Current Pharmaceutical Design - Volume 21, Issue 11, 2015

The abuse of licit and illicit drugs is a worldwide issue that is a cause for concern in pregnant women. It may lead to complications in pregnancy that may affect the mother, fetus, and /or neonate. The effects of any substance on the developing embryo and fetus are dependent upon dosing, timing, duration of drug exposure, and the extent of drug distribution. Teratogenic effects have been described when exposure takes place during the embryonic stage; however drugs have subtle effects, including abnormal growth and/or maturation, alterations in neurotransmitters and their receptors, and brain organization. The mechanisms by which intrauterine exposure to many substances may result in neuronal injury have not been completely elucidated. Oxidative stress and epigenetic changes have been recently implicated in the pathogenesis of long – term adverse health sequelae, and neuro-developmental impairment in the offspring of addicted mothers. Transgenerational epigenetics may also explain the alarming datum that developmental abnormalities, impairment in learning and memory, and attention deficit can occur even in the absence of direct fetal exposure, when drugs are consumed prior to conception. There is a growing body of evidence demonstrating a link between redox state unbalance, epigenetic markers, developmental anomalies, and neurodegeneration. The reviewed literature data uphold redox homeostasis disruption as an important factor in the pathogenesis of drug of abuse- induced neurodegeneration, and highlight the potential for new therapies that could prevent neurodegeneration through antioxidant and epigenetic modulatory mechanisms. This therefore reveals important targets for novel neuroprotective strategies.

Depression is a chronic, recurrent and long-term disorder characterized by high rates of impairment and several comorbidities. Early life stress (ELS) is associated with the increased risk for developing depression in adulthood, influences its clinical course and predicts a poorer treatment outcome. Stressful life events play an important role in the pathogenesis of depression, being well established as acute triggers of psychiatric illness. The vulnerability for developing depression is associated to changes in neurobiological systems related to stress regulation. The hypothalamic-pituitaryadrenal (HPA) axis responds to external and internal stimuli. Reported results indicate that stress in early phases of development can induce persistent changes in the response of the HPA axis to stress in adulthood, leading to a raised susceptibility to depression. These abnormalities appear to be related to the HPA axis deregulation in depression, partially due to an imbalance between glucocorticoid receptors (GR) and mineral ocorticoid receptors (MR). While most studies have consistently demonstrated that GR function is impaired in major depression (reduced GR-mediated feedback in HPA axis), data about the MR role in depression are still limited and contr oversial. Thus, in this review article we summarize the main reported findings about the consequences of ELS in HPA axis functioning and in the responsivity of MR/GR receptors in depression.

The modern concept of stress is based on responses to events or factors (“stressors”) experienced as aversive, threatening or excessive for maintaining physiological equilibrium of an organism. Prolonged exposure to stressors, particularly during early life, is strongly associated with later psychiatric disorders. Underlying mechanistic connections between stress responses and development of psychiatric illnesses remain uncertain and typically appear to be nonspecific. Relevant candidate mechanisms are likely to include the hypothalamic-pituitary-adrenal (HPA) axis, marked by sustained excessive release of cortisol from the adrenal cortex. In turn, this process is influenced by and alters various central neurotransmitter and other molecular signaling systems that include glutamate, dopamine, serotonin, and neurotrophic peptides. A dditional manifestations of stress include altered neurogenesis and neuroplasticity, as well as oxidative neuron-damaging effects. The complex molecular systems involved in these processes present many opportunities for innovative pharmacological interventions that may have preventive or therapeutic benefits regarding mental illnesses arising from stress.

The impact of early physical and social environments on life-long pathological phenotypes is well known and there is now compelling evidence that stressful experiences during gestation or early in life can lead to enhanced susceptibility to mental illness. Here, we discuss the data from preclinical studies aimed at investigating the molecular consequences of the exposure to stressful events during prenatal or early postnatal life that might contribute to later psychopathology. Particularly, we will discuss the existence of age windows of vulnerability to environmental conditions during brain maturation using as examples several studies performed with different animal models. Specifically, major deviations from normative neurobehavioural trajectories have been reported in animal models obtained following exposure to severe stress (maternal separation) ea rly in infancy or with rodent models of difficult and/or stressful pregnancies, including obstetric complications (e.g. prenatal restrain stress) and gestational exposure to infection (e.g prenatal immune challenge). These models have been associated with profound long-lasting deficits in the offspring's emotional and social behaviour, and with molecular changes associated with neuroplasticity.

Schizophrenia is a complex pathology characterized by the occurrence of a variety of symptoms classified as positive, negative and cognitive. Although the exact etiopathogenesis of this disorder has not been unraveled yet, many theories have been endorsed during the last years. Among these, the neurochemical theories have been the most suited, considering the dopaminergic and glutamatergic dysfunctions to be mainly responsible for psychotic symptoms. However, the lack of efficacy of the available drugs, namely antipsychotics, toward negative and cognitive symptoms led to hypothesize alternative approaches. In this regard, the neurodevelopmental theory of schizophrenia has emerged, proposing the association between the occurrence of environmental risk factors in early-life and the development of psychosis in late-life. In particular, exposure to early life stressing situations, such as pre- and peri-natal stress, has been suggested as a risk factor to d evelop psychopathologies in adulthood in people genetically predisposed. A crucial support in favor of this hypothesis came from neurodevelopmental animal models of schizophrenia, such as maternal malnutrition, maternal deprivation, maternal infections as well as post-weaning social isolation rearing. Moreover, data from these models, corroborated by clinical findings, indicate that oxidative and nitrosative stress play a crucial role in the etiopathogenesis of psychiatric disorders. In the present work, we reviewed the recent progress in literature regarding data available from animal models linking oxidative and nitrosative stress to psychiatric disorders in order to evaluate novel biomarkers of pathology as well as novel therapeutical targets.

Stress is an inevitable part of human life and it is experienced even before birth. Stress to some extent could be considered normal and even necessary for the survival and the regular psychological development during childhood or adolescence. However, exposure to prolonged stress could become harmful and strongly impact mental health increasing the risk of developing psychiatric disorders. Recent studies have attempted to clarify how the human central nervous system (CNS) reacts to early life stress, focusing mainly on neurobiological modifications. Oxidative stress, defined as a disequilibrium between the oxidant generation and the antioxidant response, has been recently described as a candidate for most of the observed modifications. In this review, we will discuss how prolonged stressful events during childhood or adolescence (such as early maternal separation, parental divorce, physical violence, sexual or psychological abuses, or exposure to war events) can lead to increased oxidative stress in the CNS and enhance the risk to develop psychiatric diseases such as anxiety, depression, drug abuse or psychosis. Defining the sources of oxidative stress following exposure to early life stress might open new beneficial insights in therapeutic approaches to these mental disorders.

Childhood maltreatment (CM) is all too frequent among western societies, with an estimated prevalence of 10 to 15%. CM associates with increased risk of several psychiatric disorders, and therefore represents a worrying public and socioeconomic burden. While associated clinical outcomes are well characterized, determining by which mechanisms early-life adverse experiences affect mental health over the lifespan is a major challenge. Epigenetic mechanisms, in particular DNA methylation, represent a form of molecular memory that may modify brain function over extended periods of time, as well as serve as a bio-marker of behavioral phenotypes associated with CM. Here, we review human studies suggesting that DNA methylation is a crucial substrate mediating neurobiological consequences of CM throughout life, thereby potentiating maladaptive behavioral patterns and psychopathological risk.

Recent advances in medical care have significantly improved the survival rate of neonates who suffer a hypoxic/ ischemic event, before, during, or after birth. These infants are extremely vulnerable to brain injury and are at high risk of developing motor and cognitive abnormalities later on in life. The regional distribution of perinatal brain injury varies, and depends primarily on; the severity, pattern and type of insult, the metabolic status, and on the gestational age. The principal neuropathological substrate that is affected in the premature infant is cerebral white matter. The aim of this article is to re-examine the current knowledge on the ischemic pathophysiology of all cellular components that comprise the white matter, pred ict the consequences of the long-term neurological outcome, and analyze possible therapeutic strategies. Although oligodendrocytes have long been regarded as the hallmark of perinatal white matter injury, axons, astrocytes and microglia, all contribute to the complex pattern of brain injury that occurs in this cohort of individuals. It is hoped that a better understanding of the pathophysiology of white matter injury and its underlying prognostic factors, may lead to the development of new therapeutic strategies for such a complex and debilitating condition.

This study aimed to investigate the safety and feasibility of intracoronary injection of human umbilical cord mesenchymal stem cell to the very old patients with coronary chronic total occlusion. 15 consecutive patients received mesenchymal stem cells from human umbilical cord in epicardial coronary artery supplying collateral circulation. The patients were randomly allocated to low-dose 3x106, mid-dose 4x106 and high-dose 5x106 groups.

Neonatal hypoxic-ischemic (HI) injury still remains an important issue as it is a frequent cause of neonatal death and life-long neurobehavioral and cognitive dysfunction. In spite of the decades of research which led us to a better knowledge of the pathological mechanism of hypoxic-ischemic brain injury, the clinical use of potential neuroprotective drugs (including, among others, excitatory amino acids antagonists, free radical inhibitors and scavengers, growth factors, xenon, cannabinoids, anti-inflammatory and anti-apoptotic agents) became avoided owing to insufficiency and /or treatment-induced undesirable side effects. The only available effective treatment, hypothermia, neither provides complete brain protection nor stimulates the repair necessary for neurodevelopmental outcome. This fact brings about increased interest in alternative methods of therapy, such as regenerative medicine using stem cells. Growing number of in vivo preclinical studies revealed that mesenchymal stem cells as well as human cord blood cells may improve functional outcome after HI insult and may represent a new beneficial treatment modality for infants developing hypoxic-ischemic encephalopathy. In this review we briefly highlight the present and potential forthcoming therapeutic treatments aimed at attenuation of the detrimental effects of neonatal hypoxia-ischemia.

Radical prostatectomy (RP) is the most commonly employed curative intervention for the treatment of prostate cancer. However, due to the proximity of the cavernous nerves (CN) to the prostate, RP results in transient and/often permanent erectile dysfunction (ED). While the prevention of traction injuries during the RP is critical for the preservation of erectile function, several preclinical studies have demonstrated the beneficial effects of neuroprotective (or neuroregenerative) agents in mitigating neuronal injuries sustained during RP. The maintenance or restoration of erectile function after injury may be enhanced in the postoperative period by the stimulation of neurogenesis to protect and restore injured nerves from further deterioration. The present review aims to evaluate and summarize research of these treatment strategies as published in the National Library of Medicine (Pubmed) from 2000 to 2015. The keywords used for the search were ED, RP, CN injury, immunophilin ligands, neurotrophins and phosphodiesterase (PDE)5 inhibitors, and animal models. Current guidelines for treatment targeting CN recovery recommend the use of immunophilin ligands, neurotrophins, brain-derived neurotrophic factor, glial cell-line derived neurotrophic factor, sonic hedgehog (Shh), Rho-kinase, PDE5 inhibitors, erythropoietin (EPO), hyperbaric oxygen, gene, stem cells, and triiodothyronine (T3) therapy. Additionally, this review identifies remaining gaps in general knowledge and recent updates recognizing the need for further preclinical and clinical trials.

Objectives: To evaluate the relationship between the five common polymorphisms in miRNAs (miR-146a rs2910164 G>C, miR-149 rs2292832 C>T, miR-196a2 rs11614913 C>T, miR-499 rs3746444 A>G and miR-27a rs895819 A>G), and breast cancer (BC) risk. Methods: Meta-analyses were performed on 15 published studies involving 8, 361 BC patients and 8, 504 cancer-free controls. There were 8 studies with 4, 314 cases and 4, 485 controls for rs2910164, 3 studies with 1, 439 cases and 1, 508 controls for rs2292832, 10 studies with 4, 618 cases and 5, 590 controls for rs11614913, 5 studies with 2, 924 cases and 3, 563 controls for rs3746444, and 5 studies with 2, 912 cases and 3, 697 controls for rs895819. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the BC risk. Results: Meta-analyses showed that rs2910164 (miR-146a) was associated with BC risk in Caucasian population (homozygote comparison: OR = 1.29, 95%CI = 1.02-1.63, P=0.03; dominant model: OR = 1.31, 95% CI = 1.05-1.65, P=0.02), whereas negative results were obtained for Asians in all genetic models. rs11614913 (miR-196a2) was associated with BC risk in the overall population based on the recessive model (OR = 0.89, 95% CI = 0.80-0.99, P=0.03). Association of rs3746444 (miR-499) with BC risk was detected under three genetic models (allele contrast genetic model: OR = 1.13, 95%CI = 1.03-1.23, P=0.007; homozygote comparison: OR = 1.36, 95 %CI = 1.10-1.69, P=0.005 and recessive model: OR = 1.38, 95% CI = 1.12-1.70, P=0.003). When stratified by ethnicity, the effects remained in Asians. rs895819 (miR-27a) was associated with BC risk in the overall population based on the allele contrast genetic model (OR = 0.91, 95%CI = 0.85-0.98, P=0.02); heterozygote comparison (OR = 0.89, 95 %CI = 0.80-0.99, P=0.03) and the dominant model (OR = 0.89, 95% CI = 0.80-0.98, P=0.02). However, there was no association between rs2292832 (miR-149) polymorphism and BC susceptibility. Conclusion: Our meta-analysis results suggested that the rs2910164 and rs3746444 polymorphisms are associated with increased BC risk, while the rs11614913 and rs895819 polymorphisms correlate with reduced BC risk.

Objective: Bariatric surgery has been reported to be very effective in the remission of type 2 diabetes mellitus (T2DM). However, the mechanism is still under debate. Nesfatin-1, a recently discovered anorexigenic neuropeptide, was reported to be very important in glucose metabolism and regulating food intake. In this study, the effects of bariatric surgery on the expression and regulation of nesfatin-1 were discussed. Methods: T2DM was induced in SD rats by a diet high in sugar and fat plus a low dose of streptozotocin (STZ) (25 mg/kg) injection. Bariatric surgeries, including Roux-En-Y Gastric Bypass (RYGB) and sleeve gastrectomy (SG), were performed on these rats. Two months after the surgery, the plasma nesfatin-1 level and the expression of nesfatin-1 in different organs of the rats were tested. Next, in vivo administration of nesfatin-1 after surgery was performed to investigate the role of nesfatin-1 in bariatric surgery. Results: Both RYGB and SG could reduce the weight of the rats. However, only RYGB had significant effects on the blood glucose level. Neither surgeries seemed to affect the blood concentration of insulin. However, RYGB significantly improved insulin sensitivity. Expression of nesfatin-1 in the plasma and relative organs decreased in T2DM rats and rose again after RYGB; however, this pattern did not occur in SG. Injection of nesfatin-1 after SG significantly improved insulin resistance and reduced blood glucose levels. Conclusions: Nesfatin-1 may improve insulin sensitivity in T2DM rats and thus plays a very important role in the remission of T2DM after RYGB. This neuropeptide could be a new target for directing future improvements in the bariatric surgical process.

Histone deacetylases (HDACs), which act on acetylated histones and/or other non-histone protein substrates, represent validated epigenetic targets for the treatment of cancer and other human diseases. The inhibition of HDAC activity was shown to induce cell cycle arrest, differentiation, apoptosis as well as a decrease in proliferation, angiogenesis, migration, and cell resistance to chemotherapy. Targeting single HDAC isoforms with selective inhibitors will help to reveal the role of individual HDACs in cancer development or uncover further biological consequences of protein acetylation. This review focuses on conventional zinc-containing HDACs. In its first part, the biological role of individual HDACs in various types of cancer is summarized. In the second part, promising HDAC inhibitors showing activity both in enzymatic and cell-based assays are surveyed with an emphasis on the inhibitors selective to the individual HDACs.