Zuleide M. Ignácio

Epigenetic and epistatic interactions between serotonin transporter and brain-derived neurotrophic factor genetic polymorphism: Insights in depression

Epidemiological studies have shown significant results in the interaction between the functions of brain-derived neurotrophic factor (BDNF) and 5-HT in mood disorders, such as major depressive disorder (MDD). The latest research has provided convincing evidence that gene transcription of these molecules is a target for epigenetic changes, triggered by stressful stimuli that starts in early childhood and continues throughout life, which are subsequently translated into structural and functional phenotypes culminating in depressive disorders. The short variants of 5-HTTLPR and BDNF-Met are seen as forms which are predisposed to epigenetic aberrations, which leads individuals to a susceptibility to environmental adversities, especially when subjected to stress in early life. Moreover, the polymorphic variants also feature epistatic interactions in directing the functional mechanisms elicited by stress and underlying the onset of depressive disorders. Also emphasized are works which show some mediators between stress and epigenetic changes of the 5-HTT and BDNF genes, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cAMP response element-binding protein (CREB), which is a cellular transcription factor. Both the HPA axis and CREB are also involved in epistatic interactions between polymorphic variants of 5-HTTLPR and Val66Met. This review highlights some research studying changes in the epigenetic patterns intrinsic to genes of 5-HTT and BDNF, which are related to lifelong environmental adversities, which in turn increases the risks of developing MDD.

A single dose of S-ketamine induces long-term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation

Ketamine, an antagonist of N‐methyl‐d‐aspartate receptors, has produced rapid antidepressant effects in patients with depression, as well as in animal models. However, the extent and duration of the antidepressant effect over longer periods of time has not been considered. This study evaluated the effects of single dose of ketamine on behavior and oxidative stress, which is related to depression, in the brains of adult rats subjected to maternal deprivation. Deprived and nondeprived Wistar rats were divided into four groups nondeprived + saline; nondeprived + S‐ketamine (15 mg/kg); deprived + saline; deprived + S‐ketamine (15 mg/kg). A single dose of ketamine or saline was administrated during the adult phase, and 14 days later depressive‐like behavior was assessed. In addition, lipid damage, protein damage, and antioxidant enzyme activities were evaluated in the rat brain. Maternal deprivation induces a depressive‐like behavior, as verified by an increase in immobility and anhedonic behavior. However, a single dose of ketamine was able to reverse these alterations, showing long‐term antidepressant effects. The brains of maternally deprived rats had an increase in protein oxidative damage and lipid peroxidation, but administration of a single dose of ketamine reversed this damage. The activities of antioxidant enzymes superoxide dismutase and catalase were reduced in the deprived rat brains. However, ketamine was also able to reverse these changes. In conclusion, these findings indicate that a single dose of ketamine is able to induce long‐term antidepressant effects and protect against neural damage caused by oxidative stress in adulthood rats following maternal deprivation.

New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs

Despite the revolution in recent decades regarding monoamine involvement in the management of major depressive disorder (MDD), the biological mechanisms underlying this psychiatric disorder are still poorly understood. Currently available treatments require long time courses to establish antidepressant response and a significant percentage of people are refractory to single drug or combination drug treatment. These issues, and recent findings demonstrating the involvement of synaptic plasticity in the pathophysiological mechanisms of MDD, are encouraging researchers to explore the molecular mechanisms underlying psychiatric disease in more depth. The discovery of the rapid antidepressant effect exerted by glutamatergic and cholinergic agents highlights the mammalian target of rapamycin (mTOR) pathway as a critical pathway that contributes to the efficacy of these pharmacological agents in clinical and pre-clinical research. The mTOR pathway is a downstream intracellular signal that transmits information after the direct activation of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and neurotrophic factor receptors. Activation of these receptors is hypothesized to be one of the major axes involved in the synthesis of synaptogenic proteins underlying synaptic plasticity and critical to both the rapid and delayed effects exerted by classic antidepressants. This review focuses on the involvement of mTOR in the pathophysiology of depression and on molecular mechanisms involved in the activity of emerging and classic antidepressant agents.

Quetiapine treatment reverses depressive-like behavior and reduces DNA methyltransferase activity induced by maternal deprivation

ABSTRACT Stress in early life has been appointed as an important phenomenon in the onset of depression and poor response to treatment with classical antidepressants. Furthermore, childhood trauma triggers epigenetic changes, which are associated with the pathophysiology of major depressive disorder (MDD). Treatment with atypical antipsychotics such as quetiapine, exerts therapeutic effect for MDD patients and induces epigenetic changes. This study aimed to analyze the effect of chronic treatment with quetiapine (20 mg/kg) on depressive‐like behavior of rats submitted to maternal deprivation (MD), as well as the activity of histone acetylation by the enzymes histone acetyl transferases (HAT) and deacetylases (HDAC) and DNA methylation, through DNA methyltransferase enzyme (DNMT) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus. Maternally deprived rats had a depressive‐like behavior in the forced swimming test and an increase in the HDAC and DNMT activities in the hippocampus and NAc. Treatment with quetiapine reversed depressive‐like behavior and reduced the DNMT activity in the hippocampus. This is the first study to show the antidepressant‐like effect of quetiapine in animals subjected to MD and a protective effect by quetiapine in reducing epigenetic changes induced by stress in early life. These results reinforce an important role of quetiapine as therapy for MDD.

Glutamatergic NMDA Receptor as Therapeutic Target for Depression.

Major depressive disorder (MDD) affects approximately 121 million individuals globally and poses a significant burden to the healthcare system. Around 50-60% of patients with MDD respond adequately to existing treatments that are primarily based on a monoaminergic system. However, the neurobiology of MDD has not been fully elucidated; therefore, it is possible that other biochemical alterations are involved. The glutamatergic system and its associated receptors have been implicated in the pathophysiology of MDD. In fact, the N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor, is a binding or modulation site for both classical antidepressants and new fast-acting antidepressants. Thus, this review aims to present evidence describing the effect of antidepressants that modulate NMDA receptors and the mechanisms that contribute to the antidepressant response.

LC/QTOF profile and preliminary stability studies of an enriched flavonoid fraction of Cecropia pachystachya Trécul leaves with potential antidepressant‐like activity

There is increasing interest in natural antioxidants that are candidates for the prevention of brain damage occurring in major depressive disorders. Cecropia pachystachya is a tropical tree species of Central and South America and a rich source of polyphenols, particularly flavonoids. The aim of this study was to characterize the flavonoid profile of an enriched flavonoid fraction of C. pachystachya (EFF-Cp) and evaluate the antidepressant-like effects of its acute administration in behavior, cytokine levels, oxidative stress and energy metabolism parameters. The EFF-Cp chemical characterization was performed by HPLC/DAD and LC/QTOF. The antidepressant-like effects were performed by the forced swimming test, splash test and open field test. EFF-Cp revealed 15 flavonoids, including seven new glycosyl flavonoids for C. pachystachya. Quantitatively, EFF-Cp showed isoorientin (43.46 mg/g), orientin (23.42 mg/g) and isovitexin (17.45 mg/g) as major C-glycosyl flavonoids. In addition, EFF-Cp at doses 50 and 100 mg/kg reduced the immobility time in the forced swimming test, without changing the locomotor activity and grooming time. In addition, EFF-Cp was able to prevent the oxidative damage in some brain areas. In conclusion, the results of this study suggest that EFF-Cp exerts antidepressant-like effects with its antioxidant properties.

Depressive disorders and comorbidities among the elderly: a population-based study

Objective The present study assessed the prevalence of depressive disorders and associated factors in a sample of elderly persons in the south of Santa Catarina. Methods A cross-sectional study based on population data was performed, evaluating 1021 elderly individuals aged between 60 and 79 years. Home interviews were carried out using the Portuguese version of the Mini International Neuropsychiatric Interview (MINI), in order to collect demographic data, information on hypertension and reports of acute myocardial infarction. The disorders studied were current depressive episode, dysthymia and a comorbidity of a depressive episode and dysthymia, representing double depression. The comparison of mean age and prevalence was made with the t-test and other associations were analyzed using the Chi-squared test. Results The prevalence of depression was 26.2%, while 5.5% of the sample suffered from dysthymia and 2.7% experienced double depression. Risk factors for depression were: nine or more years of schooling [PR = 1.44 (1.17 to 1.77); p <0.05] and being a current smoker [OR = 1.63 (1.30-2.05); p <0.05]. Dysthymia was associated with the male gender [OR = 6.46 (3.29 to 12.64); p <0.05], reports of hypertension [OR = 2.55 (1.53 to 4.24); p <0.05] and being either a current [OR = 1.86 (1.02 to 3.42); p <0.05] or past or former [OR = 2.89 (1.48 to 5.65); p <0.05] smoker. The same risk factors as for dysthymia were found for double depression: male [OR = 4.21 (1.80 to 9.81); p <0.05], reports of hypertension [OR = 8.11 (3.32 to 19.80); p <0.05], and being either a current [OR = 5.72 (1.64 to 19.93); p <0.05] or past [PR = 13.11 (3.75 to 45.86); p <0.05] smoker. Conclusions The present study shows that depressive disorders are a common phenomenon among the elderly. The results not only corroborated with other studies, but found slightly higher levels of depressive disorders among the elderly population.

Antioxidant Therapy Alters Brain MAPK-JNK and BDNF Signaling Path-ways in Experimental Diabetes Mellitu s

This study was designed to investigate the effects of treatment with the antioxidants N-acetylcysteine (NAC) and deferoxamine (DFX) in intracellular pathways in the brain of diabetic rats. To conduct this study we induced diabetes in Wistar rats with a single injection of alloxan, and afterwards rats were treated with NAC or DFX for 14 days. Following treatment completion, the immunocontent of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase-38 (MAPK38), brain-derived neurotrophic factor (BDNF), and protein kinases A and C (PKA and PKC) were determined in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). DFX treatment increased JNK content in the PFC and NAc of diabetic rats. In the amygdala, JNK was increased in diabetics treated with saline or NAC. MAPK38 was decreased in the PFC of control and in diabetic rats treated with NAC or DFX; and in the NAc in all groups. PKA was decreased in the PFC with DFX treatment. In the amygdala, PKA content was increased in diabetic rats treated with either saline or NAC, compared to controls; and it was decreased in either NAC or DFX-treated groups, compared to saline-treated diabetic animals. In the NAc, PKA was increased in NAC-treated diabetic rats. PKC was increased in the amygdala of NAC-treated diabetic rats. In the PFC, the BDNF levels were decreased following treatment with DFX in diabetic rats. In the hippocampus of diabetic rats the BDNF levels were decreased. However, treatment with DFX reversed this effect. In the amygdala the BDNF increased with DFX in non-diabetic rats. In the NAc DFX treatment increased the BDNF levels in diabetic rats. In conclusion, both diabetes and treatment with antioxidants were able to alter intracellular pathways involved in the regulation of cell survival in a brain area and treatment-dependent fashion.

Pathophysiological Mechanisms of Huntington’s Disease

Huntington’s disease (HD) is a dominant autosomal monogenic disease whose pathophysiological basis comes from a mutation in the huntingtin (HTT) protein. HTT is one of the proteins whose gene has a polymorphic CAG trinucleotide repeat tract, leading to the formation of polyglutamine tract in the N-terminal region of the protein. The expansion of CAG repeat is the basic characteristic of mutated huntingtin (mHTT). HD is therefore characterized as one of the polyglutamine diseases (PolyQ). The initially apparent main symptoms are motor changes, with choreic movements, progressive loss of motor coordination, cognitive decline, and psychiatric disorders. The pathophysiology of this disease involves a wide range of biological mechanisms, whose alterations culminate in gliosis, with loss of astrocytes and oligodendrocytes, and in neuronal death and atrophy of brain tissues, with the most affected regions starting with the striatum, which integrates circuit of the basal ganglia and the cerebral cortex. Medium-sized spiny projecting neurons which release inhibitory γ-aminobutyric acid (GABA) neurotransmitter are the most affected, but many other neurons and neurotransmitters are involved in the circuit dysfunction. Among biological alterations inherent or consequent to the dysfunctions in the neurotransmission system are cellular inclusions of protein aggregates, changes in cellular signaling pathways, energy metabolism, oxidative balance, and inflammatory mechanisms. This chapter discourse some well-defined basic pathophysiological features and some mechanisms that are the most recent study objects in HD.

New Perspective on mTOR Pathways: A New Target of Depression

Major depressive disorder (MDD) is a severe psychiatric condition that affects a large number of individuals worldwide. The understanding of the pathophysiology of this disorder is still not well elucidated, and considering that acute availability of monoamines in the synapses does not provide an equally acute response, and a large number of patients do not respond satisfactorily, new research has emerged in the search for markers and biological mechanisms underlying MDD. Clinical and experimental studies have been suggesting that mammalian target of rapamycin (mTOR) signaling is compromised in pathophysiology of MDD. In addition, this pathway is required for the rapid antidepressant action of ketamine, an antagonist of N-methyl-d-aspartate (NMDA) receptor. Thus, this chapter will highlight clinical and experimental evidences of the role of mTOR signaling pathway in the pathophysiology and treatment of MDD.