Current Drug Targets - Volume 14, Issue 5, 2013

This mini-review focuses on the studies of late Prof. IP Lapin (1903 – 2012) and his research team on the role of methoxyindole and kynurenine (KYN) pathways of tryptophan (TRP) metabolism in the pathogenesis of depression and action mechanisms of antidepressant effect. In the late 60s of the last century Prof. IP Lapin suggested that “intensification of central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component” while “activation of noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressant effect”. The cause of serotonin deficiency in depression was attributed to the shunt of TRP “metabolism away from 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 its metabolites affect brain functions, and proposed the role of neurokynurenines in pathogenesis of depression and action mechanisms 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 associated conditions.

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 different neuropsychiatric disorders. Research in this field has been substantially promoted by the evidence that the reuptake protein (SERT), present in presynaptic neurons, is a key element in terminating the activity of the neurotransmitter in the synaptic cleft. For this reason, it was specifically targeted for the development of second-generation antidepressants, in particular 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 functional SERT 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 immune system that need to be better clarified in MD, as well as the possibility of reciprocal modulation of the two systems by different drugs. This paper aims to review briefly the literature on the 5-HT hypothesis of depression with a major focus on the possible role of SERT in this disorder, while highlighting how recent data are more oriented on dimensional rather than nosological involvement of this structure in different conditions spanning from normality to pathology.

Major depression (MD) is a major health problem, partly due to the incomplete understanding of the pathogenic mechanisms of the disease. Research efforts have mainly focused on alterations in monoaminergic neurotransmission, especially in 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 key regulators of the serotonergic neurotransmission have been considered as optimal candidates. The present review is focused on the role of genes coding for serotonin receptors in MD pathogenesis, since the serotonin transporter and enzymes involved 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 and rs6311 (HTR2A gene) A allele or A/A genotype and MD or depressive symptoms. Preclinical and imaging/post-mortem studies in humans provide strong support for the involvement of HTR1A and HTR2A genes in MD. Nevertheless, the inconsistency across previous studies clearly suggests that innovative approaches should be designed in order to overcome the 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 in the detection of multiple-loci models, which could potentially explain the high percentage of MD susceptibility ascribed to genetic factors.

Disorders of emotion regulation such as anxiety disorders and depression are common and yet debilitating. Accumulating evidence suggests involvement of serotonin (5-HT) in the regulation of emotion. Mice with targeted deletion of genes encoding mediators of the serotonergic transmission have proven to be a powerful tool for understanding contributions of such mediators of emotion regulation. Over the last decade, research on mice with a targeted inactivation of the 5-HT transporter (5-Htt, Sert, Slc6a4) has considerably advanced our knowledge about functions that the 5-HTT plays in the context of emotion related to depression. Moreover, the recent advent of knockout (KO) mice for tryptophan hydroxylase 2 (Tph2 KO), which lacks the rate-limiting enzyme for 5-HT synthesis in the brain, has further provided insight to the brain serotonergic system and its role in emotion dysregulation. Here, we first highlight basic characteristics of the serotonergic system 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 variants of 5-HTT and TPH2 in emotional regulation. Among various targets of serotonergic projections, which originate from the raphe nuclei in the brain stem, particular focus is placed on the hippocampus due to its unique dual role in memory and emotion. Finally, effects of therapeutic drugs and psychoactive drugs on KO mouse models as well as on synaptic plasticity will be discussed.

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 given way to combining various additional pharmacologic mechanisms with SERT inhibition, including dual actions by single drugs (e.g., SNRIs or serotonin norepinephrine reuptake inhibitors), or by augmenting SSRIs with a second drug of a different mechanism (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 5HT1A partial agonism; other atypical antipsychotics with 5HT2C/5HT7 antagonism and other mechanisms). Novel drugs in development include those that combine multiple simultaneous pharmacologic mechanisms in addition to SERT inhibition within the same molecule, such as vilazodone (combining 5HT1A partial agonism with SERT inhibition), triple reuptake inhibitors (combining norepinephrine and dopamine reuptake inhibition with SERT inhibition), and vortioxetine, a multimodal antidepressant combining actions at the G protein receptor mode (5HT1A and 5HT1B partial agonism and 5HT7 antagonism), 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 reducing side effects, such as sexual dysfunction.

The critical role of mitochondria in cardiomyocyte survival and death has become an exciting field of research in cardiac biology. Indeed, it is accepted that mitochondrial dysfunction plays a crucial role in the pathogenesis of multiple cardiac diseases. Besides the obvious relevance of mitochondria in energy production, calcium homeostasis, and reactive oxygen species (ROS) production, new processes like mitochondrial fusion/fission, phosphorylation and nitrosylation modifications in mitochondrial proteins have been suggested to form part of a cast of key players in cardiac disease. This review 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. Drugs for treatment of Helicobacter infection relieve pain or gastritis symptoms but they are not targeted specifically to Helicobacter pylori. Therefore, there is dire need for discovery of new drug targets and drugs for the treatment of H. pylori. The main objective of this study is to screen the potential drug targets by in silico analysis for the potent strains of H. pylori which include HpB38, HpP12, HpG27, Hpshi470 and HpSJM180. Genome and metabolic pathways of pathogen H. pylori and 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 total number 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 potential drug targets. Membrane fusion protein of hefABC efflux system, 50 S ribosomal protein L33, Hydrogenase expression protein/formation of HypD, Cag pathogenecity island protein X, Apolipoprotein N acyl transferase, DNA methyalse, Histone like 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 credence to our unique approach.

Keratins are naturally derived proteins that can be fabricated into several biomaterials morphologies including films, sponges and hydrogels. As a physical matrix, keratin biomaterials have several advantages of both natural and synthetic materials that are useful in tissue engineering and controlled released applications. Like other naturally derived protein biomaterials, 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 is the 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 engineering and drug delivery applications, with highlight to reports of particular relevance to the development of the underlying biomaterials science in this area.