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

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.M.L.S. was supported by the Ministerio de Ciencia, Innovacion y Universidades, Instituto de Salud Carlos III (projects PI14/00860 and PI17/01766, and grant CPII14/00005), co-financed by European Regional Development Fund (ERDF), "A way of making Europe", CIBER of Mental Health (CIBERSAM), Delegacion del Gobierno para el Plan Nacional sobre Drogas (2017/085), Fundacion Mapfre and Fundacion Alicia Koplowitz. M.C.-V. was supported by Fundacion Tatiana Perez de Guzman el Bueno. D.R.-M. was supported by Consejeria de Educacion e Investigacion, Comunidad de Madrid, co-funded by European Social Fund "Investing in your future" (grant, PEJD-2018-PRE/BMD-7899). N.L.-R. was supported by Instituto de investigacion Sanitaria Gregorio Maranon. A.R.-M. was supported by Consejeria de Educacion e Investigacion, Comunidad de Madrid, co-funded by European Social Fund "Investing in your future" (grant, PEJ15/BIO/TL-0216). The CNIC was supported by the Spanish Ministerio de Ciencia, Innovacion y Universidades (MCIU) and the Pro-CNIC Foundation. J.C.L. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECOEU-FEDER) SAF2016-75500-R and CIBERSAM. E.B.D., S.T.-S., and J.A.G.-P. were supported by grants: co-financed by the "Fondo Europeo de Desarrollo Regional" (FEDER)-UE "A way to build Europe" from the "Ministerio de Economia y Competitividad" (MINECO: RTI2018-099778-B-I00) and the "Ministerio de SaludInstituto de Salud Carlos III (PI18/01691); from the "Plan Nacional sobre Drogas, Ministerio de Sanidad, Consumo y Bienestar Social" (2019I041); from the "Programa Operativo de Andalucia FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejeria Salud, Junta de Andalucia" (PI-0080-2017 and PI-0009-2017); from the Consejeria de Salud de la Junta de Andalucia (PI-0134-2018); from the University of Cadiz (PR2019-046); from the "Instituto de Investigacion e Innovacion en Ciencias Biomedicas de Cadiz-INiBICA" (IN-C22; LI19/06IN-CO22); from the "Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia" (CTS-510); from the "CIBERSAM" (CB/07/09/0033)