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.

The microbiota-gut-brain axis is a complex interconnected system altered in schizophrenia. The antioxidant N-acetylcysteine (NAC) has been proposed as an adjunctive therapy to antipsychotics in clinical trials, but its role in the microbiota-gut-brain axis has not been sufficiently explored. We aimed to describe the effect of NAC administration during pregnancy on the gut-brain axis in the offspring from the maternal immune stimulation (MIS) animal model of schizophrenia. Pregnant Wistar rats were treated with PolyI:C/Saline. Six groups of animals were studied according to the study factors: phenotype (Saline, MIS) and treatment (no NAC, NAC 7 days, NAC 21 days). Offspring were subjected to the novel object recognition test and were scanned using MRI. Caecum contents were used for metagenomics 16S rRNA sequencing. NAC treatment prevented hippocampal volume reduction and long-term memory deficits in MIS-offspring. In addition, MIS-animals showed lower bacterial richness, which was prevented by NAC. Moreover, NAC7/NAC21 treatments resulted in a reduction of proinflammatory taxons in MIS-animals and an increase in taxa known to produce anti-inflammatory metabolites. Early approaches, like this one, with anti-inflammatory/anti-oxidative compounds, especially in neurodevelopmental disorders with an inflammatory/oxidative basis, may be useful in modulating bacterial microbiota, hippocampal size, as well as hippocampal-based memory impairments.

Schizophrenia is a chronic neurodevelopmental disorder with an inflammatory/prooxidant component. N-acetylcysteine (NAC) has been evaluated in schizophrenia as an adjuvant to antipsychotics, but its role as a preventive strategy has not been sufficiently explored. We aimed to evaluate the potential of NAC administration in two-time windows before the onset of symptoms in a schizophrenia-like maternal immune stimulation (MIS) rat model. Pregnant Wistar rats were injected with Poly I:C or Saline on gestational day (GD) 15. Three different preventive approaches were evaluated: 1) NAC treatment during periadolescence in the offspring (from postnatal day [PND] 35 to 49); 2) NAC treatment during pregnancy after MIS challenge until delivery (GD15–21); and 3) NAC treatment throughout all pregnancy (GD1–21). At postnatal day (PND) 70, prepulse inhibition (PPI) and anxiety levels were evaluated. In vivo magnetic resonance (MR) imaging was acquired on PND100 to assess structural changes in gray and white matter, and brain metabolite concentrations. Additionally, inflammation and oxidative stress (IOS) markers were measured ex vivo in selected brain regions. MIS offspring showed behavioral, neuroanatomical, and biochemical alterations. Interestingly, NAC treatment during periadolescence prevented PPI deficits and partially counteracted some biochemical imbalances. Moreover, NAC treatments during pregnancy not only replicated the beneficial outcomes reported by the treatment in periadolescence, but also prevented some neuroanatomical deficits, including reductions in hippocampal and corpus callosum volumes. This study suggests that early reduction of inflammation and prooxidation could help prevent the onset of schizophrenia-like symptoms, supporting the importance of anti-IOS compounds in ameliorating this disorder.

Omega-3 fatty acids (OM) have been employed as adjunctive therapy in patients with schizophrenia, but their potential as a preventive strategy remains unclear. This study aims to evaluate whether dietary OM supplementation during pregnancy may prevent schizophrenia-like deficits in a maternal immune stimulation (MIS) model. Pregnant Wistar rats were injected with PolyI:C (i.e. MIS) or Saline on gestational day 15. They were fed with OM-enriched chow, either from MIS until delivery (OM7) or throughout gestation (OM21). Two control groups (Saline-naïve & MIS-naïve) were maintained on standard chow. In adulthood, offspring were assessed through tests for locomotion, anxiety and short- and long-term memory (STM, LTM). Brain glucose metabolism and structural in vivo neuroimaging studies were performed using PET and MRI techniques. OM7/OM21 treatments prevented the hyperlocomotion in MIS-offspring while STM deficits were only improved by OM7. Both OM7/OM21 treatments prevented certain metabolic and volumetric changes in the cortex, as well as the enlargement of the ventricles. Additionally, OM21 protected WM integrity in MIS-offspring. Altogether, our study highlights the potential of prenatal OM dietary supplementation to ameliorate some of the SCZ-like deficits observed in the MIS model.

The lateral hypothalamus (LH) plays a key role in regulating energy balance and appetite, making it a potential target for deep brain stimulation (DBS) in treatment-resistant obesity. In this study, we evaluated the short and long-term in vivo effects of continuous LH-DBS over 15 days in a genetic model of obesity: the Zucker rat. We examined changes in body weight, brain glucose metabolism (via positron emission tomography, PET), and memory performance, along with ex vivo neuroplasticity in different hippocampal layers one month post-treatment. Contrary to expectations, continuous LH-DBS did not reduce the weight gain or food intake. While stimulated rats exhibited hippocampal hypermetabolism and enhanced synaptogenesis, these changes did not translate into cognitive improvements. Interestingly, long-term memory benefits were observed in all animals that underwent surgery, regardless of whether they received stimulation. In conclusion, our results do not support continuous LH-DBS as an effective treatment to reduce body weight in cases of obesity with genetic leptin resistance. However, the hippocampal modulation induced by continuous LH-DBS shows potential for addressing cognitive impairments associated with leptin resistance. These findings suggest that alternative DBS protocols may help restore hippocampal function, warranting further investigation.