Danielle Macedo | Universidade Federal do Ceará (original) (raw)

Papers by Danielle Macedo

Agents and actions supplements, 2020

Biological sex is an important risk factor for neurodevelopmental disorders (ND), such as autism ... more Biological sex is an important risk factor for neurodevelopmental disorders (ND), such as autism spectrum disorder (ASD) and schizophrenia. Indeed, sex influences the incidence, onset, and clinical course of ND. For example, schizophrenia is diagnosed in men at younger ages when compared to women. However, postmenopausal women diagnosed with schizophrenia present more severe symptoms and worse prognosis when compared to men. Regarding ASD, the male-to-female ratio is close to 3:1. Notably in ASD, a diagnostic gender bias seems to occur. Preclinical models based on maternal immune activation (MIA) or neonatal immune activation (NIA) were developed for a better understanding of neurobiological alterations underlying the development of schizophrenia and ASD. Importantly, MIA models relate to immune challenges on the first and second trimesters of human pregnancy, whereas NIA models to immune challenge at the end of the third trimester in humans. Despite the importance of perinatal infections for the pathogenesis of ND and for a better understanding of sex influences in the neurobiology of these disorders, preclinical studies evaluating sex-related alterations in animal models of perinatal immune activation (PIA) are still limited. This chapter summarizes the current findings on sex influences in PIA models and brings some perspectives for novel studies in this field.

Oxidative Medicine and Cellular Longevity

Anxiety disorders are the most prevalent psychiatric disorders being also a comorbid state of oth... more Anxiety disorders are the most prevalent psychiatric disorders being also a comorbid state of other diseases. We aimed to evaluate the anxiolytic-like effects of carvedilol (CVD), a drug used to treat high blood pressure and heart failure with potent antioxidant effects, in animals exposed to chronic unpredictable stress (CUS). To do this, female Swiss mice were exposed to different stressors for 21 days. Between days 15 and 21, the animals received oral CVD (5 or 10 mg/kg) or the antidepressant desvenlafaxine (DVS 10 mg/kg). On the 22nd day, behavioral tests were conducted to evaluate locomotor activity (open field) and anxiety-like alterations (elevated plus-maze—EPM and hole board—HB tests). After behavioral determinations, the animals were euthanized, and the adrenal gland, blood and brain areas, prefrontal cortex (PFC), and hippocampus were removed for biochemical analysis. CUS reduced the crossings while increased rearing and grooming, an effect reversed by both doses of CVD a...

Psychopharmacology, 2022

RATIONALE Depression is a severe psychiatric disorder with oxidative imbalance and neurotrophic d... more RATIONALE Depression is a severe psychiatric disorder with oxidative imbalance and neurotrophic deficits as underlying mechanisms. OBJECTIVES Based on the antioxidant effects of carvedilol (CARV), here, we aimed to evaluate CARV's effects against depression induced by the chronic unpredictable stress (CUS) model. METHODS Female Swiss mice were submitted to the CUS protocol for 21 days. Between days 15 and 22, the animals received CARV (5 or 10 mg/kg) or desvenlafaxine (DVS 10 mg/kg) orally. On the 22nd day, mice were subjected to behavioral tests to evaluate locomotion, depressive-like behavior (tail suspension test), motivation/self-care with the splash test (ST), social interaction, and working memory Y-maze test. The prefrontal cortex (PFC) and hippocampus were dissected to evaluate alterations of oxidative and brain-derived neurotrophic factor (BDNF). RESULTS The CUS model reduced locomotion and increased grooming latency, while it reduced the number of groomings in the ST. Both doses of CARV and DVS reverted these alterations. In addition, DVS and CARV reversed CUS model-induced working memory and social interaction deficits. The CUS model decreased hippocampal reduced glutathione (GSH), while DVS and CARV increased GSH in the PFC (CARV5) and hippocampus (CARV5 and 10). The CUS model increased nitrite and malondialdehyde (MDA) concentrations in both areas. All treatments reversed nitrite alterations, while CARV10 changed MDA levels in PFC and all treatments in the hippocampus. The CUS model reduced BDNF levels. CARV10 increased BDNF in the PFC, while both doses of CARV increased hippocampal levels of this neurotrophin. CONCLUSIONS CARV presents antidepressant-like effects comparable to those observed with DVS. In addition, it has an antioxidant effect and is capable of increasing BDNF brain concentrations. Further studies are needed to elucidate the mechanisms involved in the antidepressant effect of CARV.

Neuroscience of Alcohol, 2019

Abstract Ethanol consumption is related to pathological changes in various organs across all age ... more Abstract Ethanol consumption is related to pathological changes in various organs across all age groups. The consequences of ethanol exposure on neurodevelopment are a critical public health problem, mainly affecting people’s lives during their childhood and adolescence. Thus, the purpose of this chapter is to revise the literature regarding the consequences of ethanol exposure during neurodevelopment. Several mechanisms are proposed to explain how alcohol can produce deleterious effects on the developing brain; however, the type and extent of the damage depends on the dosage, time of exposure, and stage of brain development along with other maternal and genetic factors. In this regard, prenatal alcohol exposure (PAE) disrupts brain development causing long-term impairment in cognitive, motor, and behavioral functions. Alcohol consumption is considered the primary, potentially preventable, cause of intellectual disabilities. High levels of alcohol consumption during the gestational period may result in fetal alcohol spectrum disorders, which are considered as a set of permanent conditions characterized by typical craniofacial dysmorphology, deficiency in prenatal and postnatal growth, central nervous system dysfunction, and several associated malformations. Also, psychiatric illness, including depression, anxiety, and reduction in cognitive abilities are possible outcomes associated with fetal ethanol exposure. Moreover, studies have shown an association between PAE and impaired verbal and visual–spatial episodic memory performance in children and teenagers. To date, few investigations have clarified the mechanisms underlying the neurochemical and neurobiological alterations caused by prenatal ethanol exposure. These preliminary evidences reveal a relationship between impaired social behavior and the presence of altered structural plasticity and gene expression in the frontal cortex of adult offspring prenatally exposed to ethanol (in moderate levels).

European Neuropsychopharmacology, 2014

Epilepsy & Behavior, 2014

Rationale: Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) commonly used i... more Rationale: Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) commonly used in the treatment of depression. Although a recent report showed that an antidepressant of the same class, venlafaxine, demonstrated a potential anticonvulsant action in low doses in the pentylenetetrazole-induced seizure paradigm, there is no study, to date, investigating if duloxetine is able to play a similar role against seizures. Therefore, the main goal of this study was to verify the potential anticonvulsant effect of duloxetine on seizures induced by pentylenetetrazole (PTZ) in rats. Methods: Adults male Wistar rats weighing 150-250 g were divided into two groups. The groups were treated with intraperitoneal (i.p.) saline solution (C: 0.1 ml/10 g) or duloxetine (DUL: 20 mg/kg) 30 min before induction of chemical convulsion (PTZ: 60 mg/kg; i.p.). Then, convulsive behavior was observed for 30 min. Analysis of the threshold to the first generalized tonic-clonic seizure, duration of the first convulsion, total time in convulsion, and the number of seizures was carried out. All data were analyzed with Student's t test assuming p b 0.05 as a significant value. Results: Animals treated with duloxetine showed an average threshold twelvefold higher than that of the control group (DUL: 889.0 ± 334.0 s, C: 71.25 ± 4.78 s; p = 0.0338). No significant differences were detected in the duration, number of seizures, or total time in convulsion when the treated group was compared with the control group. Discussion/conclusions: Seizures can be modulated by experimental manipulation of serotonergic neurotransmission. Additionally, noradrenaline is a potent endogenous anticonvulsant. As demonstrated in our results, an increase in serotonergic and noradrenergic neurotransmission produced by the treatment with duloxetine was able to modulate the seizure threshold in pentylenetetrazole-induced seizures. The mechanism underlying this action should be still clarified, but the present work already contributes to better understand the comorbid relationship between epilepsy and depression. The results suggest that duloxetine may become a new adjuvant in the treatment of patients with the comorbidity, still providing a safer and more effective therapy that may avoid side effects caused by traditional polytherapy used to treat those patients. Acknowledgments/financial support: CAPES.

Journal of Psychopharmacology, 2013

It has been hypothesized that oxidative imbalance and alterations in nitrergic signaling play a r... more It has been hypothesized that oxidative imbalance and alterations in nitrergic signaling play a role in the neurobiology of schizophrenia. Preliminary evidence suggests that adjunctive minocycline treatment is efficacious for cognitive and negative symptoms of schizophrenia. This study investigated the effects of minocycline in the prevention and reversal of ketamine-induced schizophrenia-like behaviors in mice. In the reversal protocol, animals received ketamine (20 mg/kg per day intraperitoneally or saline for 14 days, and minocycline (25 or 50 mg/kg daily), risperidone or vehicle treatment from days 8 to 14. In the prevention protocol, mice were pretreated with minocycline, risperidone or vehicle prior to ketamine. Behaviors related to positive (locomotor activity and prepulse inhibition of startle), negative (social interaction) and cognitive (Y maze) symptoms of schizophrenia were also assessed. Glutathione (GSH), thiobarbituric acid-reactive substances (TBARS) and nitrite leve...

Journal of Ethnopharmacology, 2007

The anticonvulsant effects of hydroalcoholic extracts (HAEs) from the stem bark of Erythrina velu... more The anticonvulsant effects of hydroalcoholic extracts (HAEs) from the stem bark of Erythrina velutina and Erythrina mulungu on pentylenetetrazole (PTZ) and strychnine-induced seizure tests and the potentiation of pentobarbital-induced sleeping time in mice with the extracts were examined in this study. These medicinal plants belong to the Fabaceae family and are popularly used in Brazil for their effects on the central nervous system. The extracts of Erythrina velutina (intraperitoneally or orally) and Erythrina mulungu (intraperitoneally) were administered in mice at single doses (200 or 400mg/kg). While Erythrina velutina and Erythrina mulungu did not exhibit any protector effect in PTZ-induced seizures, at any dose, an increase in the latency of convulsion and in the death time was observed with both doses and routes of Erythrina velutina and at higher dose of Erythrina mulungu, in strychnine-induced seizure. No alteration was observed with Erythrina velutina and Erythrina mulungu on sleeping latency at both doses as compared to control (362.8+/-59.5). However, the sleeping time was increased in both plants as compared to control (943.8+/-129.6). In conclusion, we showed that the hydroalcoholic extracts of Erythrina velutina and Erythrina mulungu have anticonvulsant effects only in the strychnine-induced seizure model, suggesting their possible action in glycine system and a potentiation of pentobarbital sleeping time, suggesting depressant action in the central nervous system.

European Neuropsychopharmacology, 2012

European Neuropsychopharmacology, 2013

Behavioural Pharmacology, 2011

Tardive dyskinesia (TD) is a serious motor disorder related to antipsychotic therapy, whose patho... more Tardive dyskinesia (TD) is a serious motor disorder related to antipsychotic therapy, whose pathophysiology is associated to oxidative stress. Treatments that maintain antipsychotic efficacy while reducing TD risk are awaited. Haloperidol (HAL), a typical antipsychotic, is used as a putative murine model of TD. Here, we evaluated the protective role of vitamins B1, B6, and B12 alone or in combination (vitamin B cocktail) in preventing the HAL-induced orofacial dyskinesia (OD), based on their antioxidant properties. HAL (1 mg/kg) administered intraperitoneally to Wistar rats for 21 days caused OD and increased catalepsy time. The daily administration of B vitamins (B1 : B6 : B12 at 60 : 60 : 0.6 mg/kg) alone or the vitamin B cocktail, along with HAL, prevented the development of OD. Catalepsy time reduced in all groups treated with B vitamins, but to a lesser extent than OD. The participation of oxidative stress was assessed by the determination of reduced glutathione (GSH) levels and lipid peroxide formation in the striatum. HAL significantly decreased GSH levels and enhanced lipid peroxidation, whereas B1, B12, and vitamin B cocktail prevented the decrease in GSH levels. All groups treated with B vitamins presented a decrease in lipid peroxide formation. The data suggest a promising role for B vitamins in the prevention of OD.

Metabolic Brain Disease, 2021

The current drug therapy for schizophrenia effectively treats acute psychosis and its recurrence;... more The current drug therapy for schizophrenia effectively treats acute psychosis and its recurrence; however, this mental disorder's cognitive and negative symptoms are still poorly controlled. Antipsychotics present important side effects, such as weight gain and extrapyramidal effects. The essential oil of Alpinia zerumbet (EOAZ) leaves presents potential antipsychotic properties that need further preclinical investigation. Here, we aimed to determine the effects of EAOZ in the prevention and reversal of schizophrenia-like symptoms (positive, negative, and cognitive) induced by ketamine (KET) repeated administration in mice and putative neurobiological mechanisms related to this effect. To this end, we evaluated antioxidant (GSH, nitrite levels), anti-in ammatory [interleukin (IL)-6], and neurotrophic [brainderived neurotrophic factor (BDNF)] effects of this oil in hippocampal tissue. The atypical antipsychotic olanzapine (OLZ) was used as standard drug therapy. EOAZ, similarly to OLZ, prevented and reversed most KET-induced schizophrenia-like behavioral alterations, i.e., sensorimotor gating de cits and social impairment. EOAZ had a modest effect on the prevention of KET-associated working memory de cit. Compared to OLZ, EOAZ showed a more favorable side effects pro le, inducing less cataleptic and weight gain changes. EOAZ e ciently protected the hippocampus against KET-induced oxidative imbalance, IL-6 increments, and BDNF impairment. In conclusion, our data add more mechanistic evidence for the anti-schizophrenia effects of EOAZ, based on its antioxidant, anti-in ammatory, and BDNF up-regulating actions. The absence of signi cant side effects observed in current antipsychotic drug therapy seems to be an essential bene t of the oil.

Cells, 2020

Schizophrenia is a complex psychiatric disorder that exhibits an interconnection between the immu... more Schizophrenia is a complex psychiatric disorder that exhibits an interconnection between the immune system and the brain. Experimental and clinical studies have suggested the presence of neuroinflammation in schizophrenia. In the present study, the effect of antipsychotic drugs, including clozapine, risperidone, and haloperidol (10, 20 and 20 μM, respectively), on the production of IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IL-18, INF-γ, and TNF-α was investigated in the unstimulated and polyriboinosinic-polyribocytidilic acid [poly (I:C)]-stimulated primary microglial cell cultures. In the unstimulated cultures, clozapine, risperidone, and haloperidol did not influence the cytokine levels. Nevertheless, in cell cultures under strong inflammatory activation by poly (I:C), clozapine reduced the levels of IL-1α, IL-1β, IL-2, and IL-17. Risperidone and haloperidol both reduced the levels of IL-1α, IL-1β, IL-2, and IL-17, and increased the levels of IL-6, IL-10, INF-γ, and TNF-...

Progress in neuro-psychopharmacology & biological psychiatry, Jan 23, 2016

Kindling is a form of behavioral sensitization that is related to the progression of several neur... more Kindling is a form of behavioral sensitization that is related to the progression of several neuropsychiatric disorders such as bipolar disorder. We recently demonstrated that female periadolescent rats are more vulnerable to nicotine (NIC)-induced kindling than their male counterparts. Furthermore, we evidenced that decreases in brain antioxidative defenses may contribute to this gender difference. Here we aimed to determine the preventive effects of the antioxidant N-acetyl cysteine (NAC) against NIC-kindling in female periadolescent rats. To do this female Wistar rats at postnatal day 30 received repeated injections of NIC 2mg/kg, i.p. every weekday for up to 19days. NAC90, 180 or 270mg/kg, i.p. was administered 30min before NIC. The levels of glutathione (GSH), superoxide dismutase (SOD) activity, lipid peroxidation (LP) and nitrite were determined in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). The development of kindling occurred at a median time of 16.5day...

Infarma Ciencias Farmaceuticas, Jan 25, 2013

Current topics in behavioral neurosciences, 2021

Progress in Neuro-Psychopharmacology and Biological Psychiatry

$Research paper thumbnail of Bipolar disorder: an association of body mass index and cingulate gyrus fractional anisotropy not mediated by systemic inflammation$

OBJECTIVE To investigate body mass index (BMI) associations with white matter fractional anisotro... more OBJECTIVE To investigate body mass index (BMI) associations with white matter fractional anisotropy (FA) and C-reactive protein (CRP) in individuals with bipolar disorder (BD) during euthymia in comparison with a control group of healthy subjects (CTR). METHODS The sample consisted of 101 individuals (BD n=35 and CTR n=66). Regions of interest (ROI) were defined through machine learning approach. For each ROI, a regression model tested the association of FA and BMI controlling for covariates. Peripheral levels of CRP were dosed, correlated with BMI and included in a mediational analysis. RESULTS BMI predicted FA of the right cingulate gyrus in BD (AdjR²=.312 F(3)=5.537 p=.004; β=-.340 p=.034), while in CTR, there was no association. There was an interaction effect of BMI and BD diagnosis (F(5)=3.5857 p=.012; Fchange=.227 AdjR²=.093; β=-1.093, p=.048). Furthermore, there was a positive correlation between BMI and CRP in both groups (AdjR²=.170 F(3)=7.337 p<.001; β=.364 p=.001), bu...

Bipolar Disorder: From Neuroscience to Treatment

Bipolar disorder (BD) is a severe, debilitating psychiatric condition with onset in adolescence o... more Bipolar disorder (BD) is a severe, debilitating psychiatric condition with onset in adolescence or young adulthood and often follows a relapsing and remitting course throughout life. The concept of neuroprogression in BD refers to the progressive path with an identifiable trajectory that takes place with recurrent mood episodes, which eventually leads to cognitive, functional, and clinical deterioration in the course of BD. Understanding the biological basis of neuroprogression helps to explain the subset of BD patients who experience worsening of their disorder over time. Additionally, the study of the neurobiological mechanisms underpinning neuroprogression will help BD staging based on systems biology. Replicated epidemiological studies have suggested inflammatory mechanisms as primary contributors to the neuroprogression of mood disorders. It is known that dysregulated inflammatory/immune pathways are often associated with BD pathophysiology. Hence, in this chapter, we focus on the evidence for the involvement of inflammation and immune regulated pathways in the neurobiological consequences of BD neuroprogression. Herein we put forth the evidence of immune markers from autoimmune disorders, chronic infections, and gut-brain axis that lead to BD neuroprogression. Further, we highlighted the peripheral and central inflammatory components measured along with BD progression.

Journal of Neuroimmune Pharmacology

The recent outbreak of coronavirus disease 2019 (COVID-19) has gained considerable attention worl... more The recent outbreak of coronavirus disease 2019 (COVID-19) has gained considerable attention worldwide due to its increased potential to spread and infect the general population. COVID-19 primarily targets the human respiratory epithelium but also has neuro-invasive potential. Indeed, neuropsychiatric manifestations, such as fatigue, febrile seizures, psychiatric symptoms, and delirium, are consistently observed in COVID-19. The neurobiological basis of neuropsychiatric COVID-19 symptoms is not fully understood. However, previous evidence about systemic viral infections pointed to an ongoing neuroinflammatory response to viral antigens and proinflammatory mediators/immune cells from the periphery. Microglia cells mediate the overproduction of inflammatory cytokines, free radicals, and damage signals, culminating with neurotoxic consequences. Semi-synthetic second-generation tetracyclines, including minocycline (MINO) and doxycycline (DOXY), are safe bacteriostatic agents that have remarkable neuroprotective and anti-inflammatory properties. Promising results have been obtained in clinical trials using tetracyclines for major psychiatric disorders, such as schizophrenia and major depression. Tetracyclines can inhibit microglial reactivity and neuroinflammation by inhibiting nuclear factor kappa B (NF-kB) signaling, cyclooxygenase 2, and matrix metalloproteinases (MMPs). This drug class also has a broad profile of activity against bacteria associated with community-based pneumonia, including atypical agents. COVID-19 patients are susceptible to secondary bacterial infections, especially those on invasive ventilation. Therefore, we suggest tetracyclines' repurposing as a potential treatment for COVID-19 neuropsychiatric manifestations. These drugs can represent a valuable multi-modal treatment for COVID-19-associated neuroinflammatory alterations based on their broad antimicrobial profile and neuroinflammation control.