Current Neuropharmacology - Volume 17, Issue 4, 2019

Background: It is now widely established that the devastating effects of prenatal alcohol exposure on the embryo and fetus development cause marked cognitive and neurobiological deficits in the newborns. The negative effects of the gestational alcohol use have been well documented and known for some time. However, also the subtle role of alcohol consumption by fathers prior to mating is drawing special attention. Objective: Both paternal and maternal alcohol exposure has been shown to affect the neurotrophins' signalling pathways in the brain and in target organs of ethanol intoxication. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are molecules playing a pivotal role in the survival, development and function of the peripheral and central nervous systems but also in the pathogenesis of developmental defects caused by alcohol exposure. Methods: New researches from the available literature and experimental data from our laboratory are presented in this review to offer the most recent findings regarding the effects of maternal and paternal prenatal ethanol exposure especially on the neurotrophins' signalling pathways. Results: NGF and BDNF changes play a subtle role in short- and long-lasting effects of alcohol in ethanol target tissues, including neuronal cell death and severe cognitive and physiological deficits in the newborns. Conclusion: The review suggests a possible therapeutic intervention based on the use of specific molecules with antioxidant properties in order to induce a potential prevention of the harmful effects of the paternal and/or maternal alcohol exposure.

Background: Lithium is a first-line treatment for bipolar disorder in adults, but its mechanism of action is still far from clear. Furthermore, evidences of its use in pediatric populations are sparse, not only for bipolar disorders, but also for other possible indications. Objectives: To provide a synthesis of published data on the possible mechanisms of action of lithium, as well as on its use in pediatric samples, including pharmacokinetics, efficacy, and safety data. Methods: Clinical trials in pediatric samples with at least one standardized measure of efficacy/ effectiveness were included in this review. We considered: i) randomized and open label trials, ii) combination studies iii) augmentation studies iv) case series including at least 5 patients. Results: Different and non-alternative mechanisms of action can explain the clinical efficacy of lithium. Clinical studies in pediatric samples suggest that lithium is effective in managing manic symptoms/episodes of bipolar disorder, both in the acute phase and as maintenance strategy. Efficacy on depressive symptoms/phases of bipolar disorder is much less clear, while studies do not support its use in unipolar depression and severe mood dysregulation. Conversely, it may be effective on aggression in the context of conduct disorder. Other possible indications, with limited published evidence, are the acute attacks in Kleine-Levin syndrome, behavioral symptoms of X-fragile syndrome, and the management of clozapine- or chemotherapy- induced neutropenia. Generally, lithium resulted relatively safe. Conclusions: Lithium seems an effective and well-tolerated medication in pediatric bipolar disorder and aggression, while further evidences are needed for other clinical indications.

Gliomas are the most frequent brain tumors in the adult population and unfortunately the adjuvant therapies are not effective. Brain tumorigenesis has been related both to the increased levels of free radicals as inductors of severe damages in healthy cells, but also with the reduced response of endogenous enzyme and non-enzymatic antioxidant defenses. In turn, both processes induce the change to malignant cells. In this review, we analyzed the role of the imbalance between free radicals production and antioxidant mechanism in the development and progression of gliomas but also the influence of redox status on the two major distinctive forms of programmed cell death related to cancer: apoptosis and autophagy. These data may be the reference to the development of new pharmacological options based on redox microenvironment for glioma treatment.

Alzheimer’s disease (AD) is genetically complex with multifactorial etiology. Here, we aim to identify the potential viral pathogens leading to aberrant inflammatory and oxidative stress response in AD along with potential drug candidates using systems biology approach. We retrieved protein interactions of amyloid precursor protein (APP) and tau protein (MAPT) from NCBI and genes for oxidative stress from NetAge, for inflammation from NetAge and InnateDB databases. Genes implicated in aging were retrieved from GenAge database and two GEO expression datasets. These genes were individually used to create protein-protein interaction network using STRING database (score≥0.7). The interactions of candidate genes with known viruses were mapped using virhostnet v2.0 database. Drug molecules targeting candidate genes were retrieved using the Drug- Gene Interaction Database (DGIdb). Data mining resulted in 2095 APP, 116 MAPT, 214 oxidative stress, 1269 inflammatory genes. After STRING PPIN analysis, 404 APP, 109 MAPT, 204 oxidative stress and 1014 inflammation related high confidence proteins were identified. The overlap among all datasets yielded eight common markers (AKT1, GSK3B, APP, APOE, EGFR, PIN1, CASP8 and SNCA). These genes showed association with hepatitis C virus (HCV), Epstein– Barr virus (EBV), human herpes virus 8 and Human papillomavirus (HPV). Further, screening of drugs targeting candidate genes, and possessing anti-inflammatory property, antiviral activity along with a suggested role in AD pathophysiology yielded 12 potential drug candidates. Our study demonstrated the role of viral etiology in AD pathogenesis by elucidating interaction of oxidative stress and inflammation causing candidate genes with common viruses along with the identification of potential AD drug candidates.

Background: Despite its various side effects, morphine has been widely used in clinics for decades due to its powerful analgesic effect. Morphine tolerance is one of the major side effects, hindering its long-term usage for pain therapy. Currently, the thorough cellular and molecular mechanisms underlying morphine tolerance remain largely uncertain. Methods: We searched the PubMed database with Medical subject headings (MeSH) including ‘morphine tolerance’, ‘cytokines’, ‘interleukin 1’, ‘interleukin 1 beta’, ‘interleukin 6’, ‘tumor necrosis factor alpha’, ‘interleukin 10’, ‘chemokines’. Manual searching was carried out by reviewing the reference lists of relevant studies obtained from the primary search. The searches covered the period from inception to November 1, 2017. Results: The expression levels of certain chemokines and pro-inflammatory cytokines were significantly increased in animal models of morphine tolerance. Cytokines and cytokine receptor antagonist showed potent effect of alleviating the development of morphine tolerance. Conclusion: Cytokines play a fundamental role in the development of morphine tolerance. Therapeutics targeting cytokines may become alternative strategies for the management of morphine tolerance.

Background: Reactive oxygen species and reactive nitrogen species, which are collectively called reactive oxygen-nitrogen species, are the inevitable by-products of cellular metabolic redox reactions, such as oxidative phosphorylation in the mitochondrial respiratory chain, phagocytosis, reactions of biotransformation of exogenous and endogenous substrata in endoplasmic reticulum, eicosanoid synthesis, and redox reactions in the presence of metal with variable valence. Among medicinal plants, there is growing interest in Crocus Sativus L. It is a perennial, stemless herb, belonging to Iridaceae family, cultivated in various countries such as Greece, Italy, Spain, Israel, Morocco, Turkey, Iran, India, China, Egypt and Mexico. Objective: The present study aims to address the protective role of Crocus Sativus L. in neurodegeneration with an emphasis in Parkinson’s and Alzheimer’s disease. Materials and Methods: An electronic literature search was conducted by two of the authors from 1993 to August 2017. Original articles and systematic reviews (with or without meta-analysis), as well as case reports were selected. Titles and abstracts of papers were screened by a third reviewer to determine whether they met the eligibility criteria, and full texts of the selected articles were retrieved. Results: Hence, the authors focused on the literature concerning the role of Crocus Sativus L. on its anti-oxidant and neuroprotective properties. Conclusion: Literature findings represented in current review herald promising results for using Crocus Sativus L. and/or its active constituents as antioxidants, anti-inflammatory, and neuroprotective agents.