV integration site (Wnt)/β-catenin signaling in the modulation of neurogenesis, neuroprotection, and synaptic plasticity coupled to our recent findings uncovering an active role for inflammation and Wnt/β-catenin signaling in MPTP-induced loss and repair of nigrostriatal dopaminergic (DAergic) neurons prompted us to study the impact of neuroinflammation and the Wnt/β-catenin pathway in the response of SVZ neuroprogenitors (NPCs) in MPTP-treated mice. In vivo experiments, using bromodeoxyuridine and cell-specific markers, and ex vivo time course analyses documented an inverse correlation between the reduced proliferation of NPCs and the generation of new neuroblasts with the phase of maximal exacerbation of microglia reaction, whereas a shift in the microglia proinflammatory phenotype...

Research paper thumbnail of Hormonal Regulation of β-Adrenergic Receptors in the Rat Mammary Gland during the Estrous Cycle and Lactation: Role of Sex Steroids and Prolactin

Endocrinology, 1990

ABSTRACT

Research paper thumbnail of β-Adrenergic Receptors in the Rat Mammary Gland during Pregnancy and Lactation: Characterization, Distribution, and Coupling to Adenylate Cyclase

Endocrinology, 1990

ABSTRACT

Research paper thumbnail of Prolactin Inhibits Pituitary Luteinizing Hormone-Releasing Hormone Receptors in the Rat

Endocrinology, 1982

Pituitary LHRH receptors were studied in intact immature and mature female rats as well as in adu... more Pituitary LHRH receptors were studied in intact immature and mature female rats as well as in adult castrated animals of both sexes under experimental conditions leading to marked alterations of plasma PRL levels. Implantation of three anterior pituitary glands under the kidney capsule on the morning of estrus prevented the increase in pituitary LHRH receptor content measured 3 days later on the morning of expected proestrus. Pituitary implants slightly decreased pituitary LHRH receptor levels in ovariectomized adult rats while simultaneous treatment with 17β-estradiol (E2; 1 μg daily) markedly potentiated the inhibitory effect of pituitary implants and led to much higher plasma PRL concentrations. Although pituitary implants alone had no effect on plasma gonadotropin levels, they potentiated the inhibitory effect of E2 on both plasma LH and FSH on both plasma LH and FSH on both plasma LH and FSH levels. Treatment with the dopaminergic agonist 2α-bromoergocryptine (CB-154) completely reversed the inhibito...

Research paper thumbnail of Dissociated Changes of Pituitary Luteinizing Hormone-Releasing Hormone (LHRH) Receptors and Responsiveness to the Neurohormone Induced by 17β- Estradiol and LHRH in Vivo in the Rat

Endocrinology, 1981

A single injection of 17 beta-estradiol into castrated male or female rats results in an initial ... more A single injection of 17 beta-estradiol into castrated male or female rats results in an initial decrease in plasma concentrations of LH and pituitary responsiveness to LHRH, followed by a rapid return to normal or slightly elevated values. Under such experimental conditions, no acute change of binding of [125I-labeled D-Ser(TBU)6]LHRH ethylamide to anterior pituitary homogenate could be observed. Moreover, the self-priming effect of LHRH, as illustrated by a 10-fold increase in the LH response to a second injection of LHRH in the afternoon of proestrus, is accompanied by a 40% loss of pituitary LHRH receptors. During the estrous cycle, a 100% increase in pituitary LHRH receptors is already found on diestrus II, while the maximal LH responsiveness to LHRH occurs later, namely on the afternoon of proestrus. The present findings of a dissociation between changes in LHRH receptor levels and LH responsiveness to the neurohormone suggest that postreceptor events play a predominant role in the control of gonadotropin secretion by sex steroids and LHRH itself. Moreover, LHRH can cause an acute down-regulation of its own receptor in the anterior pituitary gland.

Research paper thumbnail of Ovarian Adrenergic Nerves Directly Participate in the Control of Luteinizing Hormone-Releasing Hormone and β-Adrenergic Receptors during Puberty: A Biochemical and Autoradiographic Study

Endocrinology, 1987

The rat ovary receives sympathetic innervation from the superior ovarian nerve (SON) and the plex... more The rat ovary receives sympathetic innervation from the superior ovarian nerve (SON) and the plexus nerve (OP). To examine the possibility of a direct adrenergic mechanism controlling ovarian receptor distribution during the onset of puberty, we have studied the acute (48-h) effect of unilateral nervotomy (combined section of SON and OP nerves) on ovarian LHRH and beta-adrenergic receptor concentrations and distribution using both radioreceptor assays and in vitro autoradiography. Ovarian LHRH receptor concentration increased sharply between 12 and 20 days of age. At this time receptors were mostly associated with follicles and interstitial cells, whereas at 37 days of age, when a measurable loss in the receptor concentration was observed, light and diffuse autoradiographic labeling of receptors was also found in the corpora lutea. Complete removal of adrenergic input to the gland produced a sharp decrease in LHRH-binding activity within the denervated ovary at each time interval studied, with no effect in the innervated contralateral gland. Autoradiographic data also revealed a decrease in both the number of labeled follicles and the intensity of the labeling. beta-Adrenergic receptor concentration increased progressively between days 12 and 27, reaching a peak value at 37 days of age. Labeling was very weak at 12 days of age and increased progressively at 20 and 27 days of age. At this time, receptors were mostly localized by autoradiography in the interstitial cells, while at 37 days of age corpora lutea were strongly labeled. Ovarian beta-adrenergic receptors showed a marked drop when acutely deprived of their neural tone, as illustrated by the 2- to 3-fold decrease in receptor-binding capacity within the denervated gland. The autoradiographic data also showed marked changes in beta-adrenergic receptor distribution, specially at 37 days of age. At this time, the labeling of corpora lutea was markedly decreased in denervated ovaries. The present results clearly demonstrate that complete removal of ovarian adrenergic tone produces a profound decrease in the concentrations of LHRH and beta-adrenergic receptors within the ovary, although it cannot be excluded that peptidergic factors also arriving via the SON and OP could have some influence on the regulation of these receptors. The results support the concept of a direct involvement of the central nervous system in ovarian function. They also suggest that during ovarian development a neural efferent system might be involved in the adjustment of ovarian responsiveness to stimulation by the gonadotropins via changes in receptor content and/or distribution in the different ovarian compartments.

Research paper thumbnail of Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)

Proceedings of the National Academy of Sciences, 2004

Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging ast... more Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration ( B f )of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma mem...

Research paper thumbnail of A Wnt1 regulated Frizzled-1/β-Cateninsignaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection

Molecular Neurodegeneration, 2011

Background Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitu... more Background Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. Results In vitro experiments identi...

Research paper thumbnail of Uncovering novel actors in astrocyte-neuron crosstalk in Parkinson's disease: the Wnt/β-catenin signaling cascade as the common final pathway for neuroprotection and self-repair

European Journal of Neuroscience, 2013

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss... more Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neuronal cell bodies in the substantia nigra pars compacta and gliosis. The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are ill-defined, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD pathophysiology, playing both protective and destructive roles. Here, the contribution of reactive astrocytes and their ability to modulate DAergic neurodegeneration, neuroprotection and neurorepair in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model of PD will be discussed in the light of novel emerging evidence implicating wingless-type mouse mammary tumor virus integration site (Wnt)/b-catenin signaling as a strong candidate in MPTP-induced nigrostriatal DAergic plasticity. In this work, we highlight an intrinsic Wnt1/frizzled-1/b-catenin tone that critically contributes to the survival and protection of adult midbrain DAergic neurons, with potential implications for drug design or drug action in PD. The dynamic interplay between astrocyte-derived factors and neurogenic signals in MPTP-induced nigrostriatal DAergic neurotoxicity and repair will be summarized, together with recent findings showing a critical role of glia-neural stem/progenitor cell (NPC) interactions aimed at overcoming neurodegeneration and inducing neurorestoration. Understanding the intrinsic plasticity of nigrostriatal DAergic neurons and deciphering the signals facilitating the crosstalk between astrocytes, microglia, DAergic neurons and NPCs may have major implications for the role of stem cell technology in PD, and for identifying potential therapeutic targets to induce endogenous neurorepair.

Research paper thumbnail of 64 Adrenal steroids stimulate the growth of dimethylbenzanthracene (DMBA)- induced rat mammary tumors

Journal of Steroid Biochemistry

Aging influences the hypothalamic-pituitary-testicular axis in a complex fashion. Although the pr... more Aging influences the hypothalamic-pituitary-testicular axis in a complex fashion. Although the primary lesion is essentially at the testicular level, the delayed pituitary response to GnRH suggests the existence of discrete change in hypothalamopituitary function. We studied peak frequency of LH and T secretion in young and elderly males. Blood samples were taken every 20 minutes for 24 hrs in 20 young (<60 yrs) and 13 elderly 070 yrs) monks living together in a monastery. Mean T was significantly lower in the elderly (402+181 ng/dl) than in the young monks (535+134), while the opposite was true for LH (2.8FZ.l ng/ml and 1.7tO.3 respectively) (P<Tj.OS). Peak frequency, analysed by pulsar, of T and LH was significantly higher in 20-40 yrs old monks (n=lO) than in elderly monks (

Research paper thumbnail of Further characterization of the direct inhibitory effect of LHRH agonists at the testicular level in the rat

Journal of Steroid Biochemistry

To further clarify the relative importance of the pituitary and gonadal sites of LHRH action, int... more To further clarify the relative importance of the pituitary and gonadal sites of LHRH action, intact and hypophysectomized adult male rats were treated with hCG for 7 days, in the presence or absence of simultaneous treatment with increasing doses of the LHRH agonist [D-Ser(TBU)6des-Gly-NH2(10)]LHRH ethylamide, Buserelin (0.025, 0.25, 2.5 or 25 micrograms/rat, twice daily). Daily treatment of intact adult rats with hCG (25 IU) markedly increased ventral prostate and seminal vesicle weight, while a dose-dependent inhibition of the effect was observed following combined administration of Buserelin. In hypophysectomized rats, treatment with hCG resulted in a partial restoration of ventral prostate and seminal vesicle weight, while combined treatment with a high dose of the LHRH agonist (25 micrograms, twice daily) partially (P less than 0.05) inhibited the stimulatory effect of hCG. LH/hCG receptors were almost completely inhibited after hCG injection alone and a further decrease was observed in the presence of simultaneous LHRH agonist treatment. The hCG-induced stimulation of GH/PRL receptors was counteracted by Buserelin treatment in hypophysectomized animals. The present data demonstrate that although LHRH-induced LH release has been shown to play a major role in the loss of testicular functions induced by low doses of LHRH agonists in the rat, a direct inhibitory action of LHRH agonists can be exerted at the testicular level at high doses of the peptide.

Research paper thumbnail of Neurochemical, immunological and pharmacological assessments in a transgenic mouse model of the endocrine changes in depression

Aging Clinical and Experimental Research, 1997

Research paper thumbnail of Insulin-like Growth Factor-I Effects on ADP-Ribosylation Processes and Interactions with Glucocorticoids During Maturation and Differentiation of Astroglial Cells in Primary Culture

IGFs in the Nervous System, 1998

Nervous system function depends upon the extensive and intimate coupling between neuronal cells a... more Nervous system function depends upon the extensive and intimate coupling between neuronal cells and glial cells [1, 2]. We have recently shown [3, 4] that during differentiation in vitro, astroglial cells in primary culture release polypeptide growth factors that exert dramatic effects on the differentiation of an immortalized hypothalamic LH-RH neuronal (Gt1-1 subclone) cell line [3–6]. The growth factors (GFs) have emerged as crucial intercellular signaling agents that coordinate the developmental and adult physiological processes of both astrocytes and neurons [6–8]. Insulin-like growth factors I and II (IGF-I and IGF-II) are peptide growth factors structurally related to insulin. IGF-I, IGF-II and fibroblast growth factors (FGFs) are synthesized by developing astroglial cells and exert autocrine and paracrine mitogenic actions [6–9]. Primary astroglial cells possess IGF receptors and synthesize IGFs and IGF binding proteins [9,10]. Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), IGF-I and insulin are potent mitogens capable of inducing cell division in various cell types and in particular in cultured cells from the central nervous system (CNS) [6–8, 11–13]. The effects of bFGF on the morphology of cultured astrocytes prepared from various areas of newborn rat brain, and on their expression of glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) have also been described [14]. Furthermore, EGF acts as a neurotrophic agent preferential for dopaminergic neurons in rat embryonic mesencephalic cultures [12], and enhances the proliferation of cultured astrocytes from rat brain [7,15].

Research paper thumbnail of Control of luteinizing hormone receptor levels and activity in the anterior pituitary gland and gonads

Research paper thumbnail of Vulnerability to Parkinson's Disease: Towards an Unifying Theory of Disease Etiology

Encyclopedia of Environmental Health, 2011

Parkinson's disease (PD) is the most common neurodegenerative disorder affecting approximatel... more Parkinson's disease (PD) is the most common neurodegenerative disorder affecting approximately 1% of the population over age 65. It is characterized by the selective loss of dopamine-containing neurons in a restricted region of the midbrain called the substantia nigra pars compacta (SNpc). Several genes that cause certain forms of inherited PD ( 90%) appear to be sporadic and are likely to represent an interplay between genetic and environmental influences. More men than women develop PD; aging and menopause in women (estrogen deficiency) are the recognized risk factors. Polymorphisms in candidate genes involved in dopamine metabolism, mitochondrial function, lipoprotein metabolism, inflammation, and xenobiotic detoxification have been described. In addition, living in rural areas and pesticides exposure, head injury, and infectious diseases during childhood have also been suggested to increase risk; whereas smoking and consumption of coffee, dietary factors, exercising, social interactions, and use of certain nonsteroidal anti-inflammatory drugs reportedly reduce the incidence of PD. Neuropathological studies and animal models highlight neuroinflammation and the astroglial cell compartment as key players in these processes. The overall information points toward glia and its mediators as the final common pathway of gene×environment interactions directing toward neurodegeneration or neuroprotection and neurorepair.

Research paper thumbnail of Immortalized hypothalamic luteinizing hormone-releasing hormone (LHRH) neurons induce a functional switch in the growth factor responsiveness of astroglia: involvement of basic fibroblast growth factor

International Journal of Developmental Neuroscience, 2000

Recent evidence indicates that astroglial-derived growth factors (GFs) participate in the develop... more Recent evidence indicates that astroglial-derived growth factors (GFs) participate in the development of luteinizing hormone-releasing hormone (LHRH) neurons, but it is still unknown whether LHRH neurons may exert a reciprocal modulation of glial cell function. Using immortalized hypothalamic LHRH (GT 1-1) neurons in co-culture with glial cells, we have recently shown that basic fibroblast growth factor (bFGF) plays a prominent role in the glial-induced acquisition of the mature LHRH phenotype by GT 1-1 cells. We have resorted to this model and combined biochemical and morphological approaches to study whether the response of glial cells to a number of GFs (including bFGF, insulin-like growth factor I, IGF-I, epidermal growth factor, EGF and insulin) expressed during LHRH neuron differentiation, is modulated by co-culture with pure LHRH neurons. Pre-treatment of hypothalamic astrocytes with an inactive ('priming') dose of bFGF for 12 h powerfully increased astroglia proliferative response to IGF-I (10 ng/ml), EGF (10 g/ml) and insulin (10 mg/ml), inducing a 65-100% increase in the [ 3 H]thymidine incorporation compared to untreated cultures. When astroglial cells and developing GT 1-1 neurons were co-cultured for 5 days in vitro (DIV), the [ 3 H]thymidine incorporation was significantly higher than in astroglial cells cultured without neurons. Application of the different GFs to the co-culture for either 12 or 24 h further stimulated DNA synthesis to various extent according to the GF applied and the time of application. Localization of the proliferating cells by dual immunohistochemical staining, followed by cell counting and bromodeoxiuridine (BrdU) labeling index calculation, revealed that the incorporation of BrdU was restricted to the nuclei of LHRH-immunopositive neurons. Such changes were accompanied by extensive morphological alterations of astroglial and LHRH fiber networks, whereas neutralization of bFGF activity in GT 1-1 neuron-glial co-cultures by a bFGF-antibody, dramatically counteracted the observed effects. The functional switch of astroglia proliferative response to GFs coupled to the potent morphological and functional modifications of developing glia and pure LHRH neurons observed in vitro, support a bidirectional interaction between immortalized LHRH neurons and astroglial cells and identify bFGF as a key player in this crosstalk.

Research paper thumbnail of A potential role for catecholamines in the development and progression of carcinogen-induced mammary tumors: Hormonal control of β-adrenergic receptors and correlation with tumor growth

The Journal of Steroid Biochemistry and Molecular Biology, 1991

ABSTRACT

Research paper thumbnail of Aging-Induced Nrf2-ARE Pathway Disruption in the Subventricular Zone Drives Neurogenic Impairment in Parkinsonian Mice via PI3K-Wnt/ -Catenin Dysregulation

Journal of Neuroscience, 2013

Research paper thumbnail of Wnt/β-catenin signaling is required to rescue midbrain dopaminergic progenitors and promote neurorepair in ageing mouse model of Parkinson's disease

STEM CELLS, 2014

Wnt/β-catenin signaling is required for specification and neurogenesis of midbrain dopaminergic (... more Wnt/β-catenin signaling is required for specification and neurogenesis of midbrain dopaminergic (mDA) neurons, the pivotal neuronal population that degenerates in Parkinson’s disease (PD), and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wnt/β-catenin signaling plays a vital role in adult neurogenesis but whether it might engage DA neurogenesis/neurorepair in the affected PD brain is yet unresolved. Recently, the adult midbrain aqueduct periventricular regions (Aq-PVRs) were shown to harbor multipotent clonogenic neural stem/progenitor cells (mNPCs) with DA potential in vitro, but restrictive mechanisms in vivo are believed to limit their DA regenerative capacity. Using in vitro mNPC culture systems we herein demonstrate that aging is one most critical factor restricting mNPC neurogenic potential via dysregulation of Wnt/β-catenin signaling. Coculture paradigms between young/aged (Y/A) mNPCs and Y/A astrocytes identified glial age and a decline of glial-...

Research paper thumbnail of Neuroendocrine-immune (NEI) circuitry from neuron-glial interactions to function: Focus on gender and HPA-HPG interactions on early programming of the NEI system

Immunology and Cell Biology, 2001

Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a... more Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life. Signals generated by the hypothalamic-pituitary-gonadal axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids), and by the hypothalamic-pituitary-adrenocortical axis (glucocorticoids (GC)), are major players coordinating the development of immune system function. Conversely, products generated by immune system activation exert a powerful and long-lasting regulation on neuroendocrine axes activity. The neuroendocrine-immune system is very sensitive to preperinatal experiences, including hormonal manipulations and immune challenges, which may influence the future predisposition to several disease entities. We review our work on the ongoing mutual regulation of neuroendocrine and immune cell activities, both at a cellular and molecular level. In the central nervous system, one chief compartment is represented by the astroglial cell and its mediators. Hence, neuron-glial signalling cascades dictate major changes in response to hormonal manipulations and pro-inflammatory triggers. The interplay between LHRH, sex steroids, GC and pro-inflammatory mediators in some physiological and pathological states, together with the potential clinical implications of these findings, are summarized. The overall study highlights the plasticity of this intersystem cross-talk for pharmacological targeting with drugs acting at the neuroendocrine-immune interface.

Research paper thumbnail of Plasticity of Subventricular Zone Neuroprogenitors in MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine) Mouse Model of Parkinson's Disease Involves Cross Talk between Inflammatory and Wnt/β-Catenin Signaling Pathways: Functional Consequences for Neuroprotection and Repair

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 8, 2012

In Parkinson's disease (PD), neurogenesis is impaired in the subventricular zone (SVZ) of po... more In Parkinson's disease (PD), neurogenesis is impaired in the subventricular zone (SVZ) of postmortem human PD brains, in primate nonhuman and rodent models of PD. The vital role of Wingless-type MMTV integration site (Wnt)/β-catenin signaling in the modulation of neurogenesis, neuroprotection, and synaptic plasticity coupled to our recent findings uncovering an active role for inflammation and Wnt/β-catenin signaling in MPTP-induced loss and repair of nigrostriatal dopaminergic (DAergic) neurons prompted us to study the impact of neuroinflammation and the Wnt/β-catenin pathway in the response of SVZ neuroprogenitors (NPCs) in MPTP-treated mice. In vivo experiments, using bromodeoxyuridine and cell-specific markers, and ex vivo time course analyses documented an inverse correlation between the reduced proliferation of NPCs and the generation of new neuroblasts with the phase of maximal exacerbation of microglia reaction, whereas a shift in the microglia proinflammatory phenotype...

Research paper thumbnail of Hormonal Regulation of β-Adrenergic Receptors in the Rat Mammary Gland during the Estrous Cycle and Lactation: Role of Sex Steroids and Prolactin

Endocrinology, 1990

ABSTRACT

Research paper thumbnail of β-Adrenergic Receptors in the Rat Mammary Gland during Pregnancy and Lactation: Characterization, Distribution, and Coupling to Adenylate Cyclase

Endocrinology, 1990

ABSTRACT

Research paper thumbnail of Prolactin Inhibits Pituitary Luteinizing Hormone-Releasing Hormone Receptors in the Rat

Endocrinology, 1982

Pituitary LHRH receptors were studied in intact immature and mature female rats as well as in adu... more Pituitary LHRH receptors were studied in intact immature and mature female rats as well as in adult castrated animals of both sexes under experimental conditions leading to marked alterations of plasma PRL levels. Implantation of three anterior pituitary glands under the kidney capsule on the morning of estrus prevented the increase in pituitary LHRH receptor content measured 3 days later on the morning of expected proestrus. Pituitary implants slightly decreased pituitary LHRH receptor levels in ovariectomized adult rats while simultaneous treatment with 17β-estradiol (E2; 1 μg daily) markedly potentiated the inhibitory effect of pituitary implants and led to much higher plasma PRL concentrations. Although pituitary implants alone had no effect on plasma gonadotropin levels, they potentiated the inhibitory effect of E2 on both plasma LH and FSH on both plasma LH and FSH on both plasma LH and FSH levels. Treatment with the dopaminergic agonist 2α-bromoergocryptine (CB-154) completely reversed the inhibito...

Research paper thumbnail of Dissociated Changes of Pituitary Luteinizing Hormone-Releasing Hormone (LHRH) Receptors and Responsiveness to the Neurohormone Induced by 17β- Estradiol and LHRH in Vivo in the Rat

Endocrinology, 1981

A single injection of 17 beta-estradiol into castrated male or female rats results in an initial ... more A single injection of 17 beta-estradiol into castrated male or female rats results in an initial decrease in plasma concentrations of LH and pituitary responsiveness to LHRH, followed by a rapid return to normal or slightly elevated values. Under such experimental conditions, no acute change of binding of [125I-labeled D-Ser(TBU)6]LHRH ethylamide to anterior pituitary homogenate could be observed. Moreover, the self-priming effect of LHRH, as illustrated by a 10-fold increase in the LH response to a second injection of LHRH in the afternoon of proestrus, is accompanied by a 40% loss of pituitary LHRH receptors. During the estrous cycle, a 100% increase in pituitary LHRH receptors is already found on diestrus II, while the maximal LH responsiveness to LHRH occurs later, namely on the afternoon of proestrus. The present findings of a dissociation between changes in LHRH receptor levels and LH responsiveness to the neurohormone suggest that postreceptor events play a predominant role in the control of gonadotropin secretion by sex steroids and LHRH itself. Moreover, LHRH can cause an acute down-regulation of its own receptor in the anterior pituitary gland.

Research paper thumbnail of Ovarian Adrenergic Nerves Directly Participate in the Control of Luteinizing Hormone-Releasing Hormone and β-Adrenergic Receptors during Puberty: A Biochemical and Autoradiographic Study

Endocrinology, 1987

The rat ovary receives sympathetic innervation from the superior ovarian nerve (SON) and the plex... more The rat ovary receives sympathetic innervation from the superior ovarian nerve (SON) and the plexus nerve (OP). To examine the possibility of a direct adrenergic mechanism controlling ovarian receptor distribution during the onset of puberty, we have studied the acute (48-h) effect of unilateral nervotomy (combined section of SON and OP nerves) on ovarian LHRH and beta-adrenergic receptor concentrations and distribution using both radioreceptor assays and in vitro autoradiography. Ovarian LHRH receptor concentration increased sharply between 12 and 20 days of age. At this time receptors were mostly associated with follicles and interstitial cells, whereas at 37 days of age, when a measurable loss in the receptor concentration was observed, light and diffuse autoradiographic labeling of receptors was also found in the corpora lutea. Complete removal of adrenergic input to the gland produced a sharp decrease in LHRH-binding activity within the denervated ovary at each time interval studied, with no effect in the innervated contralateral gland. Autoradiographic data also revealed a decrease in both the number of labeled follicles and the intensity of the labeling. beta-Adrenergic receptor concentration increased progressively between days 12 and 27, reaching a peak value at 37 days of age. Labeling was very weak at 12 days of age and increased progressively at 20 and 27 days of age. At this time, receptors were mostly localized by autoradiography in the interstitial cells, while at 37 days of age corpora lutea were strongly labeled. Ovarian beta-adrenergic receptors showed a marked drop when acutely deprived of their neural tone, as illustrated by the 2- to 3-fold decrease in receptor-binding capacity within the denervated gland. The autoradiographic data also showed marked changes in beta-adrenergic receptor distribution, specially at 37 days of age. At this time, the labeling of corpora lutea was markedly decreased in denervated ovaries. The present results clearly demonstrate that complete removal of ovarian adrenergic tone produces a profound decrease in the concentrations of LHRH and beta-adrenergic receptors within the ovary, although it cannot be excluded that peptidergic factors also arriving via the SON and OP could have some influence on the regulation of these receptors. The results support the concept of a direct involvement of the central nervous system in ovarian function. They also suggest that during ovarian development a neural efferent system might be involved in the adjustment of ovarian responsiveness to stimulation by the gonadotropins via changes in receptor content and/or distribution in the different ovarian compartments.