Background and purpose Minocycline is a broad‐spectrum antibiotic, effective as a chronic treatment for recurrent bacterial infections. Beyond its antibiotic action, minocycline also has important anti‐inflammatory, antioxidant and antiapoptotic properties. Its efficacy has therefore been evaluated in many neurodegenerative and psychiatric diseases that have an inflammatory basis. Our aim was to review preclinical and clinical studies performed in neurological and psychiatric diseases whose treatment involved the use of minocycline and thereby to discern the possible beneficial effect of minocycline in these disorders. Methods Completed and ongoing preclinical studies and clinical trials of minocycline for both neurodegenerative diseases and psychiatric disorders, published from January 1995 to January 2020, were identified through searching relevant databases (https://www.ncbi.nlm.nih.gov/pubmed/, https://clinicaltrials.gov/). A total of 74 preclinical studies and 44 clinical trials and open‐label studies were selected. Results The results of the nearly 20 years of research identified are diverse. While minocycline mostly proved to be effective in animal models, clinical results showed divergent outcomes, with positive results in some studies counterbalanced by a number of cases with no significant improvements. Specific data for each disease are further individually described in this review. Conclusions Despite minocycline demonstrating antioxidant and anti‐inflammatory effects, discrepancies between preclinical and clinical data indicate that we should be cautious in analyzing the outcomes. Improving and standardizing protocols and refining animal models could help us to determine if minocycline really is a useful drug in the treatment of these pathologies.

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 were injected to pregnant Wistar rats. 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 (PPI). 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 PPI 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.

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Curcumin is a polyphenol extracted from the rhizome of the turmeric plant. Beyond its common use as a culinary spice in Eastern Asia, curcumin has been proposed as a therapeutic compound due to its antioxidant, anti-inflammatory and neuroprotective properties. Thus, its efficacy has been evaluated in various inflammatory-based psychiatric disorders, such as schizophrenia, depression, or autism. Our aim is to review those preclinical and clinical studies carried out in psychiatric disorders whose therapeutic approach has involved the use of curcumin and, therefore, to discern the possible positive effect of curcumin in these disorders. Preclinical studies and completed clinical trials of curcumin for psychiatric disorders published from January 2005 to October 2021 were identified through searching relevant databases until 31st October 2021. Sixty-five preclinical studies and 15 clinical trials and open-label studies were selected. Results showed a bias toward studies in depression and, to a lesser extent, schizophrenia. In all disorders, the results were positive in reducing psychiatric deficits. Despite the considerable number of beneficial outcomes reported, the small number of trials and the heterogeneity of protocols make it difficult to draw solid conclusions about the real potency of curcumin in psychiatric disorders.

There is evidence that in schizophrenia, imbalances in inflammatory and oxidative processes occur during pregnancy and in the early postnatal period, generating interest in the potential therapeutic efficacy of anti-inflammatory and antioxidant compounds. Mangiferin is a polyphenolic compound abundant in the leaves of Mangifera indica L. that has robust antioxidant and anti-inflammatory properties, making it a potential candidate for preventive or co-adjuvant therapy in schizophrenia. Hence, this study set-out to evaluate the effect of mango leaf extract (MLE) in a model of schizophrenia based on maternal immune activation, in which Poly I:C (4 mg/kg) is administered intravenously to pregnant rats. Young adult (postnatal day 60–70) or adolescent (postnatal day 35–49) male offspring received MLE (50 mg/kg of mangiferin) daily, and the effects of MLE in adolescence were compared to those of risperidone, assessing behavior, brain magnetic resonance imaging (MRI), and oxidative/inflammatory and antioxidant mediators in the adult offspring. MLE treatment in adulthood reversed the deficit in prepulse inhibition (PPI) but it failed to attenuate the sensitivity to amphetamine and the deficit in novel object recognition (NOR) induced. By contrast, adolescent MLE treatment prevented the sensorimotor gating deficit in the PPI test, producing an effect similar to that of risperidone. This MLE treatment also produced a reduction in grooming behavior, but it had no effect on anxiety or novel object recognition memory. MRI studies revealed that adolescent MLE administration partially counteracted the cortical shrinkage, and cerebellum and ventricle enlargement. In addition, MLE administration in adolescence reduced iNOS mediated inflammatory activation and it promoted the expression of biomarkers of compensatory antioxidant activity in the prefrontal cortex and hippocampus, as witnessed through the reduction of Keap1 and the accumulation of NRF2 and HO1. Together, these findings suggest that MLE might be an alternative therapeutic or preventive add-on strategy to improve the clinical expression of schizophrenia in adulthood, while also modifying the time course of this disease at earlier stages in populations at high-risk.

Deep brain stimulation (DBS) is a powerful neurostimulation therapy proposed for the treatment of several neuropsychiatric disorders. However, DBS mechanism of action remains unclear, being its effects on brain dynamics of particular interest. Specifically, DBS reversibility is a major point of debate. Preclinical studies in obesity showed that the stimulation of the lateral hypothalamus (LH) and nucleus accumbens (NAcc), brain centers involved in satiety and reward circuits, are able to modulate the activity of brain structures impaired in this pathology. Nevertheless, the long-term persistence of this modulation after DBS withdrawal was unexplored. Here we examine the in vivo presence of such changes 1 month after LH- and NAcc-DBS, along with differences in synaptic plasticity, following an exploratory approach. Thus, both stimulated and non-stimulated animals with electrodes in the NAcc showed a common pattern of brain metabolism modulation, presumably derived from the electrodes’ presence. In contrast, animals stimulated in the LH showed a relative metabolic invariance, and a reduction of neuroplasticity molecules, evidencing long-lasting neural changes. Our findings suggest that the reversibility or persistence of DBS modulation in the long-term depends on the selected DBS target. Therefore, the DBS footprint would be influenced by the stability achieved in the neural network involved during the stimulation.

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Introduction: Prenatal infections are associated with an increased risk of the onset of schizophrenia. Rodent models of maternal immune stimulation (MIS) have been extensively used in preclinical studies. However, many of these studies only include males, omitting pathophysiological features unique to females. The aim of this study is to characterize the MIS model in female rats using positron emission tomography (PET), structural magnetic resonance imaging (MR), and neuroplasticiy studies.Methods: In gestational day 15, Poly I:C (or Saline) was injected into pregnant Wistar rats to induce the MIS model. Imaging studies: [18F]-fluoro-2-deoxy-D-glucose-PET scans of female-offspring were acquired at post-natal day (PND) 35 and PND100. Furthermore, T2-MR brain images were acquired in adulthood. Differences in FDG uptake and morphometry between groups were assessed with SPM12 and Regions of Interest (ROI) analyses. Ex vivo study: The density of parvalbumin expressing interneurons (PV), perineuronal nets (PNN), and parvalbumin expressing interneurons surrounded by perineuronal nets (PV-PNN) were evaluated in the prelimbic cortex and basolateral amygdala using confocal microscopy. ROIs and neuroplasticity data were analyzed by 2-sample T-test and 2-way-ANOVA analyses, respectively.Results: A significant increase in brain metabolism was found in all animals at adulthood compared to adolescence. MIS hardly modified brain glucose metabolism in females, highlighting a significant hypometabolism in the thalamus at adulthood. In addition, MIS induced gray matter (GM) enlargements in the pituitary, hippocampus, substantia nigra, and cingulate cortex, and GM shrinkages in some thalamic nuclei, cerebelar areas, and brainstem. Moreover, MIS induced white matter shrinkages in the cerebellum, brainstem and corpus callosum, along with cerebrospinal fluid enlargements in the lateral and 4th ventricles. Finally, MIS reduced the density of PV, PNN, and PV-PNN in the basolateral amygdala.Conclusion: Our work showed in vivo the differential pattern of functional and morphometric affectation in the MIS model in females, as well as the deficits caused at the synaptic level according to sex. The differences obtained highlight the relevance of including both sexes in psychiatric research in order to consider their pathophysiological particularities and successfully extend the benefits obtained to the entire patient population.