Exposição intra-amniótica ao ácido valpróico induz teratogênese e reproduz endofenótipo dos modelos animais de autismo
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that includes, approximately, 1% of the world’s population. ASD is characterized by clinical observations of deficits in social communication and interaction and, also, the prevalence of repetitive behaviors and restricted interests....
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| Formato: | Dissertação |
| Idioma: | pt_BR |
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Universidade Federal do Rio Grande do Norte
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| Endereço do item: | https://repositorio.ufrn.br/handle/123456789/53104 |
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| Resumo: | Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that includes,
approximately, 1% of the world’s population. ASD is characterized by clinical
observations of deficits in social communication and interaction and, also, the
prevalence of repetitive behaviors and restricted interests. Currently, several animal
models are used to investigate the neurobiological mechanisms associated with ASD.
The animal model generated by exposing rats, during pregnancy, to valproic acid
(VPA) is already well established in the literature. The effect of VPA exposure in rats
is similar to what is observed in the clinic: the use of this drug during pregnancy
increases the prevalence of children born with the autistic phenotype. The evaluation
of several studies about this model indicates that the behavioral phenotype of these
animals is expressed differently, depending on the dose used, the route of
administration and the stage of development in which the exposure occurs. Therefore,
in this study, we sought to investigate the effects of exposure to VPA administered via
the intra-amniotic route (VPAia), directly in rat fetuses, at doses of 2.0 and 2.5 μmoles.
For this, we performed a medial laparotomy in pregnant rats, on the 12th gestational
day, for exposure of the uterine horns and subsequent microinjections of VPAia. This
administration was given during the stage of development when neural tube closure
occurs, and in which the exposure to VPA is associated with autistic phenotypes in the
offspring and the development of neural tube defects. The hypotheses of this work
were (1) that exposure to VPAia would induce autistic-like behavioral phenotypes in
the offspring; (2) that the severity of these phenotypes would be dose-dependent; and
(3) that behavioral phenotypes would be expressed more homogenously compared to
the model induced by intraperitoneal VPA administration. Once the injections were
done, we followed the births and developmental milestones of the pups during the first
few postnatal weeks. We evaluated weight, time for eye opening, recorded their
ultrasonic vocal production during maternal separation and applied behavioral tests of
social interaction. Our results show that the doses used (2.0 and 2.5 μmol/fetus)
induced teratogenicity in less than 10% of the injected animals. Analyzes of weight and
eye-opening time did not reveal developmental changes in VPAia animals compared
to control animals. As for the vocalizations, the VPAia animals vocalized less than the
controls at the age of 7 days (P7; p<0.05), without significant alterations at P14 and
P21. We also observed less exploratory activity in the open field apparatus (P21;
p<0.005), shorter time spent walking in the center of the open field apparatus (P30;
p<0.05) and a greater number of entries at the social interaction zone (ZIS; P35;
p<0.05) of VPAia animals. We can conclude, therefore, that the administration of
VPAia promoted changes in some characteristic behaviors of animal models of ASD,
such as vocalization and locomotor activity, but without significant effects on
stereotypes and social interaction. |
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