Claudio Carneiro Filgueiras

Schizophrenia and nicotine misuse comorbidity frequently emerges during adolescence. Although the dorsal striatum has received less attention than mesolimbic regions in this context, growing evidence supports its involvement in both schizophrenia-related dysfunction and the transition to compulsive drug-seeking. Here, we investigated dorsal striatal proteomic alterations in adolescent male and female C57BL/6 mice modeled to schizophrenia (phencyclidine: 2.5 mg/kg, s.c., 15 days) with a history of nicotine exposure (nicotine: 24 mg/kg/day, minipump infusions, 7 days). Dorsal striatum samples were analyzed by label-free quantitative proteomics, followed by Reactome pathway enrichment and interactome map analyses. Co-exposure induced sex-dependent alterations. Females exhibited greater proteomic disruption, whereas in males, co-exposure amplified phencyclidine-associated alterations while attenuating nicotine-driven effects. Across sexes, convergent enrichment was observed in pathways related to immune signaling, metabolic regulation and signal transduction. Female interactome analysis identified glyceraldehyde-3-phosphate dehydrogenase (Gapdh) as the most highly connected node linked to proteins involved in bioenergetics, RNA processing, and apoptosis, while the male network was centered on peptidyl-prolyl cis-trans isomerase (Fkbp1a) and associated with proteostasis-related processes. Our results identify the dorsal striatum as an emerging molecular target in an animal model combining schizophrenia-related and nicotine exposure-related insults and highlight pathways and candidate molecular markers to be further investigated and validated.

Radiotherapy, a standard treatment for brain tumors, may induce cognitive deficits and neuroinflammatory responses, including increased pro-inflammatory cytokines, microglial and astrocytic reactivity, and alterations in neuronal markers. Caffeine, a widely consumed psychostimulant with reported anti-inflammatory and neuroprotective properties, has been proposed as a potential modulator of these effects. This study evaluated whether continuous caffeine consumption is associated with attenuation of neuroinflammation, glial alterations, and behavioral impairments induced by brain irradiation in mice. Male C57BL/6J mice were assigned to four groups: non-irradiated control (C), irradiated (I), non-irradiated treated with caffeine (Ca), and irradiated treated with caffeine (ICa). Caffeine (0.25 g/L) was administered ad libitum for 94 days. Whole-brain irradiation (10 Gy) was delivered using a SARRP platform. Behavioral performance was assessed using the open-field, and object location memory tests. Immunofluorescence analyses for TNF-α, Iba1, GFAP, and NeuN were conducted in hippocampal subregions, and plasma TNF-α levels were quantified by ELISA. Irradiation impaired spatial memory, reduced locomotor activity, increased hippocampal TNF-α and GFAP immunolabeling, decreased Iba1 immunoreactivity, and reduced NeuN-positive neurons. In irradiated mice, caffeine consumption was associated with improved memory performance, preservation of locomotor activity, and attenuation of radiation-related changes in TNF-α, GFAP, Iba1, and NeuN immunolabeling. Plasma TNF-α levels did not differ across groups. Continuous caffeine consumption was associated with reduced neuroinflammatory markers and modified glial and neuronal immunolabeling patterns, coinciding with improved behavioral outcomes in irradiated mice. This effect is interpreted as post-exposure mitigation rather than true regeneration.

Considering the increased risk of cognitive deficits and mood disorders programming associated with bisphenol exposure, we used a preclinical model to identify short- and long-term effects of early exposure to Bisphenol A (BPA) and its replacement, Bisphenol S (BPS), on the central cholinergic and serotonergic systems. Wistar female and male rats born to dams exposed to BPA or BPS (both at 10 μg/kg/day or 50 μg/kg/day) during pregnancy and lactation were euthanized at weaning or adulthood. Cholinergic and serotonergic biomarkers were assessed in the frontal cortex and pons + medulla oblongata. BPA and BPS disrupted these systems, with outcomes depending on the specific bisphenol, biomarker, and time point. Effects also varied across brain regions and between sexes. The nicotinic cholinergic receptor showed more pronounced alterations than the presynaptic choline transporter. Both serotonergic receptors—5-HT1AR and 5-HT2R—were affected; however, the serotonergic transporter remained unchanged. Increased binding was the predominant effect for both systems. Maternal exposure to BPA, even at low doses, induces sex-dependent short- and long-term changes in the cholinergic and serotonergic systems of the progeny. BPS affects these same neurotransmitter systems, although leading to compound-specific outcomes. These results pose both BPA and BPS as neurotoxicants that compromise neurodevelopment and program disorders later in life.

Polychlorinated biphenyls (PCBs) are synthetic chemical compounds that have bioaccumulated and contaminated the entire global ecosystem, causing neurotoxic effects. However, polyphenols may have protective effects against this neurotoxicity. We aimed to investigate the neuroprotective effect of a hydroalcoholic extract of fresh leaves of Alpinia zerumbet (ALE), which is rich in polyphenols, on the neurobehavioral changes induced by 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). We divided C57BL/6 male mice into four groups (n = 40): Control, Control + ALE, PCB, and PCB + ALE. We administered the ALE (50 mg/kg/day) through drinking water and PCB 126 (2 mg/kg/once a week) intraperitoneally for four weeks. The mice were subjected to the elevated plus maze (EPM) and open field (OF) tests in the last week of treatment. PCB 126 reduced locomotor activity, DOPAC levels, dopamine turnover, and D2 receptor expression. This compound also increased lipid peroxidation, tyrosine levels, and BAX expression in the cerebral cortex. Notably, ALE treatment prevented locomotor activity reduction and increased DOPAC levels, dopamine turnover, and D2 receptor expression. Moreover, the extract prevented the PCB-induced increases in BAX expression and lipid peroxidation. Finally, the ALE increased SOD antioxidant activity. Our investigation highlights that using the ALE may serve as a therapeutic strategy against PCB-induced neurotoxicity.

The central renin-angiotensin system (cRAS) is a neuromodulator system that has been associated with neuropsychiatric disorders. Mainly through angiotensin II type 1 (AT1) receptor activation, cRAS increases dopamine release in striatum, and modulates glutamate release and brain cytokine levels. Considering that schizophrenia pathophysiology involves both neurotransmission and cytokine unbalance, we verified whether AT1 receptor blockade would have beneficial effects on a mouse model of schizophrenia. Phencyclidine, an NMDA receptor antagonist, was used to model schizophrenia in C57BL/6 male and female mice, while AT1 receptor antagonism was achieved by telmisartan administration. From postnatal day (PN) 60 to 70, mice received daily injections of telmisartan (0.25 or 1 mg/kg, i.p.) or saline, followed by phencyclidine (2.5 mg/kg, PN60-69; 10 mg/kg on PN70, s.c.) or saline. Mice were submitted to behavioral tests (PN63-70) and the frontal cerebral cortex and hippocampus were harvested. Telmisartan lower dose reversed phencyclidine-evoked reduced levels of interleukin-6 and interleukin-10, as well as AT1 receptor downregulation in the frontal cortex. Its higher dose mitigated hyperactivity (schizophrenia-like positive symptomatology). Deleterious effects were also identified. Both telmisartan doses, when combined with phencyclidine, impaired spatial working memory, and caused prepulse inhibition deficits (an endophenotype of schizophrenia) at one prepulse intensity used, being most unfavorable at the lower dose. Despite evidence of beneficial effects, the telmisartan-mediated impairments observed in the phencyclidine model bring concerns as to the use of this AT1 receptor antagonist as a potential therapeutic agent in schizophrenia.

Background/Objectives: Schizophrenia and nicotine misuse are a comorbid condition that frequently develops during adolescence. Considering the role of the nucleus accumbens (NAcc) as a common neurobiological substrate for these psychiatric disorders, label-free proteomics was employed to identify NAcc deregulated proteins in male and female mouse models of schizophrenia with a history of adolescent nicotine exposure. Methods: Phencyclidine was used to model schizophrenia, and minipump infusions were used to model nicotine misuse. Results: Enrichment Reactome pathway and protein–protein interaction analyses showed that the cytoskeleton and associated synaptic plasticity mechanisms, energy metabolism, and nervous system development were affected in both sexes. In particular, Ncam1 (Neural cell adhesion molecule 1) could be of interest as a candidate marker of synaptic plasticity disbalance. Its deregulation in the NAcc of both sexes suggests that it lies at the core of the comorbidity pathophysiology. When considering sex-selective effects, Cs (Citrate synthase) and Mapk3 (Mitogen-activated protein kinase 3) were identified as exclusively deregulated in female and male mice, respectively. Since both proteins were previously shown to be exclusively deregulated in the medial prefrontal cortex of co-modeled mice, a common mesocortical and mesolimbic system effect can be inferred, supporting the role of aberrant energy metabolism and synaptic plasticity in the comorbidity model. Conclusions: The current data provide insights into the NAcc proteome disbalance in an adolescent preclinical model of combined schizophrenia and nicotine misuse, pointing to relevant pathways and early markers of the comorbidity.

Background/Objectives Studies in rodents indicate that disruptions in both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling pathways are involved in the development of hyperactive behavior. We examined whether vinpocetine, a phosphodiesterase type 1 inhibitor that enhances brain cAMP and cGMP levels, could mitigate locomotor hyperactivity in mice exposed to lead during early development. Methods Swiss mice were exposed to 90 ppm of lead in their drinking water throughout gestation and the first ten postnatal days. At postnatal day 10 (PN10), blood lead levels (BLLs) were about 30 µg/dL. At PN30, animals either received vinpocetine (20 mg/kg, i.p.) or a vehicle 4 h before the evaluation of locomotor activity in the open field. Results Lead-exposed males did not display differences in locomotor activity compared to controls, while lead-exposed females showed a significant increase in locomotion. Vinpocetine treatment significantly reversed the lead-induced hyperactivity in females. Conclusions These findings suggest that the cAMP and cGMP signaling pathways play a role in the hyperactivity induced by lead exposure.

Radiotherapy can damage healthy brain tissue, leading to cognitive deficits. Physical exercise enhances neurogenesis and synaptic plasticity, improving cognitive functions like memory and learning. This study evaluated aerobic exercise’s effect on endothelial marker gene expression and memory in cranially irradiated mice. In total, 144 male Swiss mice were divided into sedentary control (SC), sedentary irradiated (SI), exercise control (EC), and irradiated exercise (EI) groups. The EI groups underwent treadmill training in three conditions: 3-months post-irradiation, 1-month pre-irradiation, and 1- month post-irradiation. Ninety days after irradiation, memory was tested using the open- field and object location memory tests. RT-qPCR analyzed hippocampal expression of VEGF-A, eNOS, and vWF. No differences were found in the open-field test, but sedentary irradiated mice showed impaired memory in the object location task. Treadmill training restored memory, especially in the 3-month post-irradiation group. Irradiation increased vWF expression, which physical exercise mitigated. Physical activity also increased VEGF-A and eNOS expression in irradiated mice. These findings suggest that post-irradiation exercise mitigates memory impairment and may influence vascular changes in the brain.

Introdução: Os bifenilos policlorados (PCBs) são compostos sintéticos que podem bioacumular e contaminar o ecossistema global. Estudos identificaram o cérebro como um alvo vulnerável para esses compostos. Substâncias com ação no Sistema Nervoso Central (SNC), como os polifenóis, têm demonstrado efeito neuroprotetor. Nosso grupo mostrou que o extrato de folhas frescas de Alpinia zerumbet (AZE), rico em polifenóis, possui efeitos antioxidantes e antiinflamatórios em um modelo de hipertensão. Objetivo: O estudo teve como objetivo avaliar se o AZE é capaz de prevenir a neurotoxicidade e alterações locomotoras induzidas pelo PCB126 em camundongos C57BL/6 adultos. Métodos: Os protocolos experimentais foram aprovados pela Comissão de Ética da UERJ (CEUA/021/2021). Camundongos C57BL/6 machos foram divididos em quatro grupos: controle (Controle), Cont+AZE (50mg/kg/dia na água de beber), PCB (2mg/Kg/uma vez por semana), PCB+AZE (2mg/Kg/uma vez por semana; 50mg/Kg/dia), durante quatro semanas. Ao final do experimento, os animais realizaram o teste do labirinto em cruz elevado e foram sacrificados. O estresse oxidativo foi avaliado por espectrofotometria em homogenato de tronco encefálico, cerebelo, mesencéfalo e córtex esquerdo. Os dados estão expressos como médias e erro padrão da média. As diferenças entre os grupos foram analisadas por análise de variância (ANOVA) seguidas pelo pós-teste de Tukey. Resultados: Houve uma diminuição da atividade locomotora no grupo PCB (59,39±2,96) em comparação ao grupo Cont+AZE (75,99±2,81), que foi prevenida pelo AZE no grupo PCB+AZE (70,92±2,77). O tempo nos braços abertos não foi diferente entre os grupos. No tronco encefálico, o grupo PCB (0,57±0,08) apresentou aumento da peroxidação lipídica em relação ao grupo Cont+AZE (0,37±0,03), o que foi prevenido pelo tratamento com AZE no grupo PCB+AZE (0,36±0,03). Não houve diferença estatística na atividade da enzima antioxidante catalase (CAT) entre os grupos. A diminuição da atividade da enzima antioxidante da superóxido dismutase (SOD) no grupo PCB (32,38±3,59) em relação aos grupos Controle (95,87±31,09) e Cont+AZE (62,54±10,77) foi prevenida pelo tratamento com AZE no grupo PCB+AZE (189,90±64,97). No cerebelo, o dano oxidativo não foi diferente entre os grupos. O tratamento com AZE preveniu a redução da atividade da CAT no grupo PCB+AZE (0,92±0,27) em comparação aos grupos Cont+AZE (0,27±0,08) e PCB (0,29±0,05). O grupo PCB (18,37±1,43) apresentou diminuição da