The teratogenic activity of α thalidomide analogue, EM<sub>12</sub>, in rabbits, rats, and monkeys

Schumacher, H.; Terapane, John F.; Jordan, Robert L.; Wilson, James G.

doi:10.1002/tera.1420050213

Cited by 49 publications

(15 citation statements)

References 8 publications

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“…VPA was the drug of choice, since thalidomide has different effects in rodents than in humans (Schumacher et al, 1972). VPA, on the other hand, is a powerful teratogen in rodents and produces many of the malformations observed in humans (Binkerd et al, 1988; Collins et al, 1991; Ehlers et al, 1992).…”

Section: Vpa Exposure In Ratsmentioning

confidence: 99%

The intense world syndrome – an alternative hypothesis for autism

Rinaldi²,

2007

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Autism is a devastating neurodevelopmental disorder with a polygenetic predisposition that seems to be triggered by multiple environmental factors during embryonic and/or early postnatal life. While significant advances have been made in identifying the neuronal structures and cells affected, a unifying theory that could explain the manifold autistic symptoms has still not emerged. Based on recent synaptic, cellular, molecular, microcircuit, and behavioral results obtained with the valproic acid (VPA) rat model of autism, we propose here a unifying hypothesis where the core pathology of the autistic brain is hyper-reactivity and hyper-plasticity of local neuronal circuits. Such excessive neuronal processing in circumscribed circuits is suggested to lead to hyper-perception, hyper-attention, and hyper-memory, which may lie at the heart of most autistic symptoms. In this view, the autistic spectrum are disorders of hyper-functionality, which turns debilitating, as opposed to disorders of hypo-functionality, as is often assumed. We discuss how excessive neuronal processing may render the world painfully intense when the neocortex is affected and even aversive when the amygdala is affected, leading to social and environmental withdrawal. Excessive neuronal learning is also hypothesized to rapidly lock down the individual into a small repertoire of secure behavioral routines that are obsessively repeated. We further discuss the key autistic neuropathologies and several of the main theories of autism and re-interpret them in the light of the hypothesized Intense World Syndrome. Keywords: autism, microcircuit, connectivity, plasticity, neocortex, amygdala, valproic acid INTRODUCTIONAutism as a syndrome was first described by Leo Kanner, a child psychologist, in 1943. His initial description, based on 11 case studies emphasized ". . .an innate inability to form the usual, biologically provided affective contact with other people." For a long time, autism was thought to be a consequence of bad parenting and the "refrigerator mother" theory (Bettelheim, 1967) lasted from the 1950s well beyond the 1970s. Bernard Rimland (Rimland, 1964) and Michael Rutter (Rutter, 1968) established empirically that the parents of autistic children were not different in their parenting from the parents of non-autistic controls and helped building a case for a neurobiological basis of autism. Autism is now recognized as a neurodevelopmental disorder manifesting within the first 3 years after birth and progressively worsening in the course of life. The core symptoms are impairments of sociability, communicative skills and imagination, together with stereotypic behaviors and repetitive tendencies (DSM-IV, 1994). At the cognitive level, all autistic children seem to display some form of abnormality in perception, attention, and memory (Ben Shalom, 2003;Dakin and Frith, 2005;Sanders et al., 2007).Genetic analyses have revealed that autism is a polygenetic disorder where any one or more set of genes can predispose toward, but no one gene has been...

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Section: Vpa Exposure In Ratsmentioning

confidence: 99%

The intense world syndrome – an alternative hypothesis for autism

Rinaldi²,

2007

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“…Since thalidomide does not have the same teratogenic effect in rodents as in primates (Schumacher et al, 1968), VPA was used to injure rats' brainstems in utero (Rodier et al, 1996(Rodier et al, , 1997. Somatic effects of VPA are known to be similar to those of thalidomide (Binkerd et al, 1988), and its teratogenic effect is also observed in human beings (Lindhout et al, 1992;Ardinger et al, 1998) also causing, in addition to somatic dysfunction, CNS dysfunction described as fetal valproate syndrome, which has recently been connected with autism (Christianson et al, 1994;Williams and Hersh, 1997;Williams et al, 2001;Moore et al, 2000;Bescoby Chambers et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism

Schneider

Przewłocki

2004

Neuropsychopharmacol

812

650

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Autism is a severe behavioral disorder characterized by pervasive impairments in social interactions, deficits in verbal and nonverbal communication, and stereotyped, repetitive patterns of behaviors and interests. Recently, a new rodent model of autism was created by exposure of rat fetuses to valproic acid (VPA) on the 12.5th day of gestation (VPA rats). The model has striking anatomical, pathological, and etiological similarities to human data; however, it has not been characterized behaviorally. In order to determine if VPA rats present behavioral aberrations observed in autism, their behavior was extensively evaluated in a battery of tests. The results of the present experiments demonstrate that VPA rats exhibit: (1) lower sensitivity to pain and higher sensitivity to nonpainful stimuli, (2) diminished acoustic prepulse inhibition, (3) locomotor and repetitive/stereotypic-like hyperactivity combined with lower exploratory activity, and (4) decreased number of social behaviors and increased latency to social behaviors. In addition, VPA rats showed delayed maturation, lower body weight, delayed motor development, and attenuated integration of a coordinated series of reflexes, delayed nest-seeking response mediated by olfactory system, and normal negative geotaxis. Interestingly, all behavioral aberrations described in this paper appear before puberty, which could distinguish the VPA rat model of autism from other animal models of neurodevelopmental disorders, especially rodent models of schizophrenia. Our results bring further support to validity of the proposed VPA animal model of autism, suggesting similarities between the observed pattern of behavioral alterations in VPA rats and features of disturbed behavior in autistic patients.

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“…Concerning the evaluation of developmental toxicity, the ICH Harmonized Tripartite Guideline, "Detection of Toxicity to Reproduction for Medical Products" (June 24, 1993), a second mammalian species traditionally has been required, with the rabbit being the referred choice as a nonrodent. Reasons for using rabbits in embryotoxicity studies include the extensive background knowledge that has been accumulated, such as availability and practicality (Christian and Hoberman, 1996;Foote, 2000;Schumacher et al, 1972). In fact, rabbits have a sensitivity to human teratogens, such as thalidomide (Fabro and Smith, 1966;Fratta et al, 1965;Schumacher et al, 1968).…”

Section: Introductionmentioning

confidence: 99%

Prenatal developmental toxicity study of ethyltertiary-butyl ether in rabbits

Asano

Ishikura

Kudoh

et al. 2011

Drug and Chemical Toxicology

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Ethyl tertiary-butyl ether (ETBE) is commonly used as an oxygenated gasoline additive. In this study, the prenatal developmental toxicity of ETBE was determined in rabbits. New Zealand white rabbits were given ETBE by gavage at 100, 300, or 1,000 mg/kg/day on gestational days (GDs) 6-27, and the pregnancy outcome was determined on GD 28. Neither death nor abortion occurred in the pregnant rabbits at any dose. Slightly and significantly suppressed maternal body-weight gain and transiently decreased maternal food consumption were found at 1,000 mg/kg/day during the administration period. At this dose, no changes in clinical or macroscopic finding were noted in dams. No treatment-related changes were observed in any dam treated at 300 mg/kg/day or less. There was no significant effect of ETBE on the numbers of corpora lutea, implantations, live fetuses, resorptions and dead fetuses, incidences of pre- and postimplantation loss, viability of fetuses, fetal body weight, sex ratio of fetuses, or weights of gravid uteri. No significant difference was detected in the incidences of fetuses with malformations or variations between the ETBE-treated and control groups. Also, no adverse effects on the progress of ossification were noted in fetuses of dams given ETBE. Based on these findings, it is concluded that the no observed adverse effect levels of ETBE were 300 mg/kg/day for dams and 1,000 mg/kg/day for fetuses in rabbits.

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The teratogenic activity of α thalidomide analogue, EM₁₂, in rabbits, rats, and monkeys

Cited by 49 publications

References 8 publications

The intense world syndrome – an alternative hypothesis for autism

The intense world syndrome – an alternative hypothesis for autism

Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism

Prenatal developmental toxicity study of ethyltertiary-butyl ether in rabbits

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The teratogenic activity of α thalidomide analogue, EM12, in rabbits, rats, and monkeys

Cited by 49 publications

References 8 publications

The intense world syndrome – an alternative hypothesis for autism

The intense world syndrome – an alternative hypothesis for autism

Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism

Prenatal developmental toxicity study of ethyltertiary-butyl ether in rabbits

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The teratogenic activity of α thalidomide analogue, EM₁₂, in rabbits, rats, and monkeys