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

• DOI: 10.1093/ijnp/pyab036
• Publication Date: 2021-06-18T19:13:51Z
• Authors: Diego Romero-Miguel; Marta Casquero-Veiga; Karina S MacDowell; Sonia Torres-Sanchez; José Antonio Garc...; Nicolás Lamanna-Rama; Ana Romero-Miranda; Esther Berrocoso; Juan C Leza; Manuel Desco; María Luisa Soto-...
• Keywords: Poly I:C; Male; Anti-Inflammatory Agents; Minocycline; Nervous System Malformations; Regular Research Articles; Antioxidants; 03 medical and health sciences; minocycline; 0302 clinical medicine; Pregnancy; Animals; Rats, Wistar; FDG-PET; Fdg-pet; C [Poly I]; inflammatory/oxidonitrosative stress; Behavior, Animal; Brain Diseases, Metabolic; Prepulse Inhibition; Inflammatory/oxidonitrosative stress; Magnetic Resonance Imaging; Rats; 3. Good health; schizophrenia; Disease Models, Animal; Oxidative Stress; Neurodevelopmental Disorders; Positron-Emission Tomography; Prenatal Exposure Delayed Effects; Schizophrenia; Female

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.