Neuroendocrine-immune Communication Research Articles

Development and Evaluation of Vasoactive Intestinal Peptide Freeze-Dried Injection

Introduction: Vasoactive intestinal peptide (VIP), a ubiquitous, naturally synthesized human peptide is extensively documented to have diverse physiological effects like anti-inflammatory, immune-modulatory, anti-hypertensive, stimulation of contractility in the heart, vasodilation, and promoting neuroendocrine-immune communication. The synthetic form of VIP is called aviptadil (AVP). The main objective of this research was to develop a novel stable lyophilized dosage of VIP (Aviptadil) using sucrose as a bulking agent. AVP is a peptide with known concern for aqueous stability, which seems to be challenging for storing finished drug products and supply chain management. The VIP injection was developed using the lyophilization technique in the presence of bulking agent and some other pH-adjusting agent. The bulking agent and solvent system selection depends upon the solubility, stability of the drug substance, and feasibility during manufacturing. During product formulation development, the bulk solution was evaluated for processing time and temperature impact. The lyophilization cycle was developed using the most advanced freeze-drying technology. Result and discussion: With the usage of bulking agent (sucrose) as may act as a cryoprotectant for peptide, the formulated bulk solution was freeze-dried, and primary drying was done at-25°C (below than critical product temperature) followed by secondary drying at 25°C. The critical quality attributes of lyophilized drug products like the description of lyophilized cake/powder, moisture content, reconstitution time, active drug content and color of the solution were evaluated. The developed formulation bulk solution was stable and compatible with contact materials like SS vessels when hold up to 24 hours at 2 to 8°C. The optimized freeze-dried product meets the predefined acceptance criteria as part of the quality target product profile. Conclusions: It can be concluded from the research work carried out that a stable lyophilized parenteral formulation containing VIP (AVP) was developed using sucrose as a bulking agent. These findings show that the freeze-dried formulation is an appropriate technological remedy for stabilizing VIP in lyophilized injectable dosage form.

Role of vasoactive intestinal peptide in osteoarthritis.

Vasoactive intestinal peptide (VIP) plays important roles in many biological functions, such as, stimulation of contractility in the heart, vasodilation, promoting neuroendocrine-immune communication, lowering arterial blood pressure, and anti-inflammatory and immune-modulatory activity. Osteoarthritis (OA) is a chronic and degenerative bone disease, which is one of the most common causes of disability and most common in both sexes as people become older. Interestingly VIP can prevent chronic cartilage damage and joint remodeling. This review article provides update information on the association of VIP and OA and its treatment. Evidences suggest that VIP is down-regulated in synovial fluid of OA, and VIP down-regulation leads to increase in the production of pro-inflammatory cytokines that might contribute to the pathogenesis of OA; however contradictory reports also exist suggesting that accumulation of VIP in joints can also contribute OA. A number of studies indicated that up-regulation of VIP can counteract the action of pro-inflammatory stimuli and alleviate the pain in OA. More clinical investigations are necessary to determine the biology of VIP and its therapeutic potential in OA that might represent the future standards of care for OA.

Neuroendocrine-immune interaction: Evolutionarily conserved mechanisms that maintain allostasis in an ever-changing environment

It has now become accepted that the immune system and neuroendocrine system form an integrated part of our physiology. Immunological defense mechanisms act in concert with physiological processes like growth and reproduction, energy intake and metabolism, as well as neuronal development. Not only are psychological and environmental stressors communicated to the immune system, but also, vice versa, the immune response and adaptation to a current pathogen challenge are communicated to the entire body, including the brain, to evoke adaptive responses (e.g., fever, sickness behavior) that ensure allocation of energy to fight the pathogen. This phenomenon is evolutionarily conserved. Hence it is both interesting and important to consider the evolutionary history of this bi-directional neuroendocrine-immune communication to reveal phylogenetically ancient or relatively recently acquired mechanisms. Indeed, such considerations have already disclosed an extensive “common vocabulary” of information pathways as well as molecules and their receptors used by both the neuroendocrine and immune systems. This review focuses on the principal mechanisms of bi-directional communication and the evidence for evolutionary conservation of the important physiological pathways involved.

A role for multiple estrogen receptors in immune regulation of common carp

Estrogens are important for bi-directional neuroendocrine-immune interaction. They act via nuclear estrogen receptors (ERα and ERβ) and/or G-protein coupled receptor - GPR30.We found expression of ERα, ERβ and GPR30 in carp lymphoid tissues and head kidney monocytes/macrophages, neutrophils and lymphocytes. Interestingly, ERβ is also expressed in some head kidney lymphocytes but not in naive PBLs. Immune stimulation altered the cell type specific profile of expression of these receptors, which depends on both activation and maturation stage.This implies direct leukocyte responsiveness to estrogen stimulation and therefore in vitro effects of 17β-estradiol (E2) on reactive oxygen species (ROS) production in monocytes/macrophages were determined. Short-time incubation with E2 increased ROS production in PMA-stimulated cells. Results comply with mediation by GPR30, partially functioning via phosphoinositide 3-kinase activation.These results furthermore demonstrate that neuroendocrine-immune communication via estrogen receptors is evolutionary conserved.

Beneficial effects of hydrotherapy on immunity and longevity in a mouse model of social isolation.

Introduction: Hydration and Hydrotherapy is a new type of environmental enrichment strategy, reverting the age-related decline of the homeostatic systems (nervous, endocrine and immune systems), enhancing the neuroendocrine-immune communication and, consequently, improving health and life span. In social species (humans, rodents), loneliness and social isolation are psychological stressors which impair the neuroendocrine- immune communication, increasing morbidity and mortality. Since aging especially affects homeostatic systems and older adults are more vulnerable to feeling lonely or socially isolated, suffering these stressors may aggravate health state in the later stages of life. Objective: The aim of this work was to study the effects of hydration-hydrotherapy on immunity and life span in socially isolated old mice. Method: ICR-CD1 old female mice were maintained in group (n=8) or isolated (n=10) during one month. Then, a group of isolated mice (n=5) was submitted to a 4-weeks hydrotherapy treatment. Peritoneal leukocytes were obtained and macrophages and lymphocytes chemotaxis, and lymphoproliferation in absence (basal) or presence of the mitogens Lipopolyssaccharide and Concanavalin A were analyzed. Mortality was also monitored. Results: Hydration and Hydrotherapy improves lymphocytes chemotaxis and lymphoproliferative response to mitogens (functions reduced with aging), decreases basal lymphoproliferation (which increases with age) and increases life span in socially isolated mice. Conclusions: Hydration-Hydrotherapy seems to be an effective strategy to reverse the immune decline induced by social isolation in elderly as well as to increase longevity.

Successful Aging

The emerging concept of successful aging is based on evidence that in healthy individual when they get aged, there are considerable variations in physiological functions alteration. Some people exhibiting greater, but others very few or no age related alteration. The first is called poor aging and the later is called successful pattern of aging (Lambert SW, 2008). Thus, in the simple words the successful aging concept is define as an opportunity of old people to stay active and productive condition despite they get aged chronologically. Aging itself might be defined as the progressive accumulation of changes with time associated with or responsible for the ever-increasing susceptibility to disease and death which accompanies advancing age (Harman D, 1981). The time needed to accumulate changes is attributable to aging process. The marked emerging questions are how does aging happen and where does aging start?To answer these questions and because of the complexity of aging process, there are more than 300 aging theories have been proposed to explain how and where aging occured and started respectively. There are too many to enumerate theories and classification of aging process. In summary, all of these aging theories can be grouped into three clusters: 1. Genetics program theory, this theory suggests that aging is resulted from program directed by the genes; 2. Epigenetic theory, in these theory aging is resulted from environmental random events not determined by the genes; 3. Evolutionary theory, which propose that aging is a medium for disposal mortal soma in order to avoid competition between organism and their progeny for food and space, did not try to explain how aging occur, but possibly answer why aging occur (De la Fuente. 2009). Among the three groups of aging theories, the epigenetic theory is useful to explain and try to solve the enigma of aging which is prominently caused by internal and external environmental influences.There are gradual decline of physiological functions in human after becoming adult in life. The declining of physiological functions might be define as decrease in protein synthesis capacity, bone mineral density, immunological function, strength and muscle mass, and otherwise increase in fat accumulation (Rudman D, et al. 1982; Charmpilas N, et al. 2015). Epidemiologic study indicated that the predominant cause of morbidity, mortality, and reduced longevity in cohort were acute and chronic inflammatory as well as oxidative stress, resulted from environmental inflammations, infections, obesity, and social distress. Acute inflammatory is commonly caused by biological agent, especially both or either bacterial and or viral, whereas chronic inflammatory is related to environmental inflammagen, obesity, and social distress (Sone H et al. 2010) Chronic oxidative stress injures cells particularly in regulatory sytem such as endocrine, nervous, immune, and the neuro-endocrine immune communication by wich cell loss its homeostasis regulatory and cannot preserve health (De la Fuente. 2009). Subsequently, it will impaire homeostasis that leads to an increase in the morbidity and mortality of aging. Likely, answer to the question of where aging start is from the mitochondrial cells of regulatory system. Various evidences indicate that the rate of mitochondrial oxygen radical generation, the degree of membrane fatty acid unsaturation, and oxidative damage to mitochodrial DNA are lower in the long-live species compared to short live species (Braja G, 2004). Several studies also indicate that majority of human adults die due to complication of atherosclerosis, cancer, dimentia, whereas in healthy age invariably accompanied by muscle weakness, and make them frail, disabled, and dependent before eventually died. Such disability prominently caused by skeletal muscle weakness due to diminution of muscle mass and its nerve, osteoarthrirtis, and others chronic degenerative diseases related to oxidative stress (Payton OD, et al. 2012) Furthermore, physical weakness in aging people, generally marked by imbalanced, immobility, low durability, and physical frailty. Consequences of such physical frailty are easy to fall, bone fracture, dependence, hence decreasing daily activity (Buchner DM, et al. 1992; Lambert SW, 2008)To ameliorate the impairment of homeostasis, a caloric restriction but not malnutrition diet and adequate exercise (aerobic, resistance, and streching) can be adopted to neutralize as part of the oxidative and inflammatory stress and to strengthen and increase muscle mass (Payton OD, et al. 2012; Park S, et al. 2012). In special individual condition, like as overweight or obesity, smoker and frequently use of mobile phone, proper antioxidant supplementation can be considered. In addition, caloric restriction, food intake is intentionally reduced by 30–50% has been shown to delay the aging process in mice by decreasing the levels of histone deacetylase2 (HDAC2), which other wise increases during the normal aging process (Mercken EM, et al. 2012).

Successful Aging

The emerging concept of successful aging is based on evidence that in healthy individual when they get aged, there are considerable variations in physiological functions alteration. Some people exhibiting greater, but others very few or no age related alteration. The first is called poor aging and the later is called successful pattern of aging (Lambert SW, 2008). Thus, in the simple words the successful aging concept is define as an opportunity of old people to stay active and productive condition despite they get aged chronologically. Aging itself might be defined as the progressive accumulation of changes with time associated with or responsible for the ever-increasing susceptibility to disease and death which accompanies advancing age (Harman D, 1981). The time needed to accumulate changes is attributable to aging process. The marked emerging questions are how does aging happen and where does aging start?To answer these questions and because of the complexity of aging process, there are more than 300 aging theories have been proposed to explain how and where aging occured and started respectively. There are too many to enumerate theories and classification of aging process. In summary, all of these aging theories can be grouped into three clusters: 1. Genetics program theory, this theory suggests that aging is resulted from program directed by the genes; 2. Epigenetic theory, in these theory aging is resulted from environmental random events not determined by the genes; 3. Evolutionary theory, which propose that aging is a medium for disposal mortal soma in order to avoid competition between organism and their progeny for food and space, did not try to explain how aging occur, but possibly answer why aging occur (De la Fuente. 2009). Among the three groups of aging theories, the epigenetic theory is useful to explain and try to solve the enigma of aging which is prominently caused by internal and external environmental influences.There are gradual decline of physiological functions in human after becoming adult in life. The declining of physiological functions might be define as decrease in protein synthesis capacity, bone mineral density, immunological function, strength and muscle mass, and otherwise increase in fat accumulation (Rudman D, et al. 1982; Charmpilas N, et al. 2015). Epidemiologic study indicated that the predominant cause of morbidity, mortality, and reduced longevity in cohort were acute and chronic inflammatory as well as oxidative stress, resulted from environmental inflammations, infections, obesity, and social distress. Acute inflammatory is commonly caused by biological agent, especially both or either bacterial and or viral, whereas chronic inflammatory is related to environmental inflammagen, obesity, and social distress (Sone H et al. 2010) Chronic oxidative stress injures cells particularly in regulatory sytem such as endocrine, nervous, immune, and the neuro-endocrine immune communication by wich cell loss its homeostasis regulatory and cannot preserve health (De la Fuente. 2009). Subsequently, it will impaire homeostasis that leads to an increase in the morbidity and mortality of aging. Likely, answer to the question of where aging start is from the mitochondrial cells of regulatory system. Various evidences indicate that the rate of mitochondrial oxygen radical generation, the degree of membrane fatty acid unsaturation, and oxidative damage to mitochodrial DNA are lower in the long-live species compared to short live species (Braja G, 2004). Several studies also indicate that majority of human adults die due to complication of atherosclerosis, cancer, dimentia, whereas in healthy age  invariably accompanied by muscle weakness, and make them frail, disabled, and dependent before eventually died. Such disability prominently caused by skeletal muscle weakness due to diminution of muscle mass and its nerve, osteoarthrirtis, and others chronic degenerative diseases related to oxidative stress (Payton OD, et al. 2012) Furthermore, physical weakness in aging people, generally marked by imbalanced, immobility, low durability, and physical frailty. Consequences of such physical frailty are easy to fall, bone fracture, dependence, hence decreasing daily activity (Buchner DM, et al. 1992; Lambert SW, 2008)To ameliorate the impairment of homeostasis, a caloric restriction but not malnutrition diet and adequate exercise (aerobic, resistance, and streching) can be adopted to neutralize as part of the oxidative and inflammatory stress and to strengthen and increase muscle mass (Payton OD, et al. 2012; Park S, et al. 2012). In special individual condition, like as overweight or obesity, smoker and frequently use of mobile phone, proper antioxidant supplementation can be considered. In addition, caloric restriction, food intake is intentionally reduced by 30–50% has been shown to delay the aging process in mice by decreasing the levels of histone deacetylase2 (HDAC2), which other wise increases during the normal aging process (Mercken EM, et al. 2012).

Variable neuroendocrine-immune dysfunction in individuals with unfavorable outcome after severe traumatic brain injury.

Bidirectional communication between the immune and neuroendocrine systems is not well understood in the context of traumatic brain injury (TBI). The purpose of this study was to characterize relationships between cerebrospinal fluid (CSF) cortisol and inflammation after TBI, and to determine how these relationships differ by outcome. CSF samples were collected from 91 subjects with severe TBI during days 0-6 post-injury, analyzed for cortisol and inflammatory markers, and compared to healthy controls (n=13 cortisol, n=11 inflammatory markers). Group-based trajectory analysis (TRAJ) delineated subpopulations with similar longitudinal CSF cortisol profiles (high vs. low cortisol). Glasgow Outcome Scale (GOS) scores at 6months served as the primary outcome measure reflecting global outcome. Inflammatory markers that displayed significant bivariate associations with both GOS and cortisol TRAJ (interleukin [IL]-6, IL-10, soluble Fas [sFas], soluble intracellular adhesion molecule [sICAM]-1, and tumor necrosis factor alpha [TNF]-α) were used to generate a cumulative inflammatory load score (ILS). Subsequent analysis revealed that cortisol TRAJ group membership mediated ILS effects on outcome (indirect effect estimate=-0.253, 95% CI (-0.481, -0.025), p=0.03). Correlational analysis between mean cortisol levels and ILS were examined separately within each cortisol TRAJ group and by outcome. Within the low cortisol TRAJ group, subjects with unfavorable 6-month outcome displayed a negative correlation between ILS and mean cortisol (r=-0.562, p=0.045). Conversely, subjects with unfavorable outcome in the high cortisol TRAJ group displayed a positive correlation between ILS and mean cortisol (r=0.391, p=0.006). Our results suggest that unfavorable outcome after TBI may result from dysfunctional neuroendocrine-immune communication wherein an adequate immune response is not mounted or, alternatively, neuroinflammation is prolonged. Importantly, the nature of neuroendocrine-immune dysfunction differs between cortisol TRAJ groups. These results present a novel biomarker-based index from which to discriminate outcome and emphasize the need for evaluating tailored treatments targeting inflammation early after injury.

VIP in Neurological Diseases: More Than A Neuropeptide

A hallmark in most neurological disorders is a massive neuronal cell death, in which uncontrolled immune response is usually involved, leading to neurodegeneration. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide that combines neuroprotective and immunomodulatory actions. Alterations on VIP/VIP receptors in patients with neurodenegerative diseases, together with its involvement in the development of embryonic nervous tissue, and findings found in VIP-deficient mutant mice, have showed the relevance of this endogenous peptide in normal physiology and in pathologic states of the central nervous system (CNS). In this review, we will summarize the role of VIP in normal CNS and in neurological disorders. The studies carried out with this peptide have demonstrated its therapeutic effect and render it as an attractive candidate to be considered in several neurological disorders linked to neuroinflammation or abnormal neural development.

Improvement of leucocyte functions in ovariectomised aged rats after treatment with growth hormone, melatonin, oestrogens or phyto-oestrogens

Ageing is accompanied by an impairment of the physiological activity of the nervous, endocrine and immune system, as well as in neuroendocrine–immune communication. However, age-related changes in this communication axis have been scarcely studied. In mammals, the process of ageing is associated with an important decline in the secretion of several hormones, such as growth hormone (GH), melatonin (MEL) and oestrogens (Os). Ovariectomy, a model of menopause in rats, has been found to lead to premature immunosenescence. In the present study, the effect of ovariectomy and the role of replacement therapies with GH, MEL, O and natural phyto-oestrogens (POs) have been assessed on several functions in leucocytes from the spleen and the axillary nodes of intact and ovariectomised rats. Chemotaxis, lymphoproliferative response to the mitogen concanavalin A (Con A), the release of interleukin-2 (IL-2) and the natural killer (NK) cell activity have been investigated. Age-controlled rats were used to compare immune functions in hormone treated aged rats with those in younger untreated animals. In all experimental groups, the immune impairment caused by ageing and ovariectomy was partially or completely reversed by hormone treatments. Since the immune system is a marker of health and a predictor of longevity, the results suggest that treatment with hormones could slow down the effects of the ageing process.

Early life environment: does it have implications for predisposition to disease?

Early life environmental factors have been associated with altered predisposition to a variety of pathologies. A considerable literature examines pre- and postnatal factors associated with increased risk of cardiovascular, metabolic (i.e. insulin resistance, hyperlipidemia) and psychiatric disease, and the importance of hormonal programming. The brain is exquisitely sensitive to environmental inputs during development and the stress responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to be both up- and down-regulated by early life exposure to limited nutrition, stress, altered maternal behaviors, synthetic steroids and inflammation. It has been suggested that peri-natal programming of HPA axis regulation might therefore contribute to metabolic and psychiatric disease etiology. In addition, glucocorticoids play modulatory roles regulating many aspects of immune function, notably controlling both acute and chronic inflammatory responses. Neuroendocrine-immune communication is bidirectional, and therefore it is expected that environmental factors altering HPA regulation have implications for stress effects on immune function and predisposition to inflammation. The impact of pre- and postnatal factors altering immune function, stress responsivity and predisposition to inflammatory disease are reviewed. It is also examined whether the early 'immune environment' might similarly influence predisposition to disease and alter neuroendocrine function. Evidence indicating a role for early life inflammation and infection as an important factor programming the neuroendocrine-immune axis and altering predisposition to disease is considered.

Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome.

The present study was designed to investigate the interaction between neuroendocrine mediators and the immune system in chronic fatigue syndrome (CFS). We examined the sensitivity of the immune system to the glucocorticoid agonist dexamethasone and the beta2-adrenergic agonist terbutaline in 15 adolescent girls with CFS and 14 age- and sex-matched controls. Dexamethasone inhibits T-cell proliferation in healthy controls and in CFS patients. However, the maximal effect of dexamethasone on T-cell proliferation is significantly reduced in CFS patients as compared with controls. The beta2-adrenergic receptor agonist terbutaline inhibits tumor necrosis factor-alpha production and enhances interleukin-10 production by monocytes. Our data demonstrate that the capacity of a beta2-adrenergic agonist to regulate the production of these two cytokines is also reduced in CFS patients. We did not observe differences in baseline or CRH-induced cortisol and ACTH between CFS patients and controls. Baseline noradrenaline was similar in CFS and controls, whereas baseline adrenaline levels were significantly higher in CFS patients. We conclude that CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest CFS should be viewed as a disease of deficient neuroendocrine-immune communication.

The importance of being receptive

Neuroendocrine system and immune system can communicate via the use of soluble mediators like hormones, neurotransmitters and cytokines. The level of mediators secreted by either of these systems creates the milieu in which immune and neuroendocrine responses take place. For adequate communication between the systems, receptors for hormones, neurotransmitters and cytokines are required. This review describes the role of regulated expression and function of receptors for hormones and neurotransmitters within the immune system in neuroendocrine-immune communication.

Leydig cell-immune cell interaction: an example of neuroendocrine-immune communication in testis

In her paper Tilings will never be the same again Dr Kathleen L. Wishner quoted Alvin Toffler's book Future Shock written in 1970. Toffler defined future shock as a time phenomenon, a product of the greatly accelerated change in society. The scientific research itself is a demonstration of this accelerated change. In particular, data systematized by Davidoff et al in this volume of Biomedical Reviews indicate the change in the understanding of the nature and origin of Leydig cells of the human testis. Biomedical Reviews 1996; 6: 1-4.

Cytokines and the brain corticosteroid receptor balance: Relevance to pathophysiology of neuroendocrine-immune communication

Interleukin-1 (IL-1) and interleukin-6 (IL-6), and their cognate receptors, are expressed in hippocampal neurons, which are targets for corticosteroid hormones. Corticosteroids bind to intracellular receptors, that is, mineralocorticoid (MRs) and glucocorticoid receptors (GRs). MRs respond to low concentrations of the steroid, while higher concentrations are needed for additional activation of GRs. MR occupation appears relevant in hippocampal neurons for stability of ongoing transmission, for basal activity and sensitivity of the stress response system, and for behavioural reactivity and response selection. Additional transient GR activation suppresses excitability, facilitates recovery from the stress response, and promotes information storage. Thus, the balance of MR- and GR-mediated effects appears critical for the long-term control exerted by corticosteroids over specific aspects of neuronal activity, stress responsiveness, and behavioural adaptation. Administration of IL-1 produces a long-lasting increase in corticosterone. IL-1 also influences MR function in hippocampus and causes a shift in the MR/GR balance, which may underlie prolonged activation of the HPA axis during an immune response.

Thymic peptides and neuroendocrine-immune communication.

Thymic peptides and neuroendocrine-immune communication.