Shaping transverse-tubules: central mechanisms that play a role in the cytosol zoning for muscle contraction.

A transverse-tubule (T-tubule) is an invagination of the plasma membrane penetrating deep into muscle cells. An extensive membrane network of T-tubules is crucial for rapid and synchronized signal transmission from the cell surface to the entire sarcoplasmic reticulum for Ca2+ release, leading to muscle contraction. T-tubules are also indispensable for the formation and positioning of other muscle organelles. Their structure and physiological roles are relatively well established; however, the mechanisms shaping T-tubules require further elucidation. Centronuclear myopathy (CNM), an inherited muscular disorder, accompanies structural defects in T-tubules. Membrane traffic-related genes, including MTM1 (Myotubularin 1), DNM2 (Dynamin 2), and BIN1 (Bridging Integrator-1), were identified as causative genes of CNM. In addition, causative genes for other muscle diseases are also reported to be involved in the formation and maintenance of T-tubules. This review summarizes current knowledge on the mechanisms of how T-tubule formation and maintenance is regulated.

Transcriptome sequencing reveals novel molecular features of SLE severity.

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of autoantibodies, immune complex deposition, and tissue/organ damage. In this study, we aimed to identify molecular features and signaling pathways associated with SLE severity using RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), and clinical parameters. Methods: We analyzed transcriptome profiles of 45 SLE patients, grouped into mild (mSLE, SLEDAI ≤ 9) and severe (sSLE, SLEDAI > 9) based on SLE Disease Activity Index (SLEDAI) scores. We also collected clinical data on anti-dsDNA, ANA, ESR, CRP, snRNP, AHA, and anti-Smith antibody status for each patient. Results: By comparing gene expression across groups, we identified 12 differentially expressed genes (DEGs), including 7 upregulated (CEACAM6, UCHL1, ARFGEF3, AMPH, SERPINB10, TACSTD2, and OTX1) and 5 downregulated (SORBS2, TRIM64B, SORCS3, DRAXIN, and PCDHGA10) DEGs in sSLE compared to mSLE. Furthermore, using the CIBERSORT algorithm, we found that Treg cells were significantly decreased in sSLE and negatively correlated with AMPH expression, which was mainly expressed in Treg cells from SLE patients according to public scRNA-seq data (GSE135779). Discussion: Overall, our findings shed light on the molecular mechanisms underlying SLE severity and provide insight into potential therapeutic targets.

Ex vivo and in vitro inhibitory potential of Kava extract on monoamine oxidase B activity in mice.

Background and aim: This study investigated the effect of Kava extract (Piper methysticum), a medicinal plant that has been worldly used by its anxiolytic effects, on monoamine oxidase (MAO) activity of mice brain after 21 days of treatment as well as anxiolytic and locomotor behavior. Furthermore, the in vitro inhibitory profile of Kava extract on MAO-B activity of mouse brain was evaluated. Experimental procedure: Mice were treated with Kava extract (10, 40, 100 and 400 mg/kg) for 21 days by gavage. After behavioral analysis (plus maze test and open field), MAO activity in different mouse brain structures (cortex, hippocampus, region containing the substantia nigra and striatum) were performed. MAO-B inhibitory profile was characterized in vitro. Results: The treatment with Kava extract (40 mg/kg) increased the percentage of entries of mice into the open arms. Ex vivo analysis showed an inhibition on MAO-B activity caused by Kava extract in cortex (10 mg/kg) and in the region containing the substantia nigra (10 and 100 mg/kg). In vitro, Kava extract also reversibly inhibited MAO-B activity with IC50 = 14.62 µg/mL and, increased Km values at the concentrations of 10 and 30 µg/mL and decreased Vmax value at 100 µg/mL. Conclusion: Kava extract showed different effects on MAO-B isoform depending on the brain structure evaluated. Therefore, the use of Kava extract could be promissory in pathologies where MAO-B is the pharmacological target.

Development of a high-throughput differential mobility separation-tandem mass spectrometry (DMS-MS/MS) method for clinical urine drug testing.

INTRODUCTION: Differential mobility separation (DMS) is an analytical technique used for rapid separation of ions and isomers based on gas phase mobility prior to entering a mass spectrometer for analysis. The entire DMS process is accomplished in fewer than 20 ms and can be used as a rapid alternative to chromatographic separation. OBJECTIVE: The primary objective was to evaluate the utility of DMS-tandem mass spectrometry (DMS-MS/MS) as a replacement for immunoassay-based clinical toxicology testing. METHODS: A sensitive DMS-MS/MS method was developed and validated for simultaneous identification of 33 drugs and metabolites in human urine samples. After DMS optimization, the method was validated and used to screen 56 clinical urine samples. These results were compared to results obtained by immunoassay. RESULTS: The DMS-MS/MS method achieved limits of detection ranging from 5 to 100 ng/mL. Moreover, the total analysis time was 2 min per sample. For the method performance evaluation, DMS-MS/MS results were compared with previously obtained urine toxicology immunoassay results. DMS-MS/MS showed higher sensitivity and identified 20% more drugs in urine, which were confirmed by LC-MS/MS. CONCLUSION: The DMS-MS/MS as applied in our lab demonstrated the capability for rapid drug screening and provided better analytical performance than immunoassay.

A case of non-small cell lung cancer presenting anti-amphiphysin antibody-positive paraneoplastic neurological syndrome.

Paraneoplastic neurological syndrome (PNS) is associated with malignancies, such as small-cell lung cancer. However, patients with non-small cell lung cancer (NSCLC) rarely develop PNS. We herein report a 72-year-old man with NSCLC who developed disturbance of consciousness on the day of initiation of treatment with an immune checkpoint inhibitor. Blood test results revealed anti-amphiphysin (AMPH) antibody positively, leading to the diagnosis of PNS. The disturbance of consciousness was improved with intravenous administration of steroid and immunoglobulin. To our knowledge, this is the first report of anti-AMPH antibody-positive PNS in a patient with NSCLC.

AMPH1 functions as a tumour suppressor in ovarian cancer via the inactivation of PI3K/AKT pathway.

AMPH1, an abundant protein in nerve terminals, plays a critical role in the recruitment of dynamin to sites of clathrin-mediated endocytosis. Recently, it is reported to be involved in breast cancer and lung cancer. However, the impact of AMPH1 on ovarian cancer is unclear. In this study, we used gain-of-function and loss-of-function methods to explore the role of AMPH1 in ovarian cancer cells. AMPH1 inhibited ovarian cancer cell growth and cell migration, and promoted caspase-3 activity, resulting in the increase of cell apoptosis. In xenograft mice model, AMPH1 prevented tumour progression. The anti-oncogene effects of AMPH1 on ovarian cancer might be partially due to the inhibition of PI3K/AKT signalling pathway after overexpression of AMPH1. Immunohistochemistry analysis showed that the staining of AMPH1 was remarkably reduced in ovarian cancer tissues compared with normal ovarian tissues. In conclusion, our study identifies AMPH1 as a tumour suppressor in ovarian cancer in vitro and in vivo. This is the first evidence that AMPH1 inhibited cell growth and migration, and induced apoptosis via the inactivation of PI3K/AKT signalling pathway on ovarian cancer, which may be used as an effective strategy.

AMPH-1 As A Critical Tumor Suppressor That Inhibits Osteosarcoma Progression.

INTRODUCTION: Amphiphysin 1 (AMPH-1) is involved in endocytosis, and its expression is upregulated in osteosarcoma compared with osteofibrous dysplasia. METHODS: We investigated the role of AMPH-1 in osteosarcoma cells via both gain-of-function and loss-of-function experiments. RESULTS: Knockdown of AMPH-1 in osteosarcoma cells promoted cell cycle progression and cell proliferation and attenuated apoptosis. Notably, silencing AMPH-1 increased osteosarcoma progression in a mouse tumor model. The results obtained upon AMPH-1 knockdown and AMPH-1 overexpression indicates that AMPH-1 is involved in regulating MEK/ERK signaling. CONCLUSION: These data suggest that AMPH-1 plays an important role in osteosarcoma and may represent a novel therapeutic target for osteosarcoma treatment.

miR-425 regulates cell proliferation, migration and apoptosis by targeting AMPH-1 in non-small-cell lung cancer.

BACKGROUND: MicroRNAs (miRNAs) have been proved to act as vital roles on non-small-cell lung cancer (NSCLC), and miR-425 has been proven to serve an important function in several tumors. However, the functional role of miR-425 on NSCLC is still unclear. METHODS: The mRNA and protein expression of miR-425 and AMPH-1 were determined by qRT-PCR and western blot analysis, respectively. NSCLC cells (SK-MES-1 and A549) proliferation and migration were measured by CCK-8 and transwell assay, respectively. Cell apoptosis was assessed by flow cytometry and western blotting, In addition, luciferase reporter assay was carried out to confirm the direct targeting of AMPH-1 by miR-425. Xenograft experiments were performed to observe the tumorigenesis of miR-425 in vivo. RESULTS: The results showed that miR-425 was overexpressed and AMPH-1 expression was downregulated in SK-MES-1 and A549 cells. Silencing miR-425 inhibited proliferation, migration and promoted apoptosis of NSCLC cells. Moreover, we proved that miR-425 could target AMPH-1. The expression of AMPH-1was upregulated in A549 with miR-425 inhibitor. Moreover, miR-425 knockdown were less tumorigenic than the control in vivo. CONCLUSIONS: Taken together, miR-425 could promote the proliferation, invasion and suppress apoptosis by targeting AMPH-1 in NSCLC cells. miR-425/AMPH-1 axis may represent a potential therapeutic strategy or novel prognostic biomarkers to NSCLC.

WHI-2 Regulates Intercellular Communication via a MAP Kinase Signaling Complex.

The formation of the fungal mycelial network is facilitated by somatic cell fusion of germinating asexual spores (or germlings). Neurospora crassa germlings in close proximity display chemotropic growth that is dependent upon an intracellular network of mitogen-activated protein kinase (MAPK) signaling cascades. Approximately 80 genes involved in intercellular communication and fusion have been identified, including three mutants with similar morphological phenotypes: Δwhi-2, Δcsp-6, and Δamph-1. Here we show that WHI-2 localizes to the cell periphery and regulates endocytosis, mitochondrial organization, sporulation, and cell fusion. WHI-2 was required to transduce signals through a conserved MAPK pathway (NRC-1/MEK-2/MAK-2) and target transcription factors (PP-1/ADV-1). The amph-1 locus encodes a Bin/Amphiphysin/Rvs domain-containing protein and mis-expression of whi-2 compensated for the cell fusion and endocytosis deficiencies of a Δamph-1 mutant. The csp-6 locus encodes a haloacid dehalogenase phosphatase whose activity was essential for cell fusion. Although fusion-deficient with themselves, cells that lacked whi-2, csp-6, or amph-1 showed a low frequency of chemotropic interactions with wild type cells. We hypothesize that WHI-2 could be important for signal perception during chemotropic interactions via a role in endocytosis.

Substitution therapy with amphetamine-isotherapic attenuates amphetamine toxicological aspects of addiction.

INTRODUCTION: amphetamine (AMPH) is related to development of addiction, anxiety-like behaviors and impairments of memory after chronic use. In the current experiment, an ultra-high dilution (10-24mg/mL) of AMPH was used, consisting of the AMPH isotherapic (AMPH-ISO), which can be used as a replacement therapy to treat AMPH addiction. AIM: To verify the influence of AMPH-ISO on toxicological aspects of AMPH addiction. METHODS: Rats received d,l-AMPH (4.0 mg/kg, i.p.) in the conditioned place preference (CPP) paradigm (8 days). Then, half of each experimental group (AMPH or saline) received AMPH-ISO/vehicle (0.2 mL per rat, once a day), for fourteen days. On the fifteenth day, animals were re-assessed in the CPP paradigm (to verify relapse behaviors) after a single dose of AMPH (2.0 mg/kg). Subsequently, anxiety-like behaviors were quantified, followed by ex vivo assays in the pre-frontal cortex. RESULTS: AMPH-ISO prevented relapse-like behavior of AMPH and reduced anxiety-like behavior per se in animals co-treated with AMPH. Molecular analysis evidenced that AMPH-ISO modulated dopaminergic targets (dopamine transporter, tyrosine hydroxylase and D1-R), whose immunoreactivity was increased by AMPH. Also, AMPH-ISO increased catalase activity and NPSH levels and reduced lipid peroxidation and protein carbonyl levels in the prefrontal cortex. CONCLUSION: This study shows that an ultra-high dilution of AMPH may be a useful alternative which can contribute with AMPH addiction treatment.

AMPH-1 is critical for breast cancer progression.

Amphiphysin 1 (AMPH-1) is a nerve terminals-enriched protein involved in endocytosis, and we observe that its expression is increased in breast cancer tumor in compared with normal breast. However, its function in breast cancer is unknown. Here we aim to explore the role of AMPH-1 in breast cancer cells. Knockdown of AMPH-1 in breast cancer cells promotes cell proliferation, cell cycle progression and cell migration, and attenuates cell apoptosis. Of note, knockdown of AMPH-1 promotes breast cancer progression in xenograft mouse model. These oncogenic phenotypes may be partially due to the activated EMT and ERK pathways after inhibition of AMPH-1. Oncomine analyses of multiple breast cancer patient datasets show that reduced AMPH-1 mRNA level is significantly associated with breast cancer patients having metastatic events, advanced stage, poor clinical outcomes, and Paclitaxel+FEC treatment resistance. In summary, our results identified the anti-oncogenic function of AMPH-1 in breast cancer in vitro and in vivo. Activation of AMPH-1 may be a promising approach to treat breast cancer patients.

Acute exacerbation of idiopathic pulmonary fibrosis triggered by Aspergillus empyema.

Acute exacerbation (AE) is a severe and life-threatening complication of idiopathic pulmonary fibrosis (IPF). In 2016, the definition and diagnostic criteria for AE-IPF were updated by an international working group. The new definition includes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events) characterized by evidence of new widespread alveolar abnormality in patients with IPF. There are no currently proven beneficial management strategies for idiopathic and triggered AE-IPF. This is the first report describing AE-IPF triggered by Aspergillus empyema, which was improved by a combination of corticosteroid, systemic antifungal therapy, local antifungal therapy, and additional pharmacological therapies. Future research may reveal optimal strategies for both idiopathic and triggered AE-IPF.

Effects of amphetamine and methylphenidate on attentional performance and impulsivity in the mouse 5-Choice Serial Reaction Time Task.

BACKGROUND: Few studies have investigated the effects of conventional attention deficit-hyperactivity disorder (ADHD) medication in the mouse 5-choice serial reaction time task (5-CSRTT), and rat studies have yielded inconsistent results. OBJECTIVE: We aimed to examine the effects of acute methylphenidate (MPH) and amphetamine (AMPH) treatment in the mouse 5-CSRTT. METHODS: Trained male C57Bl/6J mice were tested in a variable stimulus duration schedule. Effects of AMPH (0.25, 0.5, and 1 mg/kg) and MPH (0.5, 1.0, and 2.0 mg/kg) on discriminative accuracy, omissions, and premature responses were assessed. Saline treatment data determined high- and low-attentive (LA), and high- and low-impulsive (LI) subgroups according to the upper and lower 30th percentiles, respectively. RESULTS: In the LA subgroup accuracy was improved by 0.5 mg/kg AMPH and 2 mg/kg MPH, while no effect was found in the high-attentive (HA) subgroup. Premature responses were increased by 1 mg/kg AMPH and 0.5 mg/kg MPH for all animals, and by 1 mg/kg AMPH for the LI subgroup. CONCLUSIONS: The use of variable stimulus duration, along with the division into high- and LA, and high-and LI subgroups, may improve the sensitivity of the 5-CSRTT when investigating drug effects on attention and impulsivity.

Epigenetic landscape of amphetamine and methamphetamine addiction in rodents.

Amphetamine and methamphetamine addiction is described by specific behavioral alterations, suggesting long-lasting changes in gene and protein expression within specific brain subregions involved in the reward circuitry. Given the persistence of the addiction phenotype at both behavioral and transcriptional levels, several studies have been conducted to elucidate the epigenetic landscape associated with persistent effects of drug use on the mammalian brain. This review discusses recent advances in our comprehension of epigenetic mechanisms underlying amphetamine- or methamphetamine-induced behavioral, transcriptional, and synaptic plasticity. Accumulating evidence demonstrated that drug exposure induces major epigenetic modifications-histone acetylation and methylation, DNA methylation-in a very complex manner. In rare instances, however, the regulation of a specific target gene can be correlated to both epigenetic alterations and behavioral abnormalities. Work is now needed to clarify and validate an epigenetic model of addiction to amphetamines. Investigations that include genome-wide approaches will accelerate the speed of discovery in the field of addiction.

Mitochondria: key players in the neurotoxic effects of amphetamines.

Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers.

Impaired mTORC2 signaling in catecholaminergic neurons exaggerates high fat diet-induced hyperphagia.

OBJECTIVE: Food intake is highly regulated by central homeostatic and hedonic mechanisms in response to peripheral and environmental cues. Neutral energy balance stems from proper integration of homeostatic signals with those "sensing" the rewarding properties of food. Impairments in brain insulin signaling causes dysregulation of feeding behaviors and, as a consequence, hyperphagia. Here, we sought to determine how the mammalian target of rapamycin complex 2 (mTORC2), a complex involved in insulin signaling, influences high fat feeding. METHODS: Rictor is a subunit of mTORC2, and its genetic deletion impairs mTORC2 activity. We used Cre-LoxP technology to delete Rictorin tyrosine hydroxylase (TH) expressing neurons (TH Rictor KO). We assessed food intake, body weight, body composition and DA dependent behaviors. RESULTS: TH Rictor KO mice display a high-fat diet specific hyperphagia, yet, when on low-fat diet, their food intake is indistinguishable from controls. Consistently, TH Rictor KO become obese only while consuming high-fat diet. This is paralleled by reduced brain DA content, and disruption of DA dependent behaviors including increased novelty-induced hyperactivity and exaggerated response to the psycho stimulant amphetamine (AMPH). CONCLUSIONS: Our data support a model in which mTORC2 signaling within catecholaminergic neurons constrains consumption of a high-fat diet, while disruption causes high-fat diet-specific exaggerated hyperphagia. In parallel, impaired mTORC2 signaling leads to aberrant striatal DA neurotransmission, which has been associated with obesity in human and animal models, as well as with escalating substance abuse. These data suggest that defects localized to the catecholaminergic pathways are capable of overriding homeostatic circuits, leading to obesity, metabolic impairment, and aberrant DA-dependent behaviors.

Stress and withdrawal from d-amphetamine alter 5-HT2A receptor mRNA expression in the prefrontal cortex.

Psychostimulant withdrawal results in emotional, behavioral, and cognitive impairments, which may be exacerbated by stress. However, little is known about the neurochemical changes that occur when these two conditions are experienced concomitantly. 5-HT2A receptor (5-HT2AR) mRNA expression in the prefrontal cortex (PFC) is diminished following withdrawal from d-amphetamine (AMPH) and may underlie the emotional and cognitive impairments observed in psychostimulant withdrawal, but whether stress affects 5-HT2AR mRNA expression during psychostimulant withdrawal is unknown. The goal of this study was to examine the impact of forced swim test (FST) exposure during AMPH withdrawal on 5-HT2AR mRNA expression in PFC. Animals were treated 3 times a day for 4 days with escalating doses of AMPH (1-10mg/kg) and 24h or 4 days after the final injection, animals were subjected to FST. At 24h of withdrawal, AMPH-treated animals showed greater immobility in FST and at 4 days of withdrawal, AMPH-treated animals did not show immobility. At 24h of withdrawal, animals showed lower 5-HT2AR mRNA expression in the PFC relative to saline-treated animals, and exposure to FST did not further decrease expression in these animals. At 4 days of withdrawal, AMPH-treated animals showed greater 5-HT2AR mRNA expression relative to saline-treated animals in the PFC, an effect that was diminished by exposure to FST. These data indicate that stress and short-term AMPH withdrawal affect prefrontal 5-HT2AR mRNA expression to a similar degree, and stress experienced during long-term AMPH withdrawal can diminish the recovery of 5-HT2AR mRNA expression. Together, these data suggest that exposure to stress during extended AMPH withdrawal could prolong withdrawal-induced, 5-HT2AR mRNA expression which could be related to 5-HT2AR mediated deficits.

N-terminus regulation of VMAT2 mediates methamphetamine-stimulated efflux.

The 20 amino acid (AA) N-terminus of the vesicular monoamine transporter 2 (VMAT2) was examined as a regulator of VMAT2 function. Removal of the first 16 or 19 AAs of the N-terminus resulted in a molecule with reduced ability to sequester [(3)H]-5HT. A glutathione-S-transferase-construct of the N-terminus underwent phosphorylation in the presence of PKC at serines 15 and 18. These putative phosphorylation sites were examined for effects on function. Phospho-mimetic substitution of serines 15 and 18 with aspartate in the full-length VMAT2 resulted in reduced [(3)H]-5HT sequestration and reduced methamphetamine (METH)-stimulated efflux of preloaded [(3)H]-5HT. In contrast, mutation of serines 15 and 18 to alanines maintained intact net substrate sequestration but eliminated METH-stimulated efflux of pre-accumulated [(3)H]-5HT. In summary, these data suggest a model in which the VMAT2 N-terminus regulates monoamine sequestration.

Effects of withdrawal from repeated amphetamine exposure in peri-puberty on neuroplasticity-related genes in mice.

Although extensive evidence demonstrates that repeated administration of amphetamine (AMPH) induces behavioral and neurochemical sensitization, the influence of the developmental timing of AMPH administration is unknown. This is an important issue to address because it could help clarify the influence of early drug exposure on neuronal plasticity and the involvement of dopaminergic sensitization in the etiopathology of neuropsychiatric disorders. Thus, we decided to investigate the molecular alterations induced by the administration of AMPH during adolescence, when repeated exposure to the psychostimulant may interfere with developmental neuroplasticity. We investigated the expression of the neurotrophin brain-derived neurotrophic factor (BDNF) and of two inducible-early genes (arc and cfos) that bridge neuronal activity with long-lasting functional alterations. We found that peri-pubertal treatment with AMPH induces long-lasting changes in the expression of bdnf and of activity-regulated genes in the hippocampus and in the prefrontal/frontal cortex, and leads to alterations of their short-term modulation in response to a subsequent acute AMPH challenge. These data suggest that AMPH exposure in peri-puberty may negatively affect the maturation of brain structures, such as the prefrontal cortex, which facilitate the development of dopamine sensitization and may contribute to dopamine-dependent behavioral dysfunctions and molecular alterations in adulthood.

Influence of lifelong dietary fats on the brain fatty acids and amphetamine-induced behavioral responses in adult rat.

The influence of dietary fatty acids (FA) on mania-like behavior and brain oxidative damage were evaluated in rats. First generation of rats born and maintained under supplementation with soybean-oil (SO), fish-oil (FO) or hydrogenated-vegetable-fat (HVF), which are rich in n-6, n-3 and trans (TFA) FA, respectively, until adulthood, were exposed to an amphetamine (AMPH)-induced mania animal model to behavioral and biochemical evaluations. While AMPH caused hyperlocomotion in HVF and, to a less extent, in SO- and FO-groups, a better memory performance was observed in FO group. Among vehicle-groups, HVF increased reactive species (RS) generation and protein-carbonyl (PC) levels in cortex; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. Among AMPH-treated animals, HVF exacerbated RS generation in all evaluated brain areas and increased PC levels in cortex and striatum; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. FO was related to higher percentage of polyunsaturated fatty acids (PUFA) and docosahexaenoic acid (DHA) in cortex and striatum, while HVF was associated to higher incorporation of TFA in cortex, hippocampus and striatum, besides increased n-6/n-3 FA ratio in striatum. While a continuous exposure to TFA may intensify oxidative events in brain, a prolonged FO consumption may prevent mania-like-behavior; enhance memory besides decreasing brain oxidative markers. A substantial inclusion of processed foods, instead of foods rich in omega-3, in the long term is able to influence the functionality of brain structures related to behavioral disturbances and weaker neuroprotection, whose impact should be considered by food safety authorities and psychiatry experts.