Early cerebrovascular and parenchymal events following prenatal exposure to the putative neurotoxin methylazoxymethanol

Bassanini, Stefania; Hallene, Kerri; Battaglia, Giorgio; Finardi, Adele; Santaguida, Stefano; Cipolla, Marilyn J.; Janigro, Damir

doi:10.1016/j.nbd.2007.02.008

Cited by 23 publications

(25 citation statements)

References 51 publications

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“…However, in rats an administration of 7.5 mg/kg between GD 13 and 15 caused substantial changes in brain morphology (De Groot et al 2005). According to a study of Bassanini et al (2007), such a dose probably results in a fetal brain concentration of 30 µM, which is very similar to the effective concentrations in our rat in vitro results (EC 50 = 31.82 µM; Table 1), demonstrating that rNPCs were able to predict the actual risk of MAM properly.…”

Section: Discussionsupporting

confidence: 84%

Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events

et al. 2015

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The developing brain is highly vulnerable to the adverse effects of chemicals, resulting in neurodevelopmental disorders in humans. Currently, animal experiments in the rat are the gold standard for developmental neurotoxicity (DNT) testing; however, these guideline studies are insufficient in terms of animal use, time and costs and bear the issue of species extrapolation. Therefore, the necessity for alternative methods that predict DNT of chemicals faster, cheaper and with a high predictivity for humans is internationally agreed on. In this respect, we developed an in vitro model for DNT key event screening, which is based on primary human and rat neural progenitor cells grown as neurospheres. They are able to mimic basic processes of early fetal brain development and enable an investigation of species differences between humans and rodents in corresponding cellular models. The goal of this study was to investigate to what extent human and rat neurospheres were able to correctly predict the DNT potential of a well-characterized training set of nine chemicals by investigating effects on progenitor cell proliferation, migration and neuronal differentiation in parallel to cell viability, and to compare these chemical responses between human and rat neurospheres. We demonstrate that (1) by correlating these human and rat in vitro results to existing in vivo data, human and rat neurospheres classified most compounds correctly and thus may serve as a valuable component of a modular DNT testing strategy and (2) human and rat neurospheres differed in their sensitivity to most chemicals, reflecting toxicodynamic species differences of chemicals.

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Section: Discussionsupporting

confidence: 84%

Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events

et al. 2015

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“…This suggests a scenario where a “disease-primed” brain does not produce clinically relevant symptoms until the BBB is breached in the malformed region or near disease-prone neuronal circuits. This was repeatedly demonstrated in models of focal seizure disorders (e.g., methylazoxymethanol- or thalidomide-treated animals [57, 58]) or pilocarpine-treated animals or patients (26, 27, 36) where leakage of the BBB and hyperexcitability are commonly observed in the region of neuronal malformation or gliotic CNS region. Breakdown of BBB or “latency states” in the development of neurotransmitters may explain late onset of psychotic symptoms.…”

Section: Discussionmentioning

confidence: 86%

Does Systemic Inflammation Play a Role in Pediatric Psychosis?

Falcone¹,

Carlton

Lee

et al. 2015

Clinical Schizophrenia & Related Psychoses

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Context Human and animal studies have suggested an underlying inflammatory mechanism for a variety of neuropsychiatric disorders, including schizophrenia. To date, most available reports focused on adult patients. Objective We wished to test the hypothesis that the first psychotic episode in youth is associated with inflammation. Patients We studied patients admitted to a pediatric inpatient psychiatric unit. Patients (n=80) had new-onset psychosis diagnosed using DSM-IV TR criteria for Psychosis NOS, Schizophreniform Disorder or Schizoaffective Disorder. Patients were matched for age, race and gender with inpatient controls without psychosis within the same unit (n=66). We also compared these values to normal pediatric hematologic values. To study the role of inflammation in youth with psychosis, we collected serum samples of 28 children presenting with first-episode psychosis and compared their serum cytokine and S100B levels to eight healthy controls. Main Outcome Measures In this study, we measured serum markers of systemic inflammation. Results Leukocyte counts revealed a statistically significant increase in absolute monocytes compared to patients without psychosis (0.61±0.282 k/ml vs. 0.496±0.14 k/ml; p<0.01) and lymphocytes (2.51±0.84 k/ml vs. 2.24±0.72 k/ml; p<0.05) in patients with psychosis. All other hematologic values were similar between the groups. In addition, psychosis was characterized by increased serum levels of S100B, a peripheral marker of blood-brain barrier (BBB) damage. Several inflammatory mediators (e.g., TNF-α, IL-1β, IL-6, IL-5, IL-10, and IFN-γ) were elevated in children with psychosis. Conclusions These results strongly support a link between systemic inflammation, blood-brain barrier disruption and first-episode psychosis in pediatric patients.

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“…MAM is an anti-mitotic agent that can be administered to a pregnant dam via intraperitoneal injection, and passes though the placenta to damage the DNA in dividing cells of the fetal central nervous system [37]. Depending on the dose and timing of MAM administration, the severity and region of neural disruption can be modulated.…”

Section: Introductionmentioning

confidence: 99%

Developmental learning impairments in a rodent model of nodular heterotopia

Threlkeld

Hill

Cleary

et al. 2009

J Neurodevelop Disord

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Developmental malformations of neocortex—including microgyria, ectopias, and periventricular nodular heterotopia (PNH)—have been associated with language learning impairments in humans. Studies also show that developmental language impairments are frequently associated with deficits in processing rapid acoustic stimuli, and rodent models have linked cortical developmental disruption (microgyria, ectopia) with rapid auditory processing deficits. We sought to extend this neurodevelopmental model to evaluate the effects of embryonic (E) day 15 exposure to the anti-mitotic teratogen methylazoxymethanol acetate (MAM) on auditory processing and maze learning in rats. Extensive cortical anomalies were confirmed in MAM-treated rats post mortem. These included evidence of laminar disruption, PNH, and hippocampal dysplasia. Juvenile auditory testing (P21–42) revealed comparable silent gap detection performance for MAM-treated and control subjects, indicating normal hearing and basic auditory temporal processing in MAM subjects. Juvenile testing on a more complex two-tone oddball task, however, revealed a significant impairment in MAM-treated as compared to control subjects. Post hoc analysis also revealed a significant effect of PNH severity for MAM subjects, with more severe disruption associated with greater processing impairments. In adulthood (P60–100), only MAM subjects with the most severe PNH condition showed deficits in oddball two-tone processing as compared to controls. However, when presented with a more complex and novel FM sweep detection task, all MAM subjects showed significant processing deficits as compared to controls. Moreover, post hoc analysis revealed a significant effect of PNH severity on FM sweep processing. Water Maze testing results also showed a significant impairment for spatial but not non-spatial learning in MAM rats as compared to controls. Results lend further support to the notions that: (1) generalized cortical developmental disruption (stemming from injury, genetic or teratogenic insults) leads to auditory processing deficits, which in turn have been suggested to play a causal role in language impairment; (2) severity of cortical disruption is related to the severity of processing impairments; (3) juvenile auditory processing deficits appear to ameliorate with maturation, but can still be elicited in adulthood using increasingly complex acoustic stimuli; and (4) malformations induced with MAM are also associated with generalized spatial learning deficits. These cumulative findings contribute to our understanding of the behavioral consequences of cortical developmental pathology, which may in turn elucidate mechanisms contributing to developmental language learning impairment in humans.

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Early cerebrovascular and parenchymal events following prenatal exposure to the putative neurotoxin methylazoxymethanol

Cited by 23 publications

References 51 publications

Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events

Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events

Does Systemic Inflammation Play a Role in Pediatric Psychosis?

Developmental learning impairments in a rodent model of nodular heterotopia

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