Vasointestinal Peptide Research Articles

The gamma rhythm as a guardian of brain health.

Gamma oscillations in brain activity (30-150 Hz) have been studied for over 80 years. Although in the past three decades significant progress has been made to try to understand their functional role, a definitive answer regarding their causal implication in perception, cognition, and behavior still lies ahead of us. Here, we first review the basic neural mechanisms that give rise to gamma oscillations and then focus on two main pillars of exploration. The first pillar examines the major theories regarding their functional role in information processing in the brain, also highlighting critical viewpoints. The second pillar reviews a novel research direction that proposes a therapeutic role for gamma oscillations, namely the gamma entrainment using sensory stimulation (GENUS). We extensively discuss both the positive findings and the issues regarding reproducibility of GENUS. Going beyond the functional and therapeutic role of gamma, we propose a third pillar of exploration, where gamma, generated endogenously by cortical circuits, is essential for maintenance of healthy circuit function. We propose that four classes of interneurons, namely those expressing parvalbumin (PV), vasointestinal peptide (VIP), somatostatin (SST), and nitric oxide synthase (NOS) take advantage of endogenous gamma to perform active vasomotor control that maintains homeostasis in the neuronal tissue. According to this hypothesis, which we call GAMER (GAmma MEdiated ciRcuit maintenance), gamma oscillations act as a 'servicing' rhythm that enables efficient translation of neural activity into vascular responses that are essential for optimal neurometabolic processes. GAMER is an extension of GENUS, where endogenous rather than entrained gamma plays a fundamental role. Finally, we propose several critical experiments to test the GAMER hypothesis.

Vazointestinal Peptid ve Naringeninin Rotenon Kaynaklı Deneysel Parkinson Hastalığı Modeli Üzerine Etkileri

Aim: The aim of this study was to evaluate the intraperitoneal administration of naringenin and vasointestinal peptide (VIP), which are shown effective in various scientific studies, in terms of anti-Parkinsonian activity in rats. Material and Methods: Forty-eight Wistar albino female rats were divided into 4 groups. No intervention was made in the control group, rotenone was given to the RT group, rotenone and VIP (25 ng/kg) to the RT+VIP group, and rotenone and naringenin (10 mg/kg) to the RT+NG group. All treatments were administered intraperitoneally for 14 days. The hole and board method was used to show the effects of the Parkinson's model on behavior. On the last day of the experiment, motor tests were carried out with the hole and board apparatus. After the study was completed, biochemical analyzes were performed from brain tissue samples. Results: In comparison to the RT group, while the alpha-sync level in the RT+NG (p=0.023), malondialdehyde (MDA) levels both in the RT+VIP (p=0.039) and RT+NG (p=0.032), and superoxide dismutase (SOD) inhibition in the RT+VIP (p=0.042) groups decreased significantly, the 8-OHdG levels in the RT+VIP (p=0.042) and RT+NG (p=0.034) groups increased significantly. Statistically significant improvement was found both in biochemical and motor activities with the VIP and naringenin treatments applied. Conclusion: According to the results obtained, the symptoms of Parkinson's disease were formed biochemically by rotenone application. The administration of VIP and naringenin treatments has shown positive effects experimentally and has been promising as an adjunct treatment element in the fight against Parkinson's disease.

Emergence of preparatory dynamics in VIP interneurons during motor learning

To determine what actions to perform in each context, animals must learn how to execute motor programs in response to sensory cues. In rodents, the interface between sensory processing and motor planning occurs in the secondary motor cortex (M2). Here, we investigate dynamics in vasointestinal peptide (VIP) and somatostatin (SST) interneurons in M2 during acquisition of a cue-based, reach-to-grasp (RTG) task in mice. We observe the emergence of preparatory activity consisting of sensory responses and ramping activation in a subset of VIP interneurons during motor learning. We show that preparatory and movement activities in VIP neurons exhibit compartmentalized dynamics, with principal component 1 (PC1) and PC2 reflecting primarily movement and preparatory activity, respectively. In contrast, we observe later and more synchronous activation of SST neurons during the movement epoch with learning. Our results reveal how VIP population dynamics might support sensorimotor learning and compartmentalization of sensory processing and movement execution.

Avian Models of the Neurobiology of Anxiety: A Systematic Review

Objective: Anxiety is partly driven by changes in neuroendocrine signaling, which continues to be an area of study. Birds are a useful model to study anxiety disorders due to their unique behaviors and social makeup, leading to several observable behaviors indicative of anxiety. Methods: Using PRISMA guidelines, a systematic review of studies published from January 2000 to August 2022 in PubMed, PsycINFO and MedLine was conducted. Inclusion criteria included animal studies utilizing an avian model, examining the relationship between a neuroendocrine biomarker and behavioral displays of anxiety. Exclusion criteria included review articles, editorials, studies where anxiolytic drugs were used and studies where anxiety was not the primary studied behavior. Results: 376 articles were screened. 10 papers met the review criteria. Dopamine, serotonin and glycogen synthase kinase 3β (GSK-3β) were found to be inversely related to anxiety levels. Ghrelin and γ-Aminobutyric acid type A (GABAa) were directly correlated with anxiety levels. Corticosterone correlated in a bidirectional manner depending on when a stress was applied, however, lower levels at baseline were more predictive of less anxious birds. Pituitary adenylate cyclase was shown to increase anxiety but was also time-dependent. Arginine vaso-peptide was found to reduce anxiety, but was also context-dependent. Vasointestinal Peptide had no relation to anxiety. Conclusion: Birds display similar chemical responses to humans when anxious, and due to anxiety-related behaviors unique to birds, allow for an additional approach to the investigation of different neuroendocrine markers that are not always strongly considered when studying the neurobiology of anxiety in humans.

АССОЦИАЦИИ ПОЛИМОРФНОГО ВАРИАНТА RS3823082 ГЕНА ВАЗОИНТЕСТИНАЛЬНОГО ПЕПТИДА У ПАЦИЕНТОВ С РАЗЛИЧНЫМИ ФЕНОТИПАМИ БРОНХИАЛЬНОЙ АСТМЫ

Bronchial asthma (BA) is a complex, heterogeneous and one of the most common respiratory diseases affecting both children and adults worldwide. The identification of new genetic loci and the elucidation of the molecular mechanisms in which these loci are involved and affect the risk of developing AD will help complement the pathogenesis of AD. Since VIP affects the tone of the airways, it can be assumed that it affects the course of bronchial asthma, and the study of molecular genetic aspects can provide new diagnostic markers for the course of bronchial asthma. Target. Search for an association of frequencies of genotypes and alleles of the rs3823082 polymorphic variant of the vasointestinal peptide gene in patients with different phenotypes of bronchial asthma. 104 patients with moderate and severe BA were examined. Genotyping of the rs3823082 polymorphic loci was performed by real-time polymerase chain reaction. We found that the CC genotype of the VIP rs3823082 gene is associated with the development of the BA phenotype with a late onset (p=0.019; OR=4.0). The C allele is also a risk marker for the development of the BA phenotype with a late onset (p=0.002; OR=3.09). The CC genotype of the VIP rs3823082 gene is protective against the development of the BA phenotype with obesity (p=0.024; OR=0.167). The results obtained underline the importance of finding genetic variants of VIP, which allow predicting the development of a particular phenotype of bronchial asthma.

Роль нейромедиаторов в патогенезе воспалительных заболеваний кишечника

Among the diseases of the gastrointestinal tract, inflammatory bowel diseases occupy a special place and are the subject of a thorough, comprehensive study, attracting the attention of scientists and doctors around the world. The relevance of numerous studies is due to the steady increase in incidence, the presence of severe disabling forms, a variety of extraintestinal and systemic manifestations. Social and economic importance is determined by the manifestation of inflammatory bowel diseases mainly among young people of working age. At the same time, the mechanisms that trigger the inflammatory process have not been studied enough. The selection of risk factors also seems to be very arbitrary, which significantly reduces the possibility of preventing these conditions, predicting relapse and, as a result, the quality of life of patients. This literature review is an attempt to collect together the available data on the role of acetylcholine, serotonin, substance P and the vasoactive intestinal peptide in the development of the inflammatory response and modulation of the immune response in Crohn's disease and ulcerative colitis. The study of the content of neurotransmitters in the blood of patients and colon biopsy specimens can be important in developing criteria for laboratory diagnostics, assessing the degree of activity of the pathological process, making a forecast about the effectiveness of the therapy and the outcome of the disease. Key words: acetylcholine, Crohn's disease, inflammatory bowel disease, neurotransmitters, serotonin, substance P, ulcerative colitis, vasointestinal peptide

НЕЙРОГЕННОЕ ВОСПАЛЕНИЕ И ОСОБЕННОСТИ ВЕГЕТАТИВНОЙ НЕРВНОЙ СИСТЕМЫ У ПАЦИЕНТОВ С БРОНХИАЛЬНОЙ АСТМОЙ В ЗАВИСИМОСТИ ОТ СТЕПЕНИ ТЯЖЕСТИ И ФЕНОТИПА ЗАБОЛЕВАНИЯ

Abstract. Bronchial asthma (BA) is a heterogeneous disease characterized by chronic airway inflammation. The central link in the pathogenesis of the disease is the inflammatory process of the bronchial wall, the maintenance of which, along with allergens, infections and toxic agents, is facilitated by "neurogenic" inflammatory factors, and imbalance in the links of the autonomic nervous system. Vasointestinal peptide is involved in bronchodilation and substance P is currently considered as the main mediator of neurogenic inflammation, capable of causing such pathophysiological reactions as pain, mucosal edema, mucus hypersecretion, and bronchoconstriction. The research available to date does not fully reflect the mechanisms and degree of influence of the imbalance of the autonomic nervous system and neurogenic inflammation in patients with severe bronchial asthma. In this regard, the study of autonomic dysfunction and it’s connection with the clinical features of severe bronchial asthma is relevant and can contribute to the improvement of a personalized approach to the treatment of patients with asthma, which is of practical interest. Our study presents the results of the level of neuropeptides depending on the type of dysfunction of the autonomic nervous system, as well as the phenotype of bronchial asthma.

Effect of Fish Stock Density on Hormone Genes Expression from Brain and Gastrointestinal Tract of Salmo salar.

Simple SummaryVarious long-term stress conditions may exist in fish cultivation, damaging the physiological responses that regulate the fish growth and feed. Different signalers connect the brain with the gastrointestinal tract, including the perception of stress factors for the regulation of physiological responses. Here, we evaluated the effect of varying culture densities of Salmo salar post-smolt on the gene expression of some brain and gastrointestinal hormone signalers. We found that high stock densities could promote the levels of molecules associated with feed inhibition, which could be related to the stress pathway regulated by corticoids. Thus, the expression of these peptide hormones could be used as biological markers to improve production practices in fish aquaculture.A variety of long-term stress conditions may exist in fish cultivation, some of which are so severe that fish can no longer reestablish homeostasis. In teleost fish, the brain and gastrointestinal tract integrate signals that include the perception of stress factors regulating physiological responses, such as social stress by fish population density, where peripheral and central signals, such as peptide hormones, are the main regulators. Therefore, we proposed in this study to analyze the effect of different stock densities (SD) in the gene expression of brain neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP), together with the gastrointestinal peptide hormones leptin (Lep), vasointestinal peptide (VIP), and protachykinin-1 (Prk-1) in Salmo salar post-smolt. The coding sequence of S. salar VIP and Prk-1 precursors were firstly cloned and characterized. Then, the mRNA expression of these genes, together with the NPY, Lep, and CGRP genes, were evaluated in post-smolts kept at 11 Kg/m3, 20 Kg/m3, and 40 Kg/m3. At 14 days of culture, the brain CGRP and liver leptin mRNA levels increased three and tenfold in the post-smolt salmons kept at the highest SD, respectively. The high levels of leptin were kept during all the fish culture experiments. In addition, the highest expression of intestine VIP mRNA was obtained on Day 21 in the group of 40 Kg/m3 returning to baseline on Day 40. In terms of stress biochemical parameters, cortisol levels were increased in the 20 Kg/m3 and 40 Kg/m3 groups on Day 40 and were the highest in the 20 Kg/m3 group on Day 14. This study provides new insight into the gastrointestinal signals that could be affected by chronic stress induced by high stock density in fish farming. Thus, the expression of these peptide hormones could be used as molecular markers to improve production practices in fish aquaculture.

Effects of Sleep Deprivation by Olfactorily Induced Sexual Arousal Compared to Immobilization Stress and Manual Sleep Deprivation on Neuromessengers and Time Keeping Genes in the Suprachiasmatic Nuclei and Other Cerebral Entities of Syrian Hamsters-An Immunohistochemical Study.

We investigated the effects of sexual arousal induced by olfactory stimuli on the expression of neuromodulators, neurotransmitters and sexual steroid receptors in the suprachiasmatic nucleus (SCN, the circadian pacemaker of mammals) and other cerebral entities of Syrian hamsters (Mesocricetus auratus) compared to manual sleep deprivation and immobilization stress. The hamsters kept under a 12:12 hours (h) light:dark cycle were deprived of sleep by sexual stimulation, gentle manual handling or immobilization stress for 1 h at the beginning of the light phase and subsequently sacrificed at zeitgeber time 01:00, respectively; for comparison, hamsters were manually sleep deprived for 6 or 20 h or sacrificed after completing a full sleep phase. As demonstrated by immunohistochemistry, apart from various alterations after manual sleep deprivation, sexual stimulation caused down-regulation of arginine-vasopressin (AVP), vasointestinal peptide (VIP), serotonin (5-HT), substance P (SP), and met-enkephalin (ME) in the SCN. Somatostatin (SOM) was diminished in the medial periventricular nucleus (MPVN). In contrast, an increase in AVP was observed in the PVN, that of oxytocin (OXY) in the supraoptic nucleus (SON), of tyrosine-hydroxylase (TH) in the infundibular nucleus (IN), and dopamine beta-hydroxylase (DBH) in the A7 neuron population of the brain stem (A7), respectively. Testosterone in plasma was increased. The results indicate that sexual arousal extensively influences the neuropeptide systems of the SCN, suggesting an involvement of the SCN in reproductive behavior.

The Multifaceted Mas-Related G Protein-Coupled Receptor Member X2 in Allergic Diseases and Beyond.

Recent research on mast cell biology has turned its focus on MRGPRX2, a new member of the Mas-related G protein-coupled subfamily of receptors (Mrgprs), originally described in nociceptive neurons of the dorsal root ganglia. MRGPRX2, a member of this group, is present not only in neurons but also in mast cells (MCs), specifically, and potentially in other cells of the immune system, such as basophils and eosinophils. As emerging new functions for this receptor are studied, a variety of both natural and pharmacologic ligands are being uncovered, linked to the ability to induce receptor-mediated MC activation and degranulation. The diversity of these ligands, characterized in their human, mice, or rat homologues, seems to match that of the receptor’s interactions. Natural ligands include host defense peptides, basic molecules, and key neuropeptides such as substance P and vasointestinal peptide (known for their role in the transmission of pain and itch) as well as eosinophil granule-derived proteins. Exogenous ligands include MC secretagogues such as compound 48/80 and mastoparan, a component of bee wasp venom, and several peptidergic drugs, among which are members of the quinolone family, neuromuscular blocking agents, morphine, and vancomycin. These discoveries shed light on its capacity as a multifaceted participant in naturally occurring responses within immunity and neural stimulus perception, as in responses at the center of immune pathology. In host defense, the mice Mrgprb2 has been proven to aid mast cells in the detection of peptidic molecules from bacteria and in the release of peptides with antimicrobial activities and other immune mediators. There are several potential actions described for it in tissue homeostasis and repair. In the realm of pathologic response, there is evidence to suggest that this receptor is also involved in chronic inflammation. Furthermore, MRGPRX2 has been linked to the pathophysiology of non-IgE-mediated immediate hypersensitivity drug reactions. Different studies have shown its possible role in other allergic diseases as well, such as asthma, atopic dermatitis, contact dermatitis, and chronic spontaneous urticaria. In this review, we sought to cover its function in physiologic processes and responses, as well as in allergic and nonallergic immune disease.

PSV-6 Detection of sex-by-maternal immune activation effects on the molecular pathways of the pig amygdala

Abstract The prolonged and sex-dependent impact of maternal immune activation (MIA) on the molecular pathways of the amygdala, a brain region that influences social, cognitive, and sexually dimorphic behaviors, is only partially understood. To address this gap, the effect of MIA elicited by porcine reproductive and respiratory syndrome virus (PRRSV) infection during gestation on the amygdala transcriptome of pigs was studied. Gene expression levels were measured using RNA-Seq on the amygdala for 3-week-old female and male offspring from MIA and control groups. Among the 328 genes that exhibited an MIA-by-sex effect, the majority annotated to functional categories relevant to behavioral abnormalities, including neuroactive ligand-receptor pathways, glutamatergic functions, and neuropeptide systems. Genes in these categories included corticotropin releasing hormone receptor 2, glutamate metabotropic receptor 4, glycoprotein hormones, alpha polypeptide, parathyroid hormone 1 receptor, vasointestinal peptide receptor 2, neurotensin, proenkephalin, and gastrin releasing peptide. These genes and functional categories have been associated with MIA-related schizophrenia and autism spectrum behavior disorders. The transcript and network dysregulation uncovered in this study advances the understanding necessary to develop treatments that ameliorate the effects of neurodevelopmental disorders caused by gestational MIA exposure. This study is supported by USDA NIFA AFRI, grant number 2018-67015-27413.

Lasting and Sex-Dependent Impact of Maternal Immune Activation on Molecular Pathways of the Amygdala.

The prolonged and sex-dependent impact of maternal immune activation (MIA) during gestation on the molecular pathways of the amygdala, a brain region that influences social, emotional, and other behaviors, is only partially understood. To address this gap, we investigated the effects of viral-elicited MIA during gestation on the amygdala transcriptome of pigs, a species of high molecular and developmental homology to humans. Gene expression levels were measured using RNA-Seq on the amygdala for 3-week-old female and male offspring from MIA and control groups. Among the 403 genes that exhibited significant MIA effect, a prevalence of differentially expressed genes annotated to the neuroactive ligand–receptor pathway, glutamatergic functions, neuropeptide systems, and cilium morphogenesis were uncovered. Genes in these categories included corticotropin-releasing hormone receptor 2, glutamate metabotropic receptor 4, glycoprotein hormones, alpha polypeptide, parathyroid hormone 1 receptor, vasointestinal peptide receptor 2, neurotensin, proenkephalin, and gastrin-releasing peptide. These categories and genes have been associated with the MIA-related human neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Gene network reconstruction highlighted differential vulnerability to MIA effects between sexes. Our results advance the understanding necessary for the development of multifactorial therapies targeting immune modulation and neurochemical dysfunction that can ameliorate the effects of MIA on offspring behavior later in life.

Optogenetic dissection of roles of specific cortical interneuron subtypes in GABAergic network synchronization.

An increase in the excitability of GABAergic cells has typically been assumed to decrease network activity, potentially producing overall anti-epileptic effects. Recent data suggest that inhibitory networks may actually play a role in initiating epileptiform activity. We show that activation of GABAergic interneurons can elicit synchronous long-lasting network activity. Specific interneuron subpopulations differentially contributed to GABA network synchrony, indicating cell type-specific contributions of interneurons to cortical network activity. Interneurons may critically contribute to the generation of aberrant network activity characteristic of epilepsy, warranting further investigation into the contribution of distinct cortical interneuron subpopulations to the propagation and rhythmicity of epileptiform activity. In the presence of the A-type K+ channel blocker 4-aminopyrdine, spontaneous synchronous network activity develops in the neocortex of mice of either sex. This aberrant synchrony persists in the presence of excitatory amino acid receptor antagonists (EAA blockers) and is considered to arise from synchronous firing of cortical interneurons (INs). Although much attention has been given to the mechanisms underlying this GABAergic synchrony, the contribution of specific IN subtypes to the generation of these long-lasting discharges (LLDs) is incompletely understood. We employed genetically-encoded channelrhodopsin and archaerhodopsin opsins to investigate the sufficiency and necessity, respectively, of activation of parvalbumin (PV), somatostatin (SST) and vasointestinal peptide (VIP)-expressing INs for the generation of synchronous neocortical GABAergic discharges. We found light-induced activation of PV or SST INs to be equally sufficient for the generation of LLDs, whereas activation of VIP INs was not. By contrast, light-induced inhibition of PV INs strongly reduced LLD initiation, whereas suppression of SST or VIP IN activity only partially attenuated LLD magnitude. These results suggest neocortical INs perform cell type-specific roles in the generation of aberrant GABAergic cortical network activity.

Effect of different nutritional support on pancreatic secretion in acute pancreatitis

To develop and justify optimal nutritional support in early phase of acute pancreatitis (AP). 140 AP patients were enrolled. They were divided into groups depending on nutritional support: group I (n=70) - early enteral tube feeding (ETF) with balanced mixtures, group II (n=30) - early ETF with oligopeptide mixture, group III (n=40) - total parenteral nutrition (TPN). The subgroups were also isolated depending on medication: A - Octreotide, B - Quamatel, C - Octreotide + Quamatel. Pancreatic secretion was evaluated by using of course of disease, instrumental methods, APUD-system hormone levels (secretin, cholecystokinin, somatostatin, vasointestinal peptide). ETF was followed by pancreas enlargement despite ongoing therapy, while TPN led to gradual reduction of pancreatic size up to normal values. α-amylase level progressively decreased in all groups, however in patients who underwent ETF (I and II) mean values of the enzyme were significantly higher compared with TPN (group III). Secretin, cholecystokinin and vasointestinal peptide were increasing in most cases, while the level of somatostatin was below normal in all groups. Enteral tube feeding (balanced and oligopeptide mixtures) contributes to pancreatic secretion compared with TPN, but this negative impact is eliminated by antisecretory therapy. Dual medication (Octreotide + Quamatel) is more preferable than monotherapy (Octreotide or Quamatel).

Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson\u2019s disease

Phosphorylated alpha-synuclein (p-α-syn) containing Lewy bodies (LBs) and Lewy neurites (LNs) are neuropathological hallmarks of Parkinson’s disease (PD) in the central nervous system (CNS). Since they have been also demonstrated in the enteric nervous system (ENS) of PD patients, the aim of the study was to analyze enteric p-α-syn positive aggregates and intestinal gene expression. Submucosal rectal biopsies were obtained from patients with PD and controls and processed for dual-label-immunohistochemistry for p-α-syn and PGP 9.5. p-α-syn positive aggregates in nerve fibers and neuronal somata were subjected to a morphometric analysis. mRNA expression of α-syn and dopaminergic, serotonergic, VIP (vaso intestinal peptide) ergic, cholinergic, muscarinergic neurotransmitter systems were investigated using qPCR. Frequency of p-α-syn positive nerve fibers was comparable between PD and controls. Although neuronal p-α-syn positive aggregates were detectable in both groups, total number and area of p-α-syn positive aggregates were increased in PD patients as was the number of small and large sized aggregates. Increased expression of dopamine receptor D1, VIP and serotonin receptor 3A was observed in PD patients, while serotonin receptor 4 and muscarinic receptor 3 (M3R) were downregulated. M3R expression correlated negative with the number of small sized p-α-syn positive aggregates. The findings strengthen the hypothesis that the CNS pathology of increased p-α-syn in PD also applies to the ENS, if elaborated morphometry is applied and give further insights in altered intestinal gene expression in PD. Although the mere presence of p-α-syn positive aggregates in the ENS should not be regarded as a criterion for PD diagnosis, elaborated morphometric analysis of p-α-syn positive aggregates in gastrointestinal biopsies could serve as a suitable tool for in-vivo diagnosis of PD.

The importance of neuronal growth factors in the ovary.

The neurotrophin family consists of nerve growth factor (NGF), neurotrophin 3 (NT3) and neurotrophin 4/5 (NT4/5), in addition to brain-derived neurotrophic factor (BDNF) and the neuronal growth factors, glial cell line-derived neurotrophic factor (GDNF) and vasointestinal peptide (VIP). Although there are a few literature reviews, mainly of animal studies, on the importance of neurotrophins in the ovary, we aimed to provide a complete review of neurotrophins as well as neuronal growth factors and their important roles in normal and pathological processes in the ovary. Follicular assembly is probably stimulated by complementary effects of NGF, NT4/5 and BDNF and their receptors. The neurotrophins, GDNF and VIP and their receptors have all been identified in preantral and antral follicles of mammalian species, including humans. Transgenic mice with mutations in the genes encoding for Ngf, Nt4/5 and Bdnf and their tropomyosin-related kinase β receptor showed a reduction in preantral follicles and an abnormal ovarian morphology, whereas NGF, NT3, GDNF and VIP increased the in vitro activation of primordial follicles in rats and goats. Additionally, NGF, NT3 and GDNF promoted follicular cell proliferation; NGF, BDNF and VIP were shown to be involved in ovulation; VIP inhibited follicular apoptosis; NT4/5, BDNF and GDNF promoted oocyte maturation and NGF, NT3 and VIP stimulated steroidogenesis. NGF may also exert a stimulatory effect in ovarian cancer and polycystic ovarian syndrome (PCOS). Low levels of NGF and BDNF in follicular fluid may be associated with diminished ovarian reserve and high levels with endometriosis. More knowledge of the roles of neuronal growth factors in the ovary has important implications for the development of new therapeutic drugs (such as anti-NGF agents) for ovarian cancer and PCOS as well as various infertility problems, warranting further research.

Early-life serotonin dysregulation affects the migration and positioning of cortical interneuron subtypes.

Early-life deficiency of the serotonin transporter (SERT) gives rise to a wide range of psychiatric-relevant phenotypes; however, the molecular and cellular targets of serotonin dyregulation during neural circuit formation remain to be identified. Interestingly, migrating cortical interneurons (INs) derived from the caudal ganglionic eminence (CGE) have been shown to be more responsive to serotonin-mediated signalling compared with INs derived from the medial ganglionic eminence (MGE). Here we investigated the impact of early-life SERT deficiency on the migration and positioning of CGE-derived cortical INs in SERT-ko mice and in mice exposed to the SERT inhibitor fluoxetine during the late embryonic period. Using confocal time-lapse imaging and microarray-based expression analysis we found that genetic and pharmacological SERT deficiency significantly increased the migratory speed of CGE-derived INs and affected transcriptional programmes regulating neuronal migration. Postnatal studies revealed that SERT deficiency altered the cortical laminar distribution of subtypes of CGE-derived INs but not MGE-derived INs. More specifically, we found that the distribution of vasointestinal peptide (VIP)-expressing INs in layer 2/3 was abnormal in both genetic and pharmacological SERT-deficiency models. Collectively, these data indicate that early-life SERT deficiency has an impact on the migration and molecular programmes of CGE-derived INs, thus leading to specific alterations in the positioning of VIP-expressing INs. These data add to the growing evidence that early-life serotonin dysregulation affects cortical microcircuit formation and contributes to the emergence of psychiatric-relevant phenotypes.

Nociceptors in the skin: fire-raisers to be kept at bay?

Nociceptors in the skin: fire-raisers to be kept at bay?

New developments in the pharmacological treatment of hypertension: dead-end or a glimmer at the horizon?

Arterial hypertension is the most prevalent controllable disease world-wide. Yet, we still need to further improve blood pressure control, deal with resistant hypertension, and we hope to reduce risk “beyond blood pressure.” The number of candidate molecules aspiring for these aims is constantly declining. The new possible approaches to combat high blood pressure include neprilysin/neutral endopeptidase (NEP) inhibition, particularly when combined with an angiotensin receptor blockade (such as the ARNI, LCZ696), phosphodiesterase 5 (PDE5) inhibition (KD027/Slx-2101), natriuretic agents (PL3994), or a long-lasting vasointestinal peptide (VIP) analogue (PB1046). Other options exploit the protective arm of the renin-angiotensin-aldosterone system by stimulating the angiotensin AT2 receptor (compound 21), the Mas receptor (AVE-0991), or the angiotensin converting enzyme 2. Finally, we review the possibilities how to optimize the use of the available treatment options by using drug combinations or by tailoring therapy to each patient’s angiotensin peptide profile.

The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology.

The peripheral nervous system is critically involved in bone metabolism, osteogenesis, and bone remodeling. Nerve fibers of sympathetic and sensory origin innervate synovial tissue and subchondral bone of diathrodial joints. They modulate vascularization and matrix differentiation during endochondral ossification in embryonic limb development, indicating a distinct role in skeletal growth and limb regeneration processes. In pathophysiological situations, the innervation pattern of sympathetic and sensory nerve fibers is altered in adult joint tissues and bone. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters. Osteoblasts, osteoclasts, mesenchymal stem cells, synovial fibroblasts, and different types of chondrocytes produce distinct subtypes of adrenoceptors, receptors for vasointestinal peptide, for substance P and calcitonin gene-related peptide. Many of these cells even synthesize neuropeptides such as substance P and calcitonin gene-related peptide and are positive for tyrosine-hydroxylase, the rate-limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters modulate osteo-chondrogenic differentiation of mesenchymal progenitor cells during endochondral ossification in limb development. In adults, sensory and sympathetic neurotransmitters are critical for bone regeneration after fracture and are involved in the pathology of inflammatory diseases as rheumatoid arthritis which manifests mainly in joints. Possibly, they might also play a role in pathogenesis of degenerative joint disorders, such as osteoarthritis. All together, accumulating data imply that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for proper limb formation during embryonic skeletal growth. In adults, they modulate bone regeneration, bone remodeling, and articular cartilage homeostasis in addition to their classic neurological actions.