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Jean Mariani

Publications and source records attributed to Jean Mariani.

At least 19 recordsLinked to original sources
PubMed2006

Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender.

Hypoxia-ischaemia in the developing brain results in brain injury with prominent features of apoptosis. In the present study, a third generation dipeptidyl broad-spectrum caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh), was tested in a model of unilateral focal ischaemia with reperfusion in 7-day-old rats. Q-VD-OPh (1 mg/kg, i.p.) reduced cell death, resulting in significant neuroprotection at 48 h of recovery (infarct volume of 12.6 +/- 2.8 vs. 24.3 +/- 2.2%, p = 0.006). The neuroprotective effects observed at 48 h post-ischaemia hold up at 21 days of survival time and attenuate neurological dysfunction. Analysis by gender revealed that females were strongly protected (6.7 +/- 3.3%, p = 0.006), in contrast to males in which there was no significant effect, when Q-VD-OPh was given after clip removal on the left common carotid artery. Immunoblot analysis demonstrated that Q-VD-OPh inhibits caspase 3 cleavage into its p17 active form and caspase 1 up-regulation and cleavage in vivo. Following ischaemia in P7 rats, males and females displayed different time course and pattern of cytochrome c release and active p17 caspase 3 during the first 24 h of recovery. In contrast, no significant difference was observed for caspase 1 expression between genders. These results indicate that ischaemia activates caspases shortly after reperfusion and that the sex of the animal may strongly influences apoptotic pathways in the pathogenesis of neonatal brain injury. The specificity, effectiveness, and reduced toxicity of Q-VD-OPh may determine the potential use of peptide-derived irreversible caspase inhibitors as promising therapeutics.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Identification of a biphasic signaling pathway involved in ischemic resistance of the hippocampal dentate gyrus.

Dentate gyrus is usually assumed to be resistant to ischemia. However, the mechanisms underlying this functional plasticity are not fully understood. Herein, we aimed at identifying a neuroprotective mechanism in the dentate gyrus of the adult rat after global ischemia. Cyclic AMP response element (CRE)-binding protein (CREB), brain-derived neurotrophic factor (BDNF) and calcium/calmodulin-dependent protein kinase IV (CaMKIV) are known to be mediators of neuronal survival and plasticity. Involvement of CaMKIV, BDNF and CREB in ischemic resistance was therefore examined using intracerebroventricular injections of pharmacological agents such as inhibitors, antibodies and consensus oligonucleotides followed by immunohistochemical and Western blot analysis. We provide evidence that ischemia triggers activation of a biphasic pathway during the resistance period of dentate neurons: (1) CaMKIV mediates the early phosphorylation of CREB which drives a prominent synthesis of BDNF; (2) this BDNF synthesis, in turn, induces a second peak of CREB phosphorylation which is required for the maintenance of BDNF synthesis. In addition, we show that: (1) impairment of these transduction signals by the pharmacological agents causes tissular damages and apoptotic deaths in the post-ischemic dentate gyrus; (2) some similar disturbances also occur beyond the resistance period in the dentate gyrus of untreated ischemic rats; (3) these disturbing effects are mainly observed in the suprapyramidal dentate subfield. Collectively, the present results suggest that activation of the CaMKIV/CREB/BDNF pathway plays principally an early protective role in the suprapyramidal subfield of the dentate gyrus.

Animals↗
PubMed2006

Survival of interneurons and parallel fiber synapses in a cerebellar cortex deprived of Purkinje cells: studies in the double mutant mouse Grid2Lc/+;Bax(-/-).

The Lurcher mutation in the Grid2 gene causes the cell autonomous death of virtually all cerebellar Purkinje cells and the target-related death of 90% of the granule cells and 60-75% of the olivary neurons. Inactivation of Bax, a pro-apoptotic gene of the Bcl-2 family, in heterozygous Lurcher mutants (Grid2Lc/+) rescues approximately 60% of the granule cells, but does not rescue Purkinje or olivary neurons. Given the larger size of the cerebellar molecular layer in Grid2Lc/+;Bax(-/-) double mutants compared to Grid2Lc/+ mutants, we analyzed the survival of the stellate and basket interneurons as well as the synaptic connectivity of parallel fibers originating from the surviving granule cells in the absence of their Purkinje cell targets in the Grid2Lc/+;Bax(-/-) cerebellum. Quantification showed a significantly higher density of interneurons ( approximately 60%) in the molecular layer of the Grid2Lc/+;Bax(-/-) mice compared to Grid2Lc/+, suggesting that interneurons are subject to a BAX-dependent target-related death in the Lurcher mutants. Furthermore, electron microscopy showed the normal ultrastructural aspect of a number of parallel fibers in the molecular layer of the Grid2Lc/+; Bax(-/-) double mutant mice and preserved their numerous synaptic contacts on interneurons, suggesting that interneurons could play a trophic role for axon terminals of surviving granule cells. Finally, parallel fibers varicosities in the double mutant established "pseudo-synapses" on glia as well as displayed autophagic profiles, suggesting that the connections established by the parallel fibers in the absence of their Purkinje cell targets were subject to a high turnover involving autophagy.

Animals↗
PubMed2006

Glial activation in white matter following ischemia in the neonatal P7 rat brain.

This study examines cell death and proliferation in the white matter after neonatal stroke. In postnatal day 7 injured rat, there was a marked reduction in myelin basic protein (MBP) immunostaining mainly corresponding to numerous pyknotic immature oligodendrocytes and TUNEL-positive astrocytes in the ipsilateral external capsule. In contrast, a substantial restoration of MBP, as indicated by the MBP ratio of left-to-right, occurred in the cingulum at 48 (1.27 +/- 0.12) and 72 (1.30 +/- 0.18, P < 0.05) h of recovery as compared to age-matched controls (1.03 +/- 0.14). Ki-67 immunostaining revealed a first peak of newly generated cells in the dorsolateral hippocampal subventricular zone and cingulum at 72 h after reperfusion. Double immunofluorescence revealed that most of the Ki-67-positive cells were astrocytes at 48 h and NG2 pre-oligodendrocytes at 72 h of recovery. Microglia infiltration occurs over several days in the cingulum, and a huge quantity of macrophages reached the subcortical white matter where they engulfed immature oligodendrocytes. The overall results suggest that the persistent activation of microglia involves a chronic component of immunoinflammation, which overwhelms repair processes and contributes to cystic growth in the developing brain.

Animals↗
PubMed2006

Impaired sequential egocentric and allocentric memories in forebrain-specific-NMDA receptor knock-out mice during a new task dissociating strategies of navigation.

The hippocampus is considered to play a role in allocentric but not in egocentric spatial learning. How does this view fit with the emerging evidence that the hippocampus and possibly related cortical areas are necessary for episodic-like memory, i.e., in all situations in which events need to be spatially or sequentially organized? Are NMDA receptor-dependent mechanisms crucial for the acquisition of spatiotemporal relationships? To address this issue, we used knock-out (KO) mice lacking hippocampal CA1 NMDA receptors and presenting a reduction of these receptors in the deep cortical layers (NR1-KO mice). A new task (the starmaze) was designed, allowing us to distinguish allocentric and sequential-egocentric memories. NR1-KO mice were impaired in acquiring both types of memory. Our findings suggest that memories composed of multiple spatiotemporal events require intact NMDA receptors-dependent mechanisms in CA1 and possibly in the deep cortical layers.

Animals↗
PubMed2006

Retinoid-related orphan receptor alpha controls the early steps of Purkinje cell dendritic differentiation.

Dendritic differentiation involves both regressive and growth events. The mechanisms controlling the regressive events are poorly understood. This study is aimed at determining the role of the nuclear receptor retinoid-related orphan receptor alpha (RORalpha) in Purkinje cell (PC) dendritic differentiation in organotypic cultures. As observed in vivo, in these cultures, fusiform PCs with embryonic bipolar shape undergo regression before the outgrowth of the ultimate dendritic tree. We show that lentiviral-mediated hRORalpha1 overexpression in fusiform PCs leads to a cell-autonomous accelerated progression of dendritic differentiation. In addition, RORalpha is necessary for the PC regressive events: whereas staggerer RORalpha-deficient PCs remain in the embryonic fusiform stage, replacement of hRORalpha1 restores normal dendritogenesis. These results demonstrate that RORalpha expression in fusiform PCs is crucial for the dendritic regression and progression of the following step of extension of dendritic processes. However, it does not seem to participate to the last stage of dendritic growth. This study identifies RORalpha as a nuclear receptor crucial for the control of dendritic remodeling during development.

Animals↗
PubMed2006

The Lurcher mouse: fresh insights from an old mutant.

The Lurcher mouse was first discovered in 1954 as a spontaneously occurring autosomal dominant mutation that caused the degeneration of virtually all cerebellar Purkinje cells and most olivary neurons and granule cells. More recent molecular studies revealed that Lurcher is a gain of function mutation in the delta2 glutamate receptor (GluRdelta2) that converts an alanine to threonine in the highly conserved third hydrophobic segment of GluRdelta2. The mutation converts the receptor into a constitutively leaky cation channel. The GluRdelta2 receptor is predominantly expressed in cerebellar Purkinje cells and in the heterozygous Lurcher mutant (+/Lc). Purkinje cells die due to the mutation in the GluRdelta2 receptor, while olivary neurons and granule cells degenerate due to the loss of their Purkinje cell targets. The purpose of the review is to provide highlights from 5 decades of research on the Lurcher mutant that have provided insights into the developmental mechanisms that regulate cell number during development, cerebellar pattern formation, cerebellar physiology, and the role of the cerebellum in CNS function.

Animals↗
PubMed2006

Enhanced endocrine response to novel environment stress and lack of corticosterone circadian rhythm in staggerer (Rora sg/sg) mutant mice.

The staggerer (Rora sg/sg) mutation is a deletion in the retinoid-related orphan receptor (RORalpha) gene that prevents translation of the ligand-binding domain (LBD), leading to the loss of RORalpha activity. RORalpha is a transcription factor that belongs to the nuclear receptor superfamily. In the brain, RORalpha is expressed in specific areas, including the cerebellum and suprachiasmatic nucleus (SCN). The homozygous Rora sg/sg mutant mouse, of which the most obvious phenotype is ataxia associated with cerebellar degeneration, also overproduces inflammatory cytokines. Here we compared the response to novelty stress of staggerer and wild-type mice as well as their diurnal cycles of adrenocorticotropic hormone and corticosterone secretion. We show that the staggerer mouse displays an enhanced endocrine response to novelty stress, which is not due to the enhanced production of interleukin-1 (IL-1), insofar as it is not blocked by pretreatment with IL-1ra and lacks the diurnal shift in corticosterone nonstressed levels; this last feature might be related to the expression of RORalpha in the SCN, a structure that maintains the circadian clock and plays a role in timing rhythmic physiology and behavior.

Animals↗
PubMed2006

RORalpha, a pivotal nuclear receptor for Purkinje neuron survival and differentiation: from development to ageing.

RORalpha (Retinoid-related Orphan Receptor) is a transcription factor belonging to the superfamily of nuclear receptors. The spontaneous staggerer (sg) mutation, which consists of a deletion in the Rora gene, has been shown to cause the loss of function of the RORalpha protein. The total loss of RORalpha expression leads to cerebellar developmental defects, particularly to a dramatic decreased survival of Purkinje cells and an early block in the differentiation process. This review focuses on recent studies which position RORalpha as a pivotal factor controlling Purkinje cell survival and differentiation, from development to ageing.

Animals↗
PubMed2006

Human retinoic acid receptor-related orphan receptor alpha1 overexpression protects neurones against oxidative stress-induced apoptosis.

Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a transcription factor belonging to the superfamily of nuclear receptors. Disruption of the Rora gene in the mouse results in a defect in the development of Purkinje cells leading to a cerebellar atrophy, which suggests a neuroprotective role for RORalpha. To test this hypothesis, the survival rate of lentiviral-mediated human RORalpha1-overexpressing neurones has been evaluated in response to different stressors disturbing the redox homeostasis, such as beta-amyloid peptide, c(2)-ceramide and H(2)O(2). We show that overexpression of human RORalpha1 provides neuroprotection by increasing the expression of the antioxidant proteins glutathione peroxidase 1 and peroxiredoxin 6, leading to a reduction in the accumulation of stress-induced reactive oxygen species. We further demonstrate that the neuroprotective effect of RORalpha is predominantly mediated by glutathione peroxidase 1 and peroxiredoxin 6. These results suggest a new role for RORalpha in the control of the neuronal oxidative stress and thus represents a new transcription factor of interest in the regulation of reactive oxygen species-induced neurodegenerative processes during ageing.

Aging↗
PubMed2005

IGF-I protects cortical neurons against ceramide-induced apoptosis via activation of the PI-3K/Akt and ERK pathways; is this protection independent of CREB and Bcl-2?

Current understanding of IGF-I-mediated neuroprotection implies the activation of phosphatidylinositol-3-kinase (PI-3K), which leads to the activation of Akt/Protein Kinase B. In non-neuronal cells, Akt phosphorylates and activates the transcription factor CREB, implicated in the transcription of the anti-apoptotic bcl-2 gene. This paper further analyses the anti-apoptotic IGF-I action in neurons. We show that IGF-I protects cortical neurons against ceramide-induced apoptosis. Ceramide decreases Akt phosphorylation during apoptotic process whereas a simultaneous treatment with IGF-I increases Akt phosphorylation. Analysis of the signal transduction pathways revealed that IGF-I induces CREB phosphorylation via PI-3K and ERK, whereas simultaneous ceramide and IGF-I treatment decreases CREB phosphorylation. Although an overexpression of Bcl-2 protects cortical neurons against ceramide-induced apoptosis, our data indicate that the Bcl-2 protein level is not modulated during IGF-I, ceramide and/or LY294002 treatment. In consequence, we demonstrated that IGF protects neurons against ceramide-induced apoptosis and that IGF-I protection involves the PI-3K/Akt and ERK pathways; this protection may be independent of CREB and Bcl-2.

Animals↗
PubMed2005

Developmental modifications of olivocerebellar topography: the granuloprival cerebellum reveals multiple routes from the inferior olive.

Correct function of neural circuits depends on highly organized neuronal connections, refined from less precise projections through synaptic elimination, collateral regression, or neuronal death. We examined regressive phenomena that define olivocerebellar topography during maturation from Purkinje cell polyinnervation to monoinnervation. We used bilateral retrograde tracing to determine the source of olivocerebellar afferents to posterior vermis lobules VII-VIII in a model of retained immature Purkinje cell polyinnervation, the granuloprival cerebellum. In controls, labelled neurons were found only in the contralateral inferior olive (ION) clustered in a small ventromedial locus that is congruent with known olivocerebellar topography. In granuloprival animals, olivary labelling appeared more dispersed and was present in homologous ipsilateral regions. Double-labelled neurons were never seen. Retrograde tracing following unilateral olivocerebellar transection in adult granuloprival rats revealed: 1) the origin of the normal (remaining) path projecting through the contralateral inferior peduncle was more localized than in irradiated nonpedunculotomized rats, 2) a small double-crossed path, and 3) a projection that ascends the peduncle ipsilateral to the ION of origin, part of which crosses the midline within the cerebellum. Electrophysiological and immunohistochemical assessment in the neonatal cerebellum revealed that transcommissural paths are not present during development but sprout within the irradiated cerebellum. Therefore, the olivocerebellar projection in the granuloprival rat, as a model of the immature path, shows parasagittal organization similar to that of controls in its normally crossed path but possesses additional abnormal projections. Thus, maturation of olivocerebellar topography involves removal of whole developmental paths to define laterality plus synapse elimination within largely predefined parasagittal zones.

Animals↗
PubMed2005

Afferent-target interactions during olivocerebellar development: transcommissural reinnervation indicates interdependence of Purkinje cell maturation and climbing fibre synapse elimination.

We have used a model of postlesional reinnervation to observe the interactions between synaptic partners during neosynaptogenesis to determine how the developmental states of the pre- and postsynaptic cells influence circuit maturation. After unilateral transection of the neonatal rat olivocerebellar pathway (pedunculotomy), axons from the remaining ipsilateral inferior olive grow into the denervated hemicerebellum and develop climbing fibre (CF) terminal arbors on Purkinje cells (PCs) at a later stage of development than normal. However, the significance of delayed CF-PC interactions on subsequent circuit maturation remains poorly defined. To examine this question, we recorded CF-induced currents in PCs and analysed PC morphology during the first two postnatal weeks in control animals and following left unilateral inferior cerebellar pedunculotomy on postnatal day (P)3. Our results show that transcommissural olivary axons multiply-reinnervate PCs in the denervated hemisphere over 4 days following pedunculotomy. Each PC received fewer CFs than did age-matched controls and the maximal multi-reinnervation was reached on P7, 2 days later than in controls. Consequently, the onset of CF synapse elimination in reinnervated PCs was delayed, but then proceeded in parallel with controls so that all PCs were monoinnervated by P15. Furthermore, reinnervated PCs had delayed dendritic maturation and subsequent dendritic abnormalities consistent with the role of CF innervation in PC dendritic growth. Thus, within the olivocerebellar system, our data suggest that target neurons depend upon sufficient afferent investment arriving at the correct time for their normal development, and maturation of the target neuron regulates afferent selection and therefore circuit maturation.

Aging↗
PubMed2004

Cerebellar Purkinje cell loss in aging Hu-Bcl-2 transgenic mice.

The number of cerebellar Purkinje cells is increased by over 40% in young transgenic mice that overexpress a human Bcl-2 transgene (Hu-Bcl-2). To determine whether the Bcl-2-mediated rescue of Purkinje cells persists through life, the numbers of Purkinje cells were estimated in 6-, 12-, 18-, and 24-month-old Hu-Bcl-2 transgenic mice and age-matched controls. In addition, the expression of four markers for Purkinje cell differentiation, calbindin (CaBP), the 67-kDa isoform of glutamic acid decarboxylase (GAD67), gamma-aminobutyric acid transaminase (GABA-T), and the NMDA-R1 receptor subtype (NMDA-NR1) was analyzed in 6-month-old Hu-Bcl-2 transgenics and controls to determine whether overexpression of Bcl-2 and rescue from naturally occurring cell death affects the normal differentiation of Purkinje cells. The estimates of Purkinje cell numbers showed that the number of Purkinje cells in the Hu-Bcl-2 transgenics declines after 6 months to approach wild-type values by 18 months. Although the exogenous human BCL-2 is still expressed in Purkinje cells at 24 months, the expression levels of human BCL-2 appear to decline significantly after 6 months, suggesting that survival of the supernumary Purkinje cells depends on the sustained overexpression of Bcl-2. All the Purkinje cells in the Hu-Bcl-2 transgenic mice appeared to express normal levels of the differentiation markers analyzed so there was no evidence for a class of Purkinje cells that do not differentiate normally when rescued from naturally occurring cell death.

4-Aminobutyrate Transaminase↗
PubMed2004

The "CholesteROR" protective pathway in the vascular system.

Retinoic acid receptor-related Orphan Receptor alpha (RORalpha) is a member of the nuclear hormone receptor superfamily. RORalpha has long been considered as a constitutive activator of transcription in the absence of exogenous ligand; however, cholesterol has recently been identified as a natural ligand of RORalpha. The spontaneous staggerer (sg/sg) mutation is a deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of RORalpha activity. The homozygous Rora(sg/sg) mutant mouse, of which the most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes, including several vascular ones; in particular, dysfunction of smooth muscle cells and enhanced susceptibility to atherosclerosis. Moreover, RORalpha appears to participate in the regulation of plasma cholesterol levels, and has been shown to positively regulate apolipoprotein (apo)A-I and apoC-III gene expression. Yet its activity is regulated by cholesterol itself, making RORalpha an intracellular cholesterol target.

Animals↗
PubMed2004

Caspase inhibition after neonatal ischemia in the rat brain.

Caspase-3 has been identified as a key protease in the execution of apoptosis and appears to be an important downstream event after hypoxia-ischemia in the immature brain. The efficacy of a pan-caspase inhibitor, boc-aspartyl-(Ome)-fluoromethyl-ketone (BAF), was tested in a model of unilateral focal ischemia with reperfusion in 7-day-old rats. The BAF inhibitor was given intraperitoneally 5 minutes before reperfusion via the carotid artery. This procedure reduced the activity of caspase-3 by 79% but did not induce a significant reduction in infarct volume (23.8 +/- 7.5% versus 30.1 +/- 6.4%). Animals were distributed in two populations. One population exhibited an infarct, whereas the other appeared to be fully protected. BAF-treated animals exhibiting an infarct mostly displayed necrotic cell death, whereas apoptotic nuclei were observed in untreated or vehicle-treated animals. Repeated dose of BAF (5 minutes before and 9 hours after reperfusion) did not also provide benefit after neonatal ischemia, although a general trend to reduce lesion was observed (20.5 +/- 3.7% versus 34.4 +/- 5.9%). These findings raise critical questions about the use of peptide ketone apoptotic inhibitors in improving histopathologic outcomes after neonatal stroke.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Activation of mitogen-activated protein kinase pathways during the death of PC12 cells is dependent on the state of differentiation.

PC12 cells that are differentiated with NGF and cAMP become totally dependent on these factors for their survival, unlike those that are differentiated with NGF alone. We have asked whether the MAP Kinases, ERKs, JNKs and p38s play a role in the cell death induced by withdrawal of trophic factors on NGF- and NGF/cAMP-differentiated PC12 cells. By Western-blot analyses with antibodies directed against the activated forms of these kinases, we show that when the trophic factors were withdrawn, ERK phosphorylation was reduced to very low levels within 1 h in both cases. Changes in the other enzymes were observed only in the NGF/cAMP-differentiated cells, in which the JNK phosphorylation increased about 160% by 6 h and that of p38 increased linearly to at least 18-fold throughout the cell death process. The increases in p38 and JNK phosphorylation were implicated in the death of the cells, since the p38 inhibitor PD169316 and the JNK inhibitor SP600125 were protective. These results demonstrate that the state of differentiation of PC12 cells, a model for the differentiation of sympathetic neurons, determines their vulnerability to cell death by modifying the state of phosphorylation and the regulation of specific kinases implicated in signal transduction pathways that are responsible for the survival or the death of these cells.

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