Dima Obari - Academia.edu (original) (raw)

Papers by Dima Obari

Parkinson's disease (PD) is the most common neurodegenerative movement disorder (Schapira, 2009).... more Parkinson's disease (PD) is the most common neurodegenerative movement disorder (Schapira, 2009). It is mainly characterized by the progressive loss of dopaminergic (DA) neurons in the substantianigra pars compacta (SNpc) in the midbrain, which translates into typical motor symptoms collectively known as Parkinsonism (Gelb et al., 1999).Just as in most chronic and acute neurodegenerative conditions, the pathological features in PD are accompanied by inflammation and microglia activation. Microglia function as the brain's immune cells and thus are essential to the proper functioning of the central nervous system (CNS). However the activation of microglia, when chronic, is considered neurotoxic and can lead to neuronal dysfunction and death (McGeer et al., 1988).For long it has been questioned whether microglial activation in PD is a cause or consequence of the PD pathology, and particularly of the loss of dopaminergic neurons in the SNpc.In this review, we discuss the role of microglia in the pathological features characteristic of PD. We propose that microglia constitute a secondary causal mechanism in PD and act through a vicious cycle of inflammation. Mounting epidemiological and clinical evidence indeed suggests that chronic microglial activation occurs early in the disease and contributes to the demise of dopaminergic neuron. Furthermore, neurotoxin animal models have helped elucidate several molecular mechanisms thought to regulate this inflammation. If microglia do in fact contribute to the disease pathology, then understanding these mechanisms can be valuable for therapeutic treatments in PD.

INTRODUCTION: The orphan nuclear receptor Nr5a2 is expressed in granulosa cells and is essential ... more INTRODUCTION: The orphan nuclear receptor Nr5a2 is expressed in granulosa cells and is essential for fertility. We hypothesized that Nr5a2 is important for granulosa cell proliferation. METHODS: We generated granulosa-specific knockout mice (Nr5a2f/fAmhr2Cre/+; cKO) with Nr5a2 depletion from preantral follicles forward. Immature cKO and control mice were injected with eCG and ovaries or granulosa cells were isolated 44h later. To determine the proliferative competence of cKO granulosa cells we injected mice with bromodeoxyuridine 20h after eCG. The replicating cells were detected by immunofluorescence and counted. We studied how genes involved in proliferation were affected in cKO granulosa cells by determining transcripts abundance by qPCR. Last, we developped a model in vitro with depletion of Nr5a2 and inhibition of β-catenin. To create Nr5a2 knockout in vitro, we collected granulosa cells from Nr5a2f/f mice at 44h after eCG treatment. These cells were infected with adenovirus Cre to generate a cKO of Nr5a2 and harvested after 24h. To study the effects of the Nr5a2 cofactor, βcatenin, we treated Nr5a2f/f granulosa cells with ICRT3, a β-catenin inhibitor in vitro. Cells were harvested after 24h and we evaluated transcripts abundance by qPCR. RESULTS: Results showed that the percentage of proliferating cells was dramatically reduced (p<0.001) in the cKO ovary. In vivo there was a greatly reduced (p<0.05) expression cell cycle related genes, Ccnd1, Ccnd2, Ccne1, Ccne2, E2f1, E2f2 in cKO compared to control. Treating Nr5a2f/f granulosa cells with adenovirus Cre resulted in a >95 % depletion of the Nr5a2 transcript and in same reduction of the cyclin and E2fs transcripts (p<0.05), with the exception of cyclin E, as well as a downregulation of the essential stimulator of proliferation Rb1 (p<0,05). Finally, the cells treated with ICRT3 showed a significant downregulation of all the same cell cycle related genes. Nr5a2 was also dramatically downregulated. CONCLUSIONS: We conclude that β-catenin acts on Nr5a2 and both are essential for proper proliferation of granulosa cells. Their depletion or inhibition has an impact on downstream targets such as cyclins and transcription factors involved in the G1/S phase transition of cell cycle. Supported by a CIHR operating grant to BDM.

Mémoire présenté à la Faculté des études supérieures en vue de l'obtention du grade de Maîtrise è... more Mémoire présenté à la Faculté des études supérieures en vue de l'obtention du grade de Maîtrise ès Sciences (M. Sc.) en pharmacologie Août, 2017 © Dima Obari, 2017 le stress induit par la contrainte effectuée avec notre dispositif est associé à des changements de la réponse hémodynamique.

Hypertension, 2015

Arterial stiffness is an important risk factor for cognitive decline. However, its specific effec... more Arterial stiffness is an important risk factor for cognitive decline. However, its specific effects on brain homeostasis are unknown. Hence, the objective of the study is to explore the effects of arterial stiffness on brain's health, especially on oxidative stress, inflammation, cerebrovascular regulation and cognitive functions. Approach and Results: Arterial stiffness was induced by applying calcium chloride to carotid arteries of C57BL6 male mice. The control group received sodium chloride. Cerebral inflammation was assessed by quantifying immunoreactivity to activated glia markers ; Iba-1, CD68 and s100β. Oxidative stress was determined with dihydroethidium. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window and spatial memory was tested using the Morris water maze. Results show that arterial stiffness activates microglia in the hippocampus, and astrocytes in the hippocampus and the frontal cortex. Superoxi...

Current pharmaceutical design, Jan 25, 2017

Preterm birth (PTB) is a leading cause of neonatal mortality and morbidity worldwide, and survivi... more Preterm birth (PTB) is a leading cause of neonatal mortality and morbidity worldwide, and surviving infants are at increased risks of lifelong complications. PTB has been firmly linked to inflammation regardless of infection, specific aetiology or timing of birth. Deleterious inflammation is observed in maternal and fetal tissue, and correlates with the severity of perinatal complications. At present, PTB is treated with tocolytics as though it is exclusively a myometrial contractile disorder. These agents do not address underlying inflammatory processes and are thus vastly ineffective at improving neonatal outcomes. Of all inflammatory mediators, IL-1 is central to the pathophysiology of PTB and most adverse neonatal outcomes. We thus present herein a review of the various effects of IL-1 in utero, with a brief overview of its mechanism of action. We then discuss the potential of different IL-1-targeting agents based on pre-clinical testing in relevant models of PTB and neonatal in...

Neurology, Feb 7, 2017

To seek a neuropathologic signature of sudden unexpected death in epilepsy (SUDEP) in a postmorte... more To seek a neuropathologic signature of sudden unexpected death in epilepsy (SUDEP) in a postmortem cohort by use of immunohistochemistry for specific markers of inflammation, gliosis, acute neuronal injury due to hypoxia, and blood-brain barrier (BBB) disruption, enabling the generation of hypotheses about potential mechanisms of death in SUDEP. Using immunohistochemistry, we investigated the expression of 6 markers (CD163, human leukocyte antigen-antigen D related, glial fibrillary acid protein, hypoxia-inducible factor-1α [HIF-1α], immunoglobulin G, and albumin) in the hippocampus, amygdala, and medulla in 58 postmortem cases: 28 SUDEP (definite and probable), 12 epilepsy controls, and 18 nonepileptic sudden death controls. A semiquantitative measure of immunoreactivity was scored for all markers used, and quantitative image analysis was carried out for selected markers. Immunoreactivity was observed for all markers used within all studied brain regions and groups. Immunoreactivit...

Reproduction, 2016

Inflammation is essential for successful embryo implantation, pregnancy maintenance and delivery.... more Inflammation is essential for successful embryo implantation, pregnancy maintenance and delivery. In the last decade, important advances have been made in regard to endogenous, and therefore non-infectious, initiators of inflammation, which can act through the same receptors as pathogens. These molecules are referred to as damage-associated molecular patterns (DAMPs), and their involvement in reproduction has only recently been unraveled. Even though inflammation is necessary for successful reproduction, untimely activation of inflammatory processes can have devastating effect on pregnancy outcomes. Many DAMPs, such as uric acid, high-mobility group box 1 (HMGB1), interleukin (IL)-1 and cell-free fetal DNA, have been associated with pregnancy complications, such as miscarriages, preeclampsia and preterm birth in preclinical models and in humans. However, the specific contribution of alarmins to these conditions is still under debate, as currently there is lack of information on thei...

American journal of obstetrics and gynecology, Jan 8, 2016

Uterine inflammatory processes trigger pro-labor pathways and orchestrate on-time labor onset. Al... more Uterine inflammatory processes trigger pro-labor pathways and orchestrate on-time labor onset. Although essential for successful labor, inflammation needs to be regulated to avoid uncontrolled amplification and resolve post-partum. During labor, myometrial smooth muscle cells generate ATP mainly via anaerobic glycolysis, resulting in accumulation of lactate. Aside from its metabolic function, lactate has been shown to activate a G protein-coupled receptor, GPR81, reported to regulate inflammation. We therefore hypothesize that lactate produced during labor may act via GPR81 in uterus to exert in a feedback manner anti-inflammatory effects, to resolve or mitigate inflammation. To investigate the role of lactate produced during labor and its receptor, GPR81 in regulating inflammation in uterus. We investigated the expression of GPR81 in uterus and the pharmacological role of lactate acting via GPR81 during labor, using shRNA-GPR81 and GPR81-/- mice. 1) Uterine lactate levels increased...

Biology of Reproduction, 2016

Uterine labor requires the conversion of a quiescent (propregnancy) uterus into an activated (pro... more Uterine labor requires the conversion of a quiescent (propregnancy) uterus into an activated (prolabor) uterus, with increased sensitivity to endogenous uterotonic molecules. This activation is induced by stressors, particularly inflammation in term and preterm labor. Neuromedin U (NmU) is a neuropeptide known for its uterocontractile effects in rodents. The objective of the study was to assess the expression and function of neuromedin U receptor 2 (NmU-R2) and its ligands NmU and the more potent neuromedin S (NmS) in gestational tissues, and the possible implication of inflammatory stressors in triggering this system. Our data show that NmU and NmS are uterotonic ex vivo in murine tissue, and they dose-dependently trigger labor by acting specifically via NmU-R2. Expression of NmU-R2, NmU, and NmS is detected in murine and human gestational tissues by immunoblot, and the expression of NmS in placenta and of NmU-R2 in uterus increases considerably with gestation age and labor, which is associated with amplified NmU-induced uterocontractile response in mice. NmU-and NmS-induced contraction is associated with increased NmU-R2-coupled Ca ++ transients, and Akt and Erk activation in murine primary myometrial smooth muscle cells (mSMCs), which are potentiated with gestational age. NmU-R2 is upregulated in vitro in mSMCs and in vivo in uterus in response to proinflammatory interleukin 1beta (IL1beta), which is associated with increased NmU-induced uterocontractile response and Ca ++ transients in murine and human mSMCs; additionally, placental NmS is markedly upregulated in vivo in response to IL1beta. In human placenta at term, immunohistological analysis revealed NmS expression primarily in cytotrophoblasts; furthermore, stimulation with lipopolysaccharide (LPS; Gram-negative endotoxin) markedly upregulates NmS expression in primary human cytotrophoblasts isolated from term placentas. Correspondingly, decidua of women with clinical signs of infection who delivered preterm display significantly higher expression of NmS compared with those without infection. Importantly, in vivo knockdown of NmU-R2 prevents LPS-triggered preterm birth in mice and the associated neonatal mortality. Altogether, our data suggest a critical role for NmU-R2 and its ligands NmU and NmS in preterm labor triggered by infection. We hereby identify NmU-R2 as a relevant target for preterm birth.