A Characterization of the Effects of Minocycline Treatment during Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders Articles uri icon

authors

  • ROMERO MIGUEL, LUIS DIEGO
  • CASQUERO VEIGA, MARTA
  • MacDowell, Karina S.
  • Torres Sanchez, Sonia
  • Garcia Partida, Jose Antonio
  • LAMANNA RAMA, NICOLÁS
  • ROMERO MIRANDA, ANA
  • Berrocoso, Esther
  • Leza, Juan C.
  • DESCO MENENDEZ, MANUEL
  • SOTO MONTENEGRO, Mª LUISA

publication date

  • September 2021

start page

  • 734

end page

  • 748

issue

  • 9

volume

  • 24

International Standard Serial Number (ISSN)

  • 1461-1457

Electronic International Standard Serial Number (EISSN)

  • 1469-5111

abstract

  • Background: Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model.
    Methods: On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue.
    Results: MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen). Conclusions: MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.

keywords

  • fdg-pet; inflammatory/oxidonitrosative stress; minocycline; poly i:c; schizophrenia