Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: Reversal by clozapine

Ribeiro, B.M.M.; Carmo, Marta Regina Santos do; Freire, Raquel Santiago; Rocha, Nayrton Flávio Moura; Borella, V.; Menezes, A.T.; Monte, Aline Santos; Gomes, Patrícia; Sousa, Francisca Cléa Florenço de; Vale, Mariana Lima; Lucena, David Freitas de; Gama, Clarissa Severino; Macêdo, Danielle Silveira

doi:10.1016/j.schres.2013.10.040

Cited by 107 publications

(75 citation statements)

References 52 publications

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“…Other postmortem studies have found increased numbers and structural degenerative impairments of human leukocyte antigen-antigen D related+ microglia in schizophrenia [48][49][50]. There is also some evidence from schizophrenia animal models showing progressive microglial activation, increased inducible nitric oxide synthase expression, and oxidative/nitrosative stress markers in the offspring of rats exposed to the viral mimetic polyriboinosinicpolyribocytidylic acid during pregnancy, which are prevented by the administration of clozapine [51]. In addition, some antipsychotics inhibit the release of nitric oxide and cytokines from activated microglial cells, possibly through the suppression of [Ca 2+ ]i elevation in microglial cells [43,52].…”

Section: Discussionmentioning

confidence: 99%

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

et al. 2016

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Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stressinduced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples. In acute stress conditions, paliperidone enhanced NRF2 levels, possibly related to phosphoinositide 3-kinase upregulation and reduced kelch-Like ECH-associated protein 1 expression. In chronic conditions, paliperidone tended to normalize NRF2 levels through a phosphoinositide 3-kinase related-mechanism, with no effects on kelch-Like ECH-associated protein 1. Antioxidant response element-dependent antioxidant enzymes were upregulated by paliperidone in acute stress, while in chronic stress, paliperidone tended to prevent stress-induced downregulation of the endogenous antioxidant machinery. However, paliperidone increased transforming growth factor-β and interleukin-10 in favor of an M2 microglia profile in acute stress conditions, which was also corroborated by paliperidone-induced increased levels of the M2 cellular markers arginase I and folate receptor 2. This latter effect was also produced in chronic conditions. Immunofluorescence studies suggested an increase in the number of microglial cells expressing arginase I and folate receptor 2 in the stressed animals pretreated with paliperidone. In conclusion, the enhancement of endogenous antioxidant/anti-inflammatory pathways by current and new antipsychotics could represent an interesting therapeutic strategy for the future.

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Section: Discussionmentioning

confidence: 99%

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

et al. 2016

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“…To the degree that some forms of schizophrenia are characterized by aberrant ventral hippocampal development and connectivity, the NVHL model has been used to identify the expected "neuromaladaptive" consequences of such pathology and thereby help focus studies of pathophysiology and even therapeutics in this disorder. The model has been extended to demonstrate that a variety of early developmental insults to the mesial temporal lobe are accompanied by PPI deficits that emerge in adulthood, including immune/inflammatory activation of the VH (e.g., Zhu et al 2014a, b;Ribeiro et al 2013), neonatal pilocarpine-induced seizures (Labbate et al 2014), and neonatal lesions of the basolateral amygdala (Vázquez-Roque et al 2012). Other in utero or neonatal neurotoxic manipulations also produce PPI deficits in adult rats, including methylazoxymethanol (MAM) exposure (Le Pen et al 2006), elevated neonatal allopregnanolone (Darbra et al 2014), and neonatal administration of NMDA antagonists (Uehara et al 2010).…”

Section: The Evolution Of Prepulse Inhibition As a Validated Animal Mmentioning

confidence: 99%

“…Other in utero or neonatal neurotoxic manipulations also produce PPI deficits in adult rats, including methylazoxymethanol (MAM) exposure (Le Pen et al 2006), elevated neonatal allopregnanolone (Darbra et al 2014), and neonatal administration of NMDA antagonists (Uehara et al 2010). In some cases, the expression of PPI deficits induced by these early developmental manipulations can be blocked by acute treatments during adulthood, using antipsychotics (e.g., clozapine: Ribeiro et al 2013), putative neuroprotective agents (e.g., minocycline: Zhu et al 2014b), and glycinergic agents (Le Pen et al 2003). Thus, it appears that PPI deficits are a common adult behavioral response to a wide range of perturbations in early rodent brain development, and particularly those that impact the mesial temporal lobe by various mechanisms.…”

Section: The Evolution Of Prepulse Inhibition As a Validated Animal Mmentioning

confidence: 99%

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

Swerdlow

Light

2015

Translational Neuropsychopharmacology

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Animal models of impaired sensorimotor gating, as assessed by prepulse inhibition (PPI) of startle, have demonstrated clear validity at face, predictive, and construct levels for schizophrenia (SZ) therapeutics, neurophysiological endophenotypes, and potential causative insults for this group of disorders. However, with the growing recognition of the heterogeneity of the schizophrenias, and the less sanguine view of the clinical value of antipsychotic (AP) medications, our field must look beyond "validity," to assess the actual utility of these models. At a substantial cost in terms of research support and intellectual capital, what has come from these models, that we can say has actually helped schizophrenia patients? Such introspection is timely, as we are reassessing not only our view of the genetic and pathophysiological diversity of these disorders, but also the predominant strategies for SZ therapeutics; indeed, our field is gaining awareness that we must move away from a "find what's broke and fix it" approach, toward identifying spared neural and cognitive function in SZ patients, and matching these residual neural assets with learning-based therapies. Perhaps, construct-valid models that identify evidence of "spared function" in neural substrates might reveal opportunities for future therapeutics and allow us to study these substrates at a mechanistic level to maximize opportunities for neuroplasticity. Such an effort will require a retooling of our models, and more importantly, a re-evaluation of their utility. For animal models to remain relevant in the search for schizophrenia therapeutics, they will need to focus less on what is valid and focus more on what is useful.

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“…In contrast, expression of iNOS from primary inflammatory macrophages did not occur until 72 h postchallenge with ATCV-1. Nevertheless, macrophages interacting with ATCV-1 expressed inflammatory factors, many of which are linked to memory impairments and mental illnesses (14,26,27).…”

Section: Atcv-1-induced Innate Antiviral Immune Responses In Macrophamentioning

confidence: 99%

Response of Mammalian Macrophages to Challenge with the Chlorovirus Acanthocystisturfacea Chlorella Virus 1

Petro

Agarkova

Zhou

et al. 2015

J Virol

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It was recently reported that 44% of the oropharyngeal samples from the healthy humans in a study cohort had DNA sequences similar to that of the chlorovirus ATCV-1 (Acanthocystis turfacea chlorella virus 1, family Phycodnaviridae) and that these study subjects had decreases in visual processing and visual motor speed compared with individuals in whom no virus was detected. Moreover, mice inoculated orally with ATCV-1 developed immune responses to ATCV-1 proteins and had decreases in certain cognitive domains. Because heightened interleukin-6 (IL-6), nitric oxide (NO), and ERK mitogen-activated protein (MAP) kinase activation from macrophages are linked to cognitive impairments, we evaluated cellular responses and viral PFU counts in murine RAW264.7 cells and primary macrophages after exposure to ATCV-1 in vitro for up to 72 h after a virus challenge. Approximately 8% of the ATCV-1 inoculum was associated with macrophages after 1 h, and the percentage increased 2-to 3-fold over 72 h. Immunoblot assays with rabbit anti-ATCV-1 antibody detected a 55-kDa protein consistent with the viral capsid protein from 1 to 72 h and increasing de novo synthesis of a previously unidentified 17-kDa protein beginning at 24 h. Emergence of the 17-kDa protein did not occur and persistence of the 55-kDa protein declined over time when cells were exposed to heat-inactivated ATCV-1. Moreover, starting at 24 h, RAW264.7 cells exhibited cytopathic effects, annexin V staining, and cleaved caspase 3. Activation of ERK MAP kinases occurred in these cells by 30 min postchallenge, which preceded the expression of IL-6 and NO. Therefore, ATCV-1 persistence in and induction of inflammatory factors by these macrophages may contribute to declines in the cognitive abilities of mice and humans. IMPORTANCEVirus infections that persist in and stimulate inflammatory factors in macrophages contribute to pathologies in humans. A previous study showed that DNA sequences homologous to the chlorovirus ATCV-1 were found in a significant fraction of oropharyngeal samples from a healthy human cohort. We show here that ATCV-1, whose only known host is a eukaryotic green alga (Chlorella heliozoae) that is an endosymbiont of the heliozoon Acanthocystis turfacea, can unexpectedly persist within murine macrophages and trigger inflammatory responses including factors that contribute to immunopathologies. The inflammatory factors that are produced in response to ATCV-1 include IL-6 and NO, whose induction is preceded by the activation of ERK MAP kinases. Other responses of ATCV-1-challenged macrophages include an apoptotic cytopathic effect, an innate antiviral response, and a metabolic shift toward aerobic glycolysis. Therefore, mammalian encounters with chloroviruses may contribute to chronic inflammatory responses from macrophages. C hloroviruses (family Phycodnaviridae) were discovered over 35 years ago and are distinctive because they are large icosahedral double-stranded DNA (dsDNA) viruses that infect certain unicellular eukaryotic green algae, which...

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Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: Reversal by clozapine

Cited by 107 publications

References 52 publications

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

Response of Mammalian Macrophages to Challenge with the Chlorovirus Acanthocystisturfacea Chlorella Virus 1

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