Current Drug Targets (v.14, #5)

This mini-review focuses on the studies of late Prof. IP Lapin (1903 – 2012) and his research team on the roleof methoxyindole and kynurenine (KYN) pathways of tryptophan (TRP) metabolism in the pathogenesis of depressionand action mechanisms of antidepressant effect. In the late 60s of the last century Prof. IP Lapin suggested that "intensificationof central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component" while "activationof noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressanteffect". The cause of serotonin deficiency in depression was attributed to the shunt of TRP "metabolism awayfrom serotonin production towards KYN production" due to cortisol-induced activation of liver enzyme, tryptophan 2,3-dioxygenase, the rate-limiting enzyme of TRP – KYN pathway. Prof. Lapin suggested and discovered that KYN and itsmetabolites affect brain functions, and proposed the role of neurokynurenines in pathogenesis of depression and actionmechanisms of antidepressant effect (kynurenine hypothesis). Further research suggested the antidepressant and cognition-enhancing effects of post-serotonin metabolite, N-acetylserotonin (NAS), an agonist to tyrosine kinase B (TrkB) receptor;and link between depression and chronic inflammation-associated disorders (e.g., insulin resistance, hepatitis C virus)via inflammation-induced activation of indoleamine 2,3– dioxygenase, brain located rate-limiting enzyme of TRY – KYN metabolism. NAS and kynurenines might be the targets for prevention and treatment of depression and associatedconditions.

The Role of Platelet/Lymphocyte Serotonin Transporter in Depression and Beyond by Donatella Marazziti, Paola Landi, Stefano Baroni, Federica Vanelli, Natalia Bartolommei, Michela Picchetti, Liliana Dell'Osso (522-530).
A large amount of the data gathered in the last 50 years support the hypothesis that alterations of the serotonin(5-HT) neurotransmission play a crucial role in the pathophysiology of not only major depression (MD), but also of differentneuropsychiatric disorders. Research in this field has been substantially promoted by the evidence that the reuptakeprotein (SERT), present in presynaptic neurons, is a key element in terminating the activity of the neurotransmitter in thesynaptic cleft. For this reason, it was specifically targeted for the development of second-generation antidepressants, inparticular of selective 5-HT reuptake inhibitors (SSRIs), with the aim of increasing the intrasynaptic 5-HT concentrations.Moreover, since a lot of studies showed that circulating platelets and, more recently, lymphocytes possess functionalSERT proteins, they have been widely used as peripheral mirrors of the same structures located in the central nervous system.The presence of functional SERT in blood cells suggests strict relationships between the nervous and the immunesystem that need to be better clarified in MD, as well as the possibility of reciprocal modulation of the two systems by differentdrugs.This paper aims to review briefly the literature on the 5-HT hypothesis of depression with a major focus on the possiblerole of SERT in this disorder, while highlighting how recent data are more oriented on dimensional rather than nosologicalinvolvement of this structure in different conditions spanning from normality to pathology.

Genetics of Serotonin Receptors and Depression: State of the Art by Chiara Fabbri, Agnese Marsano, Alessandro Serretti (531-548).
Major depression (MD) is a major health problem, partly due to the incomplete understanding of the pathogenicmechanisms of the disease. Research efforts have mainly focused on alterations in monoaminergic neurotransmission, especiallyin relation to the serotonergic system, due to its key role in the regulation of mood and related biological functions.Given the high heritability of MD (estimated between 31% and 42% for unipolar depression), genes coding for keyregulators of the serotonergic neurotransmission have been considered as optimal candidates. The present review is focusedon the role of genes coding for serotonin receptors in MD pathogenesis, since the serotonin transporter and enzymesinvolved in serotonin metabolism have been reviewed elsewhere.Despite the large number of candidate gene studies focusing on genes coding for serotonin receptors, results have been inconsistent.The most replicated findings are the associations between rs6295 (HTR1A gene) G allele or G/G genotype andrs6311 (HTR2A gene) A allele or A/A genotype and MD or depressive symptoms. Preclinical and imaging/post-mortemstudies in humans provide strong support for the involvement of HTR1A and HTR2A genes in MD. Nevertheless, the inconsistencyacross previous studies clearly suggests that innovative approaches should be designed in order to overcomethe limitations of candidate gene studies. To date, the most appealing methodologies seem to be full exome or genome sequencing,genome-wide pathway analyses, endophenotypes, and epigenetic biomarkers. The reported tools may assist inthe detection of multiple-loci models, which could potentially explain the high percentage of MD susceptibility ascribedto genetic factors.

Disorders of emotion regulation such as anxiety disorders and depression are common and yet debilitating. Accumulatingevidence suggests involvement of serotonin (5-HT) in the regulation of emotion. Mice with targeted deletionof genes encoding mediators of the serotonergic transmission have proven to be a powerful tool for understanding contributionsof such mediators of emotion regulation. Over the last decade, research on mice with a targeted inactivation of the5-HT transporter (5-Htt, Sert, Slc6a4) has considerably advanced our knowledge about functions that the 5-HTT plays inthe context of emotion related to depression. Moreover, the recent advent of knockout (KO) mice for tryptophan hydroxylase2 (Tph2 KO), which lacks the rate-limiting enzyme for 5-HT synthesis in the brain, has further provided insight to thebrain serotonergic system and its role in emotion dysregulation. Here, we first highlight basic characteristics of the serotonergicsystem including the biosynthesis of 5-HT as well as the anatomy and firing activity of serotonergic neurons.Furthermore, characteristics of 5-Htt and Tph2 KO mice are covered together with association studies on human variantsof 5-HTT and TPH2 in emotional regulation. Among various targets of serotonergic projections, which originate from theraphe nuclei in the brain stem, particular focus is placed on the hippocampus due to its unique dual role in memory andemotion. Finally, effects of therapeutic drugs and psychoactive drugs on KO mouse models as well as on synaptic plasticitywill be discussed.

Inflammation, Serotonin and Major Depression by Mario Catena-Dell'Osso, Francesco Rotella, Adriana Dell'Osso, Andrea Fagiolini, Donatella Marazziti (571-577).
The understanding of the neurobiological processes leading to major depressive disorder (MDD) is an activefield of research in the scientific community. For years, the alteration of monoamine neurotransmission, in particular serotonin(5-HT), has been considered the most significant pathophysiological mechanism of the disorder. However, biologicaldata supporting the postulated MDD-related monoamine alterations have been inconclusive, and the use of monoaminergicantidepressants has not yielded the expected results. In the last few years, it has been demonstrated that inflammatorypathways have a significant role in the pathophysiology of MDD. According to the cytokine hypothesis, thedisorder would be due to a stress-related increased production of cytokines, including interleukins, tumor necrosis factor- αand interferon- α and γ. These, in turns, would cause the activation of the indoleamine 2,3 dioxygenase (IDO), with subsequentproduction of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and decreased availability ofTRP and 5-HT. Besides monoamines, other molecular mechanisms, as those within the inflammatory pathways, should betaken into account in the attempt to clarify the pathophysiology of MDD and to improve its treatment.

Serotonergic Drugs for Depression and Beyond by Stephen M. Stahl, Clara Lee-Zimmerman, Sylvia Cartwright, Debbi Ann Morrissette (578-585).
The current generation of antidepressant drugs acts predominantly by targeting the serotonin transporter(SERT). The original trend to do this selectively (e.g., with SSRIs or selective serotonin reuptake inhibitors) has givenway to combining various additional pharmacologic mechanisms with SERT inhibition, including dual actions by singledrugs (e.g., SNRIs or serotonin norepinephrine reuptake inhibitors), or by augmenting SSRIs with a second drug of a differentmechanism (e.g., bupropion with dopamine and norepinephrine reuptake inhibition; trazodone with 5HT2A antagonism;mirtazapine with 5HT2A/5HT2C/5HT3/alpha2 antagonism; buspirone or some atypical antipsychotics with 5HT1Apartial agonism; other atypical antipsychotics with 5HT2C/5HT7 antagonism and other mechanisms). Novel drugs in developmentinclude those that combine multiple simultaneous pharmacologic mechanisms in addition to SERT inhibitionwithin the same molecule, such as vilazodone (combining 5HT1A partial agonism with SERT inhibition), triple reuptakeinhibitors (combining norepinephrine and dopamine reuptake inhibition with SERT inhibition), and vortioxetine, a multimodalantidepressant combining actions at the G protein receptor mode (5HT1A and 5HT1B partial agonism and 5HT7antagonism), at the ion channel mode (5HT3 antagonism) as well as the neurotransmitter transporter mode (SERT inhibition).These various strategies that build upon SERT inhibition provide promise for novel therapeutic approaches to depression,including the possibility of targeting residual symptoms not well treated by SERT inhibition alone, and reducingside effects, such as sexual dysfunction.

Targeting Mitochondria for Cardiac Protection by Sauri Hernandez-Resendiz, Mabel Buelna-Chontal, Francisco Correa, Cecilia Zazueta (586-600).
The critical role of mitochondria in cardiomyocyte survival and death has become an exciting field of researchin cardiac biology. Indeed, it is accepted that mitochondrial dysfunction plays a crucial role in the pathogenesis of multiplecardiac diseases. Besides the obvious relevance of mitochondria in energy production, calcium homeostasis, and reactiveoxygen species (ROS) production, new processes like mitochondrial fusion/fission, phosphorylation and nitrosylationmodifications in mitochondrial proteins have been suggested to form part of a cast of key players in cardiac disease. Thisreview describes currently studied drugs and compounds that target mitochondria in the scenario of cardiovascular diseases.

Helicobacter species colonizes the stomach and are associated with the development of gastritis disease. Drugsfor treatment of Helicobacter infection relieve pain or gastritis symptoms but they are not targeted specifically to Helicobacterpylori. Therefore, there is dire need for discovery of new drug targets and drugs for the treatment of H. pylori. Themain objective of this study is to screen the potential drug targets by in silico analysis for the potent strains of H. pyloriwhich include HpB38, HpP12, HpG27, Hpshi470 and HpSJM180. Genome and metabolic pathways of pathogen H. pyloriand the host Homosapien sapiens are compared and genes which were unique to H. pylori were filtered and catalogued.These unique genes were subjected to gene property analysis to identify the potentiality of the drug targets. Among the totalnumber of genes analysed in different strains of H. pylori nearly 558, 569, 539, 569, 567 number of genes in HpB38,HpP12, HpG27, Hpshi470 and HpSJM180 found qualified as unique molecules and among them 17 qualified as potentialdrug targets. Membrane fusion protein of hefABC efflux system, 50 S ribosomal protein L33, Hydrogenase expressionprotein/formation of HypD, Cag pathogenecity island protein X, Apolipoprotein N acyl transferase, DNA methyalse, Histonelike binding protein, Peptidoglycan-associated lipoprotein OprL were found to be critical drug targets to H. pylori.Three (hefABC efflux system, Hydrogenase expression protein/formation of HypD, Cag pathogenecity island protein X)of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lending credenceto our unique approach.

The Use of Keratin in Biomedical Applications by Andreia Vasconcelos, Artur Cavaco-Paulo (612-619).
Keratins are naturally derived proteins that can be fabricated into several biomaterials morphologies includingfilms, sponges and hydrogels. As a physical matrix, keratin biomaterials have several advantages of both natural and syntheticmaterials that are useful in tissue engineering and controlled released applications. Like other naturally derived proteinbiomaterials, such as collagen, keratin possess amino acid sequences, similar to the ones found on extracellular matrix(ECM), that may interact with integrins showing their ability to support cellular attachment, proliferation and migration.The ability of developing biomaterials that mimic ECM has the potential to control several biological processes and this isthe case for keratin which has been used in a variety of biomedical applications due to its biocompatibility and biodegradability.This review describes the progress to date towards the use of keratin in the field of wound healing, tissue engineeringand drug delivery applications, with highlight to reports of particular relevance to the development of the underlyingbiomaterials science in this area.