Current Pharmaceutical Design - Volume 27, Issue 30, 2021

Background: The impact of abusive alcohol consumption on human health is remarkable. According to the World Health Organization (WHO), approximately 3.3 million people die annually because of harmful alcohol consumption (the figure represents around 5.9% of global deaths). Alcohol Use Disorder (AUD) is a chronic disease where individuals exhibit compulsive alcohol drinking and present negative emotional states when they do not drink. In the most severe manifestations of AUD, the individuals lose control over intake despite a decided will to stop drinking. Given the multiple faces and the specific forms of this disease, the term AUD often appears in the plural (AUDs). Since only a few approved pharmacological treatments are available to treat AUD and they do not apply to all individuals or AUD forms, the search for compounds that may help to eliminate the burden of the disease and complement other therapeutical approaches is necessary. Methods: This work reviews recent research focused on the involvement of epigenetic mechanisms in the pathophysiology of AUD. Excessive drinking leads to chronic and compulsive consumption that eventually damages the organism. The central nervous system is a key target and is the focus of this study. The search for the genetic and epigenetic mechanisms behind the intricated dysregulation induced by ethanol will aid researchers in establishing new therapy approaches. Conclusion: Recent findings in the field of epigenetics are essential and offer new windows for observation and research. The study of small molecules that inhibit key epienzymes involved in nucleosome architecture dynamics is necessary in order to prove their action and specificity in the laboratory and to test their effectivity and safety in clinical trials with selected patients bearing defined alterations caused by ethanol.

Mammalian nervous systems depend crucially on myelin sheaths covering the axons. In the central nervous system, myelin sheaths consist of lipid structures that are generated from the membrane of oligodendrocytes (OL). These sheaths allow fast nerve transmission, protect axons and provide them metabolic support. In response to specific traumas or pathologies, these lipid structures can be destabilized and generate demyelinating lesions. Multiple sclerosis (MS) is an example of a demyelinating disease in which the myelin sheaths surrounding the nerve fibers of the brain and spinal cord are damaged. MS is the leading cause of neurological disability in young adults in many countries, and its incidence has been increasing in recent decades. Related to its etiology, it is known that MS is an autoimmune and inflammatory CNS disease. However, there are no effective treatments for this disease and the immunomodulatory therapies that currently exist have proven limited success since they only delay the progress of the disease. Nowadays, one of the main goals in MS research is to find treatments which allow the recovery of neurological disabilities due to demyelination. To this end, different approaches, such as modulating intracellular signaling or regulating the lipid metabolism of OLs, are being considered. Here, in addition to immunosuppressive or immunomodulatory drugs that reduce the immune response against myelin sheaths, we review a diverse group of drugs that promotes endogenous remyelination in MS patients and their use may be interesting as potential therapeutic agents in MS disease. To this end, we compile specific treatments against MS that are currently in the market with remyelination strategies that have entered into human clinical trials for future reparative MS therapies. The method used in this study is a systematic literature review on PubMed, Web of Science and Science Direct databases up to May 31, 2020. To narrow down the search results in databases, more specific keywords, such as “myelin sheath”, “remyelination”, “demyelination”, “oligodendrocyte” and “lipid synthesis” were used to focus the search. We preferred papers published after January 2015, but did not exclude earlier seminal papers.

Background: Schizophrenia is a chronic mental illness that in 80% of cases has a genetic etiology. In the last years, 260 risk genes with a predisposition to schizophrenia have been discovered and correlations between risk genes and the therapeutic efficacy of an antipsychotic treatment/pharmacotherapy resistance have been reported. Objective: The objective of this review is to update the main risk genes involved in schizophrenia and to establish an association between the single nucleotide polymorphisms (SNPs) of these genes and pharmacotherapy resistance/efficacy of a determined antipsychotic treatment. Besides, neural networks in the brain centers involved in schizophrenia will be updated to point out the altered functions of classical neurotransmitters and neuropeptides due to risk genes. Methods: In schizophrenia, important risk genes, such as catechol-O-methyl transferase (COMT), monoamine oxidase (MAO A/B), glutamic acid decarboxylase 67 (GAD 67), dysbindin-1 and neuregulin-1 will be mentioned. To describe the function of these risk genes, neural networks in the ventral tegmental area, hippocampus and prefrontal cortex will also be developed. Results: An association between the SNPs of some risk genes and the efficacy of an antipsychotic treatment is reported: SNPs such as rs165599 (COMT gene), rs1801028 (D2 receptor gene) and rsSer⁹Gly (D3 receptor gene) are associated with a better antipsychotic treatment efficacy (e.g., treatment of negative schizophrenic symptoms with risperidone). The rs4680 SNP (COMT and D2 receptor genes) is associated with antipsychoticinduced dopamine hypersensitivity and pharmacotherapy resistance. The function of risk genes is described: COMT and MAO A/B genes, with reduced activity in the corresponding enzymes, are associated with a decrease in dopamine degradation and hence dopamine hyperactivity occurred via D2 receptors. The GAD 67 risk gene is linked with GABAergic dysfunction and consequently GABAergic neurons weakly presynaptically inhibit D2 dopaminergic neurons. The D-amino acid oxidase activator (DAOA) risk gene is connected with glutamatergic dysfunction via NMDA receptors. Glutamatergic neurons might exert a weak presynaptic inhibition upon 5- HT2A serotonergic neurons located in the ventral tegmental area and hippocampus. Neural networks in the latter two regions and in the prefrontal cortex are updated. Conclusion: It is important to examine the SNPs of the risk genes involved in schizophrenia to establish a correlation between these SNPs and the efficacy of a determined antipsychotic drug. In the future, after examining these SNPs, it might be possible to choose the most appropriate antipsychotic drug. Thus, schizophrenic patients with a good response to a determined antipsychotic treatment and patients with resistance to this treatment could be well differentiated.

Background: Suicide is a major public health problem on a global scale, with about 800.000 deaths every year. In particular, it represents one of the main causes of death among adolescents and young adults aged between 15 and 29 years. The World Health Organization (WHO) describes suicide as “an act of deliberate killing” and that is placed at the extreme end of the continuous spectrum of suicidal behaviors (SBs). These include suicidal ideation, attempted suicide and suicide itself. Objective: The aim of the present review was to better clarify the suicide vulnerability genetic biomarkers and genetic variants correlated with the response to lithium and clozapine and to evaluate some correspondences. Methods: We reviewed the current literature, focusing our attention on genetic molecular studies about neurobiological systems involved in SBs and pharmacogenetic studies about antisuicidal drugs (lithium and clozapine). Results: The studies that we have reviewed have shown mixed results. Interestingly, rs1800532 polymorphism of the SLC6A4 gene, encoding for the serotonin transporter, is potentially correlated with both suicide vulnerability and a poor response to lithium and clozapine. Conclusion: Due to the impact of suicide on public health, more studies are needed to open a promising route to prevent suicide in personalized and precise psychiatry.

The rapid pattern of population ageing in recent years increases the risk of appearance of associated neurodegenerative diseases. Dementias are one of the most feared disorders, and although not necessarily all elderly people have dementia, the number of people with this disease is increasing rapidly. The causes of dementia are multiple, and the diagnosis of the different types of dementia is complicated since most patients display mixed dementias and symptoms overlapping. Personalized diagnosis and treatments would be desirable, but this requires a deep knowledge of each type of dementia where a multidisciplinary approach would be ideal. Thus, the aim of this review is to summarize the features of the main types of dementia as well as to compilate the more recent findings on this subject, ranging from genetic and molecular studies to animal models, including the use of omics platforms based on powerful hybrid instrumental techniques, and neuroimage techniques. On the other hand, we consider the aspects that can prevent these disorders and depend on modifiable factors, such as diet, among others. Finally, new technologies, such as nanotechnology can provide novel strategies for the administration of effective treatments. In this regard, our purpose is to provide the most updated and complete overview of state of the art about characteristics of these disorders.