Inhibition of Adult Neurogenesis in Male Mice after Repeated Exposure to Paracetamol Overdose.

Paracetamol, or acetaminophen (N-acetyl-para-aminophenol, APAP), is an analgesic and antipyretic drug that is commonly used worldwide, implicated in numerous intoxications due to overdose, and causes serious liver damage. APAP can cross the blood-brain barrier and affects brain function in numerous ways, including pain signals, temperature regulation, neuroimmune response, and emotional behavior; however, its effect on adult neurogenesis has not been thoroughly investigated. We analyze, in a mouse model of hepatotoxicity, the effect of APAP overdose (750 mg/kg/day) for 3 and 4 consecutive days and after the cessation of APAP administration for 6 and 15 days on cell proliferation and survival in two relevant neurogenic zones: the subgranular zone of the dentate gyrus and the hypothalamus. The involvement of liver damage (plasma transaminases), neuronal activity (c-Fos), and astroglia (glial fibrillar acidic protein, GFAP) were also evaluated. Our results indicated that repeated APAP overdoses are associated with the inhibition of adult neurogenesis in the context of elevated liver transaminase levels, neuronal hyperactivity, and astrogliosis. These effects were partially reversed after the cessation of APAP administration for 6 and 15 days. In conclusion, these results suggest that APAP overdose impairs adult neurogenesis in the hippocampus and hypothalamus, a fact that may contribute to the effects of APAP on brain function.

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer's Disease.

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer's disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aß1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin's effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.

Sex-specific variations in spatial reference memory acquisition: Insights from a comprehensive behavioral test battery in C57BL/6JRj mice.

Sex differences in declarative memory are described in humans, revealing a female or a male advantage depending on the task. Specifically, spatial memory (i.e., spatial navigation) is typically most efficient in men. This sexual dimorphism has been replicated in male rats but not clearly in mice. In this study, sex differences in spatial memory were assessed in thirty-six C57BL/6 J mice (Janvier Labs; i.e., C57BL/6JRj mice), a widely used mouse substrain. Both male and female mice (12 weeks-old) were subjected to standard behavioral paradigms: the elevated plus maze, the open field test, the novel object and place tests, the forced swimming test, and the water maze test for spatial navigation. Across assessment, no sex differences were found in measures of locomotor activity, emotional and behavioral responses, and object and place recognition memories. In the water maze, male mice were faster in learning the platform location in the reference memory training and used more spatial strategies during the first training days. However, both sexes reached a similar asymptotic performance and performed similarly in the probe trial for long-term memory consolidation. No sex differences were found in the cued training, platform inversion sessions, or spatial working memory sessions. Hippocampal expression of the brain-derived neurotrophic factor was similar in both sexes, either in basal conditions or after performing the behavioral training battery. Importantly, female mice were not more variable than males in any measure analyzed. This outcome encourages the investigation of sex differences in animal models and the usefulness of including female mice in behavioral research.

How Healthy Is It to Fortify Cocoa-Based Products with Cocoa Flavanols? A Comprehensive Review.

(1) Background: Cocoa's healthy benefits may be attributed to the potent antioxidant activity of cocoa polyphenols, mainly flavanols, which have been characterised as existing in a high concentration in cocoa. However, the phenolic composition of cocoa and cocoa-derived products is highly variable, and manufacturing processes might significantly reduce their phenolic content. For that reason, the full characterisation of cocoa and cocoa-derived products before evaluating their bioactivity is crucial. The aim of this review is to analyse the available evidence on the effect of flavanol-fortified cocoa-derived products on human health. (2) Methods: Forty-eight clinical trials focused on the health effect of consuming flavanol-fortified drinks, bars and chocolate have been reviewed, with a total of 1523 subjects. (3) Results: Although studies differ widely in methodology, dosage, duration, and target population, beneficial effects of flavanol-rich cocoa consumption have been observed at doses ranging from 45.3 mg/d to 1078 mg/d, especially on cardiovascular health and cognitive function. (4) Conclusions: Considering the high consumption and acceptability of cocoa and cocoa-derived products, the fortification of cocoa products as well as other highly consumed foods with cocoa flavanols could be an effective strategy for health promotion.

Temozolomide treatment inhibits spontaneous motivation for exploring a complex object in mice: A potential role of adult hippocampal neurogenesis in "curiosity".

Intrinsic exploratory biases are an innate motivation for exploring certain types of stimuli or environments over others, and they may be associated with cognitive, emotional, and even personality-like traits. However, their neurobiological basis has been scarcely investigated. Considering the involvement of the hippocampus in novelty recognition and in spatial and pattern separation tasks, this work researched the role of adult hippocampal neurogenesis (AHN) in intrinsic exploratory bias for a perceptually complex object in mice. Spontaneous object preference tasks revealed that both male and female C57BL/6J mice showed a consistent unconditioned preference for exploring "complex"-irregular-objects over simpler ones. Furthermore, increasing objects' complexity resulted in an augmented time of object exploration. In a different experiment, male mice received either vehicle or the DNA alkylating agent temozolomide (TMZ) for 4 weeks, a pharmacological treatment that reduced AHN as evidenced by immunohistochemistry. After assessment in a behavioral test battery, the TMZ-treated mice did not show any alterations in general exploratory and anxiety-like responses. However, when tested in the spontaneous object preference task, the TMZ-treated mice did not display enhanced exploration of the complex object, as evidenced both by a reduced exploration time-specifically for the complex object-and a lack of preference for the complex object over the simple one. This study supports a novel role of AHN in intrinsic exploratory bias for perceptual complexity. Moreover, the spontaneous complex object preference task as a rodent model of "curiosity" is discussed.

Nutrition and adult neurogenesis in the hippocampus: Does what you eat help you remember?

Neurogenesis is a complex process by which neural progenitor cells (NPCs)/neural stem cells (NSCs) proliferate and differentiate into new neurons and other brain cells. In adulthood, the hippocampus is one of the areas with more neurogenesis activity, which is involved in the modulation of both emotional and cognitive hippocampal functions. This complex process is affected by many intrinsic and extrinsic factors, including nutrition. In this regard, preclinical studies performed in rats and mice demonstrate that high fats and/or sugars diets have a negative effect on adult hippocampal neurogenesis (AHN). In contrast, diets enriched with bioactive compounds, such as polyunsaturated fatty acids and polyphenols, as well as intermittent fasting or caloric restriction, can induce AHN. Interestingly, there is also growing evidence demonstrating that offspring AHN can be affected by maternal nutrition in the perinatal period. Therefore, nutritional interventions from early stages and throughout life are a promising perspective to alleviate neurodegenerative diseases by stimulating neurogenesis. The underlying mechanisms by which nutrients and dietary factors affect AHN are still being studied. Interestingly, recent evidence suggests that additional peripheral mediators may be involved. In this sense, the microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could act as a link between nutritional factors and AHN. The aim of this mini-review is to summarize, the most recent findings related to the influence of nutrition and diet in the modulation of AHN. The importance of maternal nutrition in the AHN of the offspring and the role of the microbiota-gut-brain axis in the nutrition-neurogenesis relationship have also been included.

Exploring the Nutritional Composition and Bioactive Compounds in Different Cocoa Powders.

Cocoa, the main derivative of the seeds of Theobroma cacao L., has been recognized to have several effects on human health including antioxidant and neuro- and cardio-protective effects, among others. These effects have been attributed mainly to its bioactive compounds. In this context, the aim of this work is to evaluate the nutritional composition, bioactive compounds (i.e., phenolic compounds, procyanidins and methylxanthines) and the antioxidant activity of seven different cocoas (alkalized and non-alkalized) from different origins (Peru, Venezuela, Ivory Coast, Dominican Republic, and West Africa). It represents the first stage of a larger project aiming to find high polyphenol cocoa-based nutritional strategies and related biomarkers that may potentiate brain plasticity and cognitive function. Cocoa powders were extracted by ultrasound-assisted technology, and the total phenolic content (TPC) was measured by Folin-Ciocalteu. Methylxanthines (caffeine and theobromine) and procyanidin contents were determined by HPLC-FLD-DAD, and the antioxidant activity was assessed through DPPH, ABTS and FRAP assays. Non-alkalized cocoas showed higher phenolic and procyanidin contents and higher antioxidant activity compared to the alkalized ones. A strongly significant (p < 0.05) positive correlation between the antioxidant activity and the TPC, especially with the total procyanidin content, but not with methylxanthines was found. In conclusion, the non-alkalized cocoas, especially the one from Peru, were the best candidates in terms of bioactive compounds. The cocoa from Peru had a TPC of 57.4 ± 14.4 mg of gallic acid equivalent/g d.w., 28,575.06 ± 62.37 µg of catechin equivalents/g d.w., and 39.15 ± 2.12 mg/g of methylxanthines. Further studies should be undertaken to evaluate its effect on brain plasticity and cognitive function.