Severe Uncontrolled Maternal Hyperglycemia Induces Microsomia and Neurodevelopment Delay Accompanied by Apoptosis, Cellular Survival, and Neuroinflammatory Deregulation in Rat Offspring Hippocampus

  • Francele Valente PiazzaEmail author
  • Ethiane Segabinazi
  • André Luís Ferreira de Meireles
  • Filipe Mega
  • Christiano de Figueiredo Spindler
  • Otávio Américo Augustin
  • Gabriela dos Santos Salvalaggio
  • Matilde Achaval
  • Maria Sol Kruse
  • Héctor Coirini
  • Simone Marcuzzo
Original Research


Maternal diabetes constitutes an unfavorable intrauterine environment for offspring development. Although it is known that diabetes can cause brain alterations and increased risk for neurologic disorders, the relationship between neuroimmune activation, brain changes, and neurodevelopment deficits in the offspring remains unclear. In order to elucidate the short- and long-term biological basis of the developmental outcomes caused by the severe uncontrolled maternal hyperglycemia, we studied apoptosis, neurogenesis, and neuroinflammation pathways in the hippocampus of neonates and young rats born to diabetic dams. Diabetes was induced on gestational day 5 by an injection of streptozotocin. Evaluations of milestones, body growth, and inhibitory avoidance were performed to monitor the offspring development and behavior. Hippocampal modifications were studied through cellular survival by BrdU in the dentate gyrus, expression of apoptosis-regulatory proteins (procaspase 3, caspase 3, and Bcl-2), BDNF, and neuroinflammatory modulation by interleukins, MHC-I, MHC-II, Iba-1, and GFAP proteins. Severe maternal diabetes caused microsomia and neurodevelopmental delay in pups and decrease of Bcl-2, procaspase 3, and caspase 3 in the hippocampus. Moreover, in a later stage of development, it was found an increase of TNF-α and a decrease of procaspase 3, caspase 3, MHC-I, IL-1β, and BDNF in the hippocampus, as well as impairment in cellular survival in the dentate gyrus. This study showed significant short- and long-term commitments on the development, apoptosis, cell survival, and neuroinflammation in the offspring hippocampus induced by severe uncontrolled maternal hyperglycemia. The data reinforce the need for treatment of maternal hyperglycemic states during pregnancy and breast-feeding.


Gestational diabetes Caspase 3 Bcl-2 Microglia Astrocytes BrdU 



The authors are very grateful to Silvia Barbosa for the technical support. This work was financial supported by the Brazilian funding agencies CNPq, CAPES, and FAPERGS (002097-2552/13-6–1), and by the International Brain Research Organization (IBRO). F.V Piazza was supported by a scholarship from CAPES and Short Stay IBRO fellowship.

Author Contributions

All the authors listed have participated sufficiently in the study, in the research design, execution, and analyses reported in this manuscript. The responsibility for writing the article rests with FVP, MSK, HC, and SM, but every coauthor had the opportunity to review it and all approved the final version. All the authors have read and followed the ethical standards statement for manuscripts submitted to Cellular and Molecular Neurobiology.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflicts of interest regarding the authorship and/or publication of this article.

Supplementary material

10571_2019_658_MOESM1_ESM.pdf (304 kb)
Supplementary material 1 (PDF 303 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Francele Valente Piazza
    • 1
    • 2
    Email author
  • Ethiane Segabinazi
    • 1
    • 2
  • André Luís Ferreira de Meireles
    • 1
    • 2
  • Filipe Mega
    • 1
    • 2
  • Christiano de Figueiredo Spindler
    • 1
    • 2
  • Otávio Américo Augustin
    • 2
  • Gabriela dos Santos Salvalaggio
    • 2
  • Matilde Achaval
    • 1
    • 2
  • Maria Sol Kruse
    • 3
  • Héctor Coirini
    • 3
    • 4
  • Simone Marcuzzo
    • 1
    • 2
  1. 1.Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Laboratorio de NeurobiologíaInstituto de Biología y Medicina ExperimentalBuenos AiresArgentina
  4. 4.Departamento de Bioquímica Humana, Facultad de MedicinaUniversidad de Buenos AiresBuenos AiresArgentina

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