Papers by Mariagrazia Grilli
Synapse, 1997
Sabeluzole was described to have antiischemic, antiepileptic, and cognitive-enhancing properties,... more Sabeluzole was described to have antiischemic, antiepileptic, and cognitive-enhancing properties, and is currently under development for Alzheimer's disease. Recently, it was reported that repeated treatments with sabeluzole protect cultured rat hippocampal neurons against NMDA-and glutamate-induced neurotoxicity. We evaluated the possibility that sabeluzole elicits neuroprotection by acting, either directly or indirectly, on tau proteins. We found that repeated treatments during development of primary cultures of cerebellar granule cells with nanomolar concentrations of sabeluzole resulted in mature cells that were resistant to the excitotoxicity induced by glutamate. Also, sabeluzole treatment specifically prevented the glutamateinduced increase of tau expression without modifying the basal pattern of expression of tau proteins, as shown by measurement of mRNA and protein levels. In human neuroblastoma cell line SH-SY5Y, differentiated by treatment with retinoic acid, doxorubicin increased tau immunoreactivity, and later induced cell death. Both effects were prevented by sabeluzole. Our data indicate that increased tau expression is a common response to different types of cells to neurotoxic agents, and that sabeluzoleinduced neuroprotection is functionally associated with the prevention of the injurymediated increase of tau expression. Synapse 26:95-103, 1997.
Alzheimer's disease linking neurodegeneration with neurodevelopment
Functional …, 2003
An association has recently been suggested between several of the genes and proteins that play a ... more An association has recently been suggested between several of the genes and proteins that play a central role in early neuronal development, particularly in neuronal migration and axon elongation, and Alzheimer's disease (AD). This paper reviews the work of several ...
Molecular Characterization of the Neuroprotective Activity of Salicylates
Advances in Behavioral Biology, 1998
... CHARACTERIZATION OF THE NEUROPROTECTIVE ACTIVITY OF SALICYLATES M. Grilli, M. Pizzi, F. Goffi... more ... CHARACTERIZATION OF THE NEUROPROTECTIVE ACTIVITY OF SALICYLATES M. Grilli, M. Pizzi, F. Goffi, M. Benarese, GM Gerardi, M. Memo, and PF ... For instance, saly-cilic acid lacks inhibitory activity on PGHS (Amin et al., 1995); moreover, doses of drugs needed to treat ...
Proceedings of the …, 2000
A direct pathophysiological role of Familial Alzheimer's Disease (FAD)-associated Presenilin 1 (P... more A direct pathophysiological role of Familial Alzheimer's Disease (FAD)-associated Presenilin 1 (PS1) mutations in neuronal vulnerability remains a controversial matter. We evaluated the relationship between PS1 and excitotoxicity in four different experimental models of neurotoxicity by using primary neurons from (i) transgenic (tg) mice overexpressing a human FAD-linked PS1 variant (L286V mutation), (ii) tg mice overexpressing human wild-type (wt) PS1, (iii) PS1 knockout mice, and (iv) wt mice in which PS1 gene expression was knocked down by antisense treatment. We found that primary neurons overexpressing mutated PS1 showed an increased vulnerability to both excitotoxic and hypoxic-hypoglycemic damage when compared with neurons obtained from either mice overexpressing human wt PS1 or in wt mice. In addition, reduced excitotoxic damage was obtained in neurons in which PS1 expression was absent or diminished. Data obtained in in vivo experimental models of excitotoxicity partially supported the in vitro observations. Accelerated neuronal death was demonstrated in the hippocampus of mice overexpressing mutated PS1 after peripheral administration of kainic acid in comparison with wt animals. However, measurement of the infarct volume after middle cerebral artery occlusion did not show significant difference between the two animal groups. The results altogether suggest that expression of FAD-linked PS1 variants increases the vulnerability of neurons to a specific type of damage in which excitotoxicity plays a relevant role. In addition, they support the view that reduction of endogenous PS1 expression results in neuroprotection. A subset of early-onset cases of autosomal dominant familial Alzheimer's disease (FAD) is caused by mutations in three different loci: the amyloid precursor protein gene (1, 2) and the Presenilin 1 (PS1) and Presenilin 2 (PS2) genes (3, 4). Of the three loci, mutations in the PS1 gene are most frequent and associated with early onset of the disease. PS1, widely expressed throughout the central nervous system and in peripheral tissues, is a multipass membrane protein localized predominantly in the endoplasmic reticulum but also in the nuclear membrane and coated transport vesicles (5-7). More recently, it has been suggested that PS1 is constitutively expressed at the cell surface of mammalian cells (8-10). On the basis of the predicted structure, it has been proposed that PS proteins may function as signal receptors, form channels, and͞or participate in protein trafficking (3). Yet, the physiological functions of PS1 in adult life remain largely unknown. Because Alzheimer's disease (AD) is a neurodegenerative disease characterized by the death of vulnerable neurons in selective brain areas, much effort has been dedicated to find a correlation between PS1 mutant isoforms and neuronal death. Recently, Guo et al. (11) found that hippocampal neurons from PS1 mutant knock-in mice show increased sensitivity to glutamate-induced cell death. In addition, PS1 mutations have been PS1 ؉/؉ , PS1 ؉/؊ , and PS1 ؊/؊ Genotyping. Mouse tail genomic DNA was purified by using standard methods followed by PCR amplification. Primer sequences were as follows: 5Ј-AGT TGG TAG GAC CAC TTT GT-3Ј and 5Ј-AGA CAC TTC CTC TTT GCT AG-3Ј (endogenous mouse PS1) and 5Ј-AGT TGG TAG
The Journal of …, 2011
In this study, we evaluated whether a cross talk between nuclear factor κB (NF-κB) and Notch may ... more In this study, we evaluated whether a cross talk between nuclear factor κB (NF-κB) and Notch may take place and contribute to regulate cell morphology and/or neuronal network in primary cortical neurons. We found that lack of p50, either induced acutely by ...
BioMed Research International, 2014
Adult hippocampal neurogenesis is a peculiar form process of neuroplasticity that in recent years... more Adult hippocampal neurogenesis is a peculiar form process of neuroplasticity that in recent years has gained great attention for its potential implication in cognition and in emotional behavior in physiological conditions. Moreover, a vast array of experimental studies suggested that adult hippocampal neurogenesis may be altered in various neuropsychiatric disorders, including major depression, where its disregulation may contribute to cognitive impairment and/or emotional aspects associated with those diseases. An intriguing area of interest is the potential influence of drugs on adult neurogenesis. In particular, several psychoactive drugs, including antidepressants, were shown to positively modulate adult hippocampal neurogenesis. Among molecules which could regulate adult hippocampal neurogenesis the NF-κB family of transcription factors has been receiving particular attention from our and other laboratories. Herein we review recent data supporting the involvement of NF-B signaling pathways in the regulation of adult neurogenesis and in the effects of drugs that are endowed with proneurogenic and antidepressant activity. The potential implications of these findings on our current understanding of the process of adult neurogenesis in physiological and pathological conditions and on the search for novel antidepressants are also discussed.
Impaired Adult Neurogenesis Associated with Short-Term Memory Defects in NF- B p50-Deficient Mice
Journal of Neuroscience, 2008
Neurogenesis proceeds throughout adulthood in the brain of most mammalian species, but the molecu... more Neurogenesis proceeds throughout adulthood in the brain of most mammalian species, but the molecular mechanisms underlying the regulation of stem/progenitor cell proliferation, survival, maturation, and differentiation have not been completely unraveled. We have studied hippocampal neurogenesis in NF-kappaB p50-deficient mice. Here we demonstrate that in absence of p50, the net rate of neural precursor proliferation does not change, but some of the steps leading to the final neuron differentiation status are hampered, resulting in approximately 50% reduction in the number of newly born neurons in the adult mutant hippocampus. Additionally, in p50(-/-) mice, we observed a selective defect in short-term spatial memory performance without impairment of hippocampal-dependent spatial long-term memory and learning. Our results highlight the role of NF-kappaB p50 in hippocampal neurogenesis and in short-term spatial memory.
Neuropsychopharmacology, 2013
Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bio... more Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bioenergetics and as donor of acetyl groups to proteins, including NF-kB p65. In humans, exogenously administered ALC has been shown to be effective in mood disturbances, with a good tolerability profile. No current information is available on the antidepressant effect of ALC in animal models of depression and on the putative mechanism involved in such effect. Here we report that ALC is a proneurogenic molecule, whose effect on neuronal differentiation of adult hippocampal neural progenitors is independent of its neuroprotective activity. The in vitro proneurogenic effects of ALC appear to be mediated by activation of the NF-kB pathway, and in particular by p65 acetylation, and subsequent NF-kB-mediated upregulation of metabotropic glutamate receptor 2 (mGlu2) expression. When tested in vivo, chronic ALC treatment could revert depressive-like behavior caused by unpredictable chronic mild stress, a rodent model of depression with high face validity and predictivity, and its behavioral effect correlated with upregulated expression of mGlu2 receptor in hippocampi of stressed mice. Moreover, chronic, but not acute or subchronic, drug treatment significantly increased adult born neurons in hippocampi of stressed and unstressed mice. We now propose that this mechanism could be potentially involved in the antidepressant effect of ALC in humans. These results are potentially relevant from a clinical perspective, as for its high tolerability profile ALC may be ideally employed in patient subpopulations who are sensitive to the side effects associated with classical antidepressants.
Molecular Pharmacology, 2014
Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippo... more Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether tapentadol, a novel central analgesic combining m-opioid receptor (MOR) agonism with norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where the MOR component is predominant. On the contrary, at higher (micromolar) concentrations, tapentadol elicited proneurogenic and antiapoptotic effects via activation of b2 and a2 adrenergic receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing longterm use of opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared with classic opiates.
Molecular pharmacology, 2012
Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studi... more Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggest that the process is involved in cognitive and emotional functions and deregulated in various neuropsychiatric disorders, including major depression. Interestingly, several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the alpha2delta α2δ ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid; GBP] and pregabalin [S-[+]-3-isobutylGABA or (S)-3-(aminomethyl)-5-methylhexanoic acid; PGB] can produce a concentration-dependent increase in the number of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells (NPC), and, in parallel, a decrease in the number of undifferentiated precursor cells. These effects were confirmed in vivo, since a significantly increased number of adult generated neurons was observed in the hippocampal region of mice chronically treated with...
F640 DISTINCT DIFFERENCES BETWEEN TAPENTADOL AND MORPHINE IN AN IN VITRO MODEL OF ADULT NEUROGENESIS
European Journal of Pain Supplements, 2011
Behavioural Brain Research, 2005
Patients with Alzheimer's disease suffer from progressive cognitive impairments and show distinct... more Patients with Alzheimer's disease suffer from progressive cognitive impairments and show distinct post-mortem neuropathology, including -amyloid plaques. Transgenic (Tg) CRND8 mice carry a mutated human amyloid precursor protein gene and show age-related increases in -amyloid production and plaque deposition. It was previously reported that during the early stages of plaque deposition, Tg CRND8 mice demonstrated Morris maze impairments. However, it is unknown if Tg mice would be impaired at an earlier age prior to plaque deposition or more impaired at a later age with more extensive plaque deposition. In the current study, we describe Tg CRND8 age-progressing -amyloid neuropathology and cognitive abilities in greater detail.
International Journal of Developmental Neuroscience, 2000
Exposure of primary cultures of cerebellar granule cells for 15 min to micromolar concentrations ... more Exposure of primary cultures of cerebellar granule cells for 15 min to micromolar concentrations of glutamate results in cell death of both necrotic and apoptotic types. Among the intracellular events triggered by glutamate, we identi®ed two transcriptional factors: the p50 member of the NF-kB family and the tumor suppressor phosphoprotein p53. Pretreatment of the cultures with aspirin, which inhibits NF-kB activation, or with speci®c p53 antisense oligonucleotide, which inhibits p53 transcription, resulted in a complete prevention of glutamate-induced p53 induction and apoptosis. These ®ndings suggest the existence of a transcriptional program activated by glutamate receptor stimulation in which p50 and p53 play a relevant role. Then, we studied the expression of two p53 downstream genes that could participate in the glutamate-induced pro-apoptotic pathway: p21, which codes for an inhibitor of dierent cyclin dependent kinases, and MSH2, which codes for a protein involved in the recognition and repair of DNA mismatches. We found that primary cerebellar neurons expressed p21 and MSH2 at very low levels in basal conditions. However, very soon after a brief exposure of the cells to glutamate, the expression of both proteins was dramatically enhanced.
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Papers by Mariagrazia Grilli