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Abstract: BACKGROUND: Multidisciplinary teamwork is essential in delivering holistic care to critically ill populations, including ventilated neurosurgery patients. Although it is considered a safe and feasible aspect of patient care, mobilization is often missed in this population because of negative healthcare provider perceptions regarding barriers and patient safety. Nurse-led teamwork has been suggested to overcome these barriers and to achieve earlier mobilization for patients, as well as positive provider perceptions, which may affect the culture and frequency of mobilization on neurointensive care units. Quantitative studies analyzing multidisciplinary teamwork perceptions to mobilize ventilated neurosurgery patients with or without a nurse-led protocol have not been previously conducted. Analyzing such perceptions may provide insight to team-related barriers related to missed mobility. This pilot quasi-experimental study aimed to determine whether the use of a nurse-led mobility protocol affects teamwork perceptions when mobilizing ventilated neurosurgery patients. METHODS: A sample of multidisciplinary teams, composed of nurses, patient care technicians, and respiratory therapists, mobilized ventilated neurosurgery patients according to either standard of care (for the control group) or a nurse-led mobility protocol (for the interventional group). Teamwork perceptions were measured via the reliable and valid Nursing Teamwork Survey tool. RESULTS: Linear mixed model analyses revealed that multidisciplinary teams in the nurse-led mobility protocol group had significantly higher levels of overall perceived teamwork than those in the control group, t3 = -3.296, P = .038. Such differences were also noted for teamwork variables of team leadership and mutual trust. CONCLUSION: Nurse-led mobility protocols should be considered to increase teamwork when performing multidisciplinary teamwork-based mobility for ventilated neurosurgery patients. Future studies should continue to evaluate teamwork perceptions after nurse-led mobility., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 American Association of Neuroscience Nurses.)

Objectives: Informal caregivers need to support their loved ones while performing caregiving responsibilities. A phenomenological qualitative study was done to understand the role of social support accessible for stroke caregivers., Materials and Methods: The respondents were enrolled from different organizations or support groups who were conducting activities specifically for stroke victims and/or their caregivers. Data collection was concluded after 10 participants were interviewed as no new major themes were discovered. Hence, saturation of data was obtained with a sample of 10 respondents., Results: Two themes were identified from the interviews: "Response to Stroke" and "Stress and Coping". Categories in theme one "Response to Stroke" were "Work Life Balance", "Reaction of Other People or Family to Stroke", and "Expectations and Responsibility from Caregivers". Categories in theme two "Stress and Coping" were "Impact of Stroke on Abilities of Victim", "Stressors and Concerns for the Caregivers", "Strategies used by Caregivers to Cope with Stress", and "Role of Support Group and Social Support to Stroke Caregiver and Care Recipient"., Conclusions: Stroke can lead to stress that can alter the responsibilities of caregivers of stroke victims. The role of social support and support groups was found to be critical for family caregivers to cope with caregiving issues., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Peptide CRF antagonists injected peripherally alleviate stress-induced visceral hypersensitivity (SIVH) to colorectal distension (CRD) in rodents. Here we further evaluated the dose and time-dependent inhibitory activity of several long-acting peptide CRF receptor antagonists related to astressin on SIVH, focusing on astressin C (AstC), which previously showed high efficacy on stress-related alterations of HPA axis and gut secretomotor functions. Male and female Sprague-Dawley rats pretreated subcutaneously (SC) with AstC were injected intraperitoneally (IP) with CRF 15 min later. The visceromotor responses (VMR) to graded phasic CRD (10, 20, 40 and 60 mmHg) were monitored at basal, 15 min and up to 1-8 days after pretreatment. Two other astressin analogs, hexanoyl-astressin D (Hex-AstD) and [CαMeVal 19,32 ]-AstC, were also tested. The response to IP CRF was sex-dependent with female rats requiring a higher dose to exhibit visceral hyperalgesia. Pretreatment with AstC (30-1000 µg/kg) resulted in a dose-related inhibition of IP CRF-induced SIVH and diarrhea in both sexes. The highest dose prevented SIVH and diarrhea up to 5-7 days after a single SC injection and was lost on day 7 (females) and day 8 (males) but reinstated after a second injection of AstC on day 8 or 9 respectively. [CαMeVal 19,32 ]-AstC and Hex-AstD (1000 µg/kg in males) also prevented SIVH. These data show the potent long-lasting anti-hyperalgesic effect of AstC in an acute model of SIVH in both male and female rats. This highlights the potential of long-acting peripheral CRF antagonists to treat stress-sensitive irritable bowel syndrome., Competing Interests: Declaration of Competing Interest Dr. Dominic Behan is CEO of Sentia Medical Sciences, Inc. Dr. Yvette Taché is part of Sentia Medical Sciences, Inc. Scientific Advisory Board. Dr. Muriel Larauche has no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Psychotherapists must choose from an overwhelming number of theoretical models and empirically supported treatments to guide their work. Meta-analytic studies show there is comparable efficacy among the choices, making the decision about which approach to use difficult. Research indicates there are pantheoretical elements found in all effective models, called the common factors, which can offer psychotherapists a focusing point to maximize their effectiveness regardless of their chosen approach. Most psychotherapists begin practicing from a traditional theoretical orientation, but then their approach evolves over time toward an unintentional eclecticism, derived primarily from their practice experience with clients., Methods: This exploratory qualitative study conducted in-depth interviews with six experienced clinical social workers about their evolution as psychotherapists and what they believe creates change in psychotherapy. The interviews were conducted using standardized prompts and then coded and analyzed utilizing thematic analysis based on a six-phase framework., Results: The analysis suggests the psychotherapists had evolved to conducting therapy via an implicit and unique approach based on an unintentional heavy use of common factors. Five prominent themes emerged as central components of change in psychotherapy: the therapeutic relationship as a primary change agent, the importance of the therapist genuineness, the need to acknowledge and act upon a poor therapist-client match, the client bearing the primary responsibility for change, and the therapists' development of unintended eclecticism in response to client interactions., Conclusions: In practice, most psychotherapists start practicing from a traditional theoretical orientation only to find their approach evolves over time toward an informal eclecticism featuring common factors. This common factors-based eclecticism emerges primarily from practice experience with clients. These findings suggest an avenue for further inquiry-if psychotherapists are going to gradually evolve in an unplanned eclectic direction guided by their client interactions, are they also concurrently and inherently drawn to the common factors? If the answer proves to be yes, what are the implications for early training? Should the gradual emphasis toward common factors be supplanted with a more intentional and efficient focus on them in the training of students and early career clinicians?, (© 2022. The Author(s).)

Abstract: BACKGROUND: Lack of mobilization in ventilated neurosurgery patients is problematic due to significant consequences. Although early mobility addresses these complications, few studies have been conducted in this population, resulting in infrequent mobilization efforts. Nurses prioritize and implement patient care interventions, including mobilization, with multidisciplinary teams. This integrative literature review examines what is known regarding nursing perceptions on mobilization and their role within a multidisciplinary team for mobilization in ventilated neurosurgery patients. METHODS: A comprehensive literature search was conducted using online databases to identify research articles on early mobility studies in ventilated critically ill and neurosurgical patients from 2010 to 2020. RESULTS: Twenty studies were identified and indicated a paucity of research specific to mobilizing ventilated neurosurgery patients. Nurses understand the purpose and benefits of early mobility in critically ill and mechanically ventilated patients. Mixed perceptions exist regarding the responsibility for prioritizing and initiating mobilization. Main barriers include patient safety concerns, untimeliness due to limited resources, unit culture, lack of nursing knowledge, and need for improved teamwork. Associations between teamwork-based interventions and decreased length of stay, increased rates of mobility, and faster time to early mobilization exist. Nurse-led interventions showed additional benefits including positive perceptions such as empowerment, confidence, increased knowledge, and a progressive shift in unit culture. CONCLUSION: This review demonstrates a continued need for understanding nursing perceptions and role in teamwork to mobilize ventilated neurosurgery patients. Future research should focus on testing nurse-led mobility interventions so higher rates of mobilization and provision of holistic patient care can be achieved., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 American Association of Neuroscience Nurses.)

New graduates' adjustment to high-acuity specialty areas was evaluated using qualitative methods in a hospital system that uses the Versant New Graduate Residency Program. Subjects were interviewed at baseline in person, answered interview questions at 6 months via computer, and were interviewed at 12 months in person. Twelve themes emerged from the interviews, reflecting intrinsic and extrinsic factors affecting new graduate nurse adjustment. Study results were used to evaluate the program and improve the program implementation., Competing Interests: The authors declare no conflicts of interests., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

This study investigates the use of a structured protocol by vascular access team (VAT) nurses compared with the practice of bedside nurses to minimize patient pain related to short peripheral catheter (SPC) insertion. During this quantitative study, 201 adults were randomly assigned to have their SPC placed either by the VAT or by bedside nurses. Results showed significantly lower pain scores with the VAT SPC placement (P = .026), and patients were significantly more likely to report the experience as better than their previous SPC placement experiences (χ = 7.8; P = .005). Therefore, the use of a VAT would be worthwhile to improve patient satisfaction.

In 2006, the American Nurses Association created a set of essential genetics and genomics (G/G) competencies for all RNs, regardless of academic preparation, practice setting, or specialty. However, more than half of the RNs practicing today received no prelicensure education on these G/G competencies. This study describes the current use of G/G nursing competencies in acute care hospitals and how nurses perceive them.

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, involve an inappropriate immune reaction in the digestive tract, causing a variety of disabling symptoms. The advent of monoclonal antibodies (anti-tumor necrosis factor, anti-integrin, anti-interleukin -23) has revolutionized IBD management. Nevertheless, these agents, with potential for immunogenicity, are associated with high rates of response loss and disease relapse over time. They are also associated with high production costs. Sphingosine-1-phosphate (S1P), a membrane-derived lysophospholipid signaling molecule, is implicated in a vast array of physiological and pathophysiological processes, primarily via extracellular activation of S1P1-S1P5 receptors. S1P1, S1P4 and S1P5 are involved in regulation of the immune system, while S1P2 and S1P3 may be associated with cardiovascular, pulmonary, and theoretical cancer-related risks. Targeting S1P receptors for inflammatory conditions has been successful in clinical trials leading to approval of the non-selective S1P modulator, fingolimod, for relapsing forms of multiple sclerosis. However, the association of this non-selective S1P modulator with serious adverse events provides the rationale for developing more selective S1P receptor modulators. Until recently, three S1P modulators with differing selectivity for S1P receptors were in clinical development for IBD: ozanimod (RPC1063), etrasimod (APD334) and amiselimod (MT-1303). The development of amiselimod has been stopped as Biogen are currently focusing on other drugs in its portfolio. Following encouraging results from the Phase 2 TOUCHSTONE trial, a Phase 3 trial of the S1P modulator ozanimod in patients with moderate-to-severe ulcerative colitis is ongoing. Etrasimod is also being tested in a phase 2 trial in ulcerative colitis. These pipeline medications can be administered orally and may avoid the formation of anti-drug antibodies that can lead to treatment failure with injectable biologic therapies for IBD. Data from ongoing clinical trials will establish the relationship between the selectivity of S1P modulators and their safety and efficacy in IBD, as well as their potential place in the clinical armamentarium for IBD., (Copyright © 2017. Published by Elsevier B.V.)

Background: Nurses have an essential role in implementing evidence-based practices (EBP) that contribute to high-quality outcomes. It remains unknown how healthcare facilities can increase nurse engagement in EBP., Purpose: To determine whether individual or organizational qualities could be identified that were related to registered nurses' (RNs') readiness for EBP as measured by their reported EBP barriers, ability, desire, and frequency of behaviors., Methods: A descriptive cross-sectional survey was used in which a convenience sample of 2,441 nurses within one United States healthcare system completed a modified version of the Information Literacy for Evidence-Based Nursing questionnaire. Descriptive statistics, t tests, one-way ANOVA, and regression modeling were used to analyze the data., Results: RNs employed by facilities designated by the American Nurses Credentialing Center (ANCC) as Magnet® or Pathway to Excellence® reported significantly fewer barriers to EBP than those RNs employed by non designated facilities. RNs in Magnet organizations had higher desire for EBP than Pathway to Excellence or non designated facilities. RNs educated at the baccalaureate level or higher reported significantly fewer barriers to EBP than nurses with less education; they also had higher EBP ability, desire, and frequency of behaviors. A predictive model found higher EBP readiness scores among RNs who participated in research, had specialty certifications, and engaged in a clinical career development program., Linking Evidence to Action: Education, research, and certification standards promoted by the Magnet program may provide a nursing workforce that is better prepared for EBP. Organizations should continue structural supports that increase professional development and research opportunities so nurses are empowered to practice at their full capacity., (© 2015 Sigma Theta Tau International.)

Background: Other studies have reported high rates of depression and anxiety among human T-lymphotropic virus Type I (HTLV-I)-infected subjects and have even suggested that HTLV-I causes psychiatric disease., Study Design and Methods: We interviewed HTLV-I, HTLV-II, and demographically similar HTLV-seronegative blood donors with the Mini-International Neuropsychiatric Interview. Prevalences of major depression and generalized anxiety disorder in each group were calculated and compared to published US population data. Adjusted odds ratios (aOR) and 95% confidence intervals (CIs) controlling for educational achievement, alcohol intake, and self-reported health status were calculated with multivariate logistic regression., Results: Major depression was diagnosed in five (5.4%) of 93 HTLV-I-positive subjects (aOR, 2.19; 95% CI, 0.63-7.55) and 17 (6.6%) of 256 HTLV-II-positive subjects (aOR, 1.61; 95% CI, 0.66-3.927), compared to 12 (2.1%) of 585 HTLV-seronegative blood donors. The prevalence of major depression among infected subjects was comparable to the 6.7% prevalence in the US general population. Generalized anxiety disorder was diagnosed in five (5.4%) HTLV-I-positive subjects (OR, 2.32; 95% CI, 0.74-7.26) and 12 (4.7%) HTLV-II-positive subjects (OR, 1.65; 95% CI, 0.68-4.01), compared to 15 (2.6%) seronegative subjects and 3.1% in the US general population., Conclusion: Major depression and generalized anxiety disorder were not significantly more prevalent among HTLV-I- and HTLV-II-infected former blood donors after controlling for health status and other confounding variables. HTLV-seronegative blood donors had lower prevalences of these conditions than the US population, probably due to a "healthy blood donor effect.", (© 2012 American Association of Blood Banks.)

Obesity results from a complex interplay between a susceptible genotype and an environment that both promotes increased caloric intake and enables sustained decreases in energy expenditure. One commonly employed approach to modeling obesity in preclinical species is the diet-induced obese (DIO) rodent. Here, theoretical and practical considerations for producing obese rodents via dietary manipulation, and for assessing drug-induced changes in food intake and body weight are described. Based on these considerations, a standardized protocol for diet-induced obesity in both mouse and rat is provided and sample data from these models are also described., (© 2012 by John Wiley & Sons, Inc.)

5-Hydroxytryptamine (5-HT)(2A) receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT(2A) inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT(2A) receptor with at least 30- and 5000-fold selectivity compared with 5-HT(2C) and 5-HT(2B) receptors, respectively. Nelotanserin dosed orally prevented (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT(2A) agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.

This pilot program is a software-based prototype providing a nurse-to-patient assignment presented to two groups of RNs enrolled in a nursing research course in a North Texas university. The goal of the pilot program was to obtain input regarding the assessment, functionality, and practicality of a nurse-to-patient electronic prototype. Registered nurse students were given a presurvey, instructions, and details on the use of the prototype, followed by a postsurvey. Prototype speed and lack of bias were reported as most favorable. Registered nurse students requested additions of multiple diagnoses, patient acuity, and experience level of the nurse to enhance the prototype. Seventy-three percent (n = 24) of the participants said that they would use the prototype, and 15% (n = 5) said that they would not.

G protein-coupled receptors (GPCRs) play an essential role in the regulation of cardiovascular function. Therapeutic modulation of GPCRs has proven to be beneficial in the treatment of human heart disease. Myocardial "orphan" GPCRs, for which the natural ligand is unknown, represent potential novel therapeutic targets for the treatment of heart disease. Here, we describe the expression pattern, signaling pathways, and possible physiological role of the orphan GPR22. GPR22 mRNA analysis revealed a highly restricted expression pattern, with remarkably abundant and selective expression in the brain and heart of humans and rodents. In the heart, GPR22 mRNA was determined to be expressed in all chambers and was comparable with transcript levels of the beta(1)-adrenergic receptor as assessed by Taqman PCR. GPR22 protein expression in cardiac myocytes and coronary arteries was demonstrated in the rat heart by immunohistochemistry. When transfected into HEK-293 cells, GPR22 coupled constitutively to G(i)/G(o), resulting in the inhibition of adenyl cyclase. No constitutive coupling to G(s) or G(q) was observed. Myocardial mRNA expression of GPR22 was dramatically reduced following aortic banding in mice, suggesting a possible role in response to the stress associated with increased afterload. The absence of detectable GPR22 mRNA expression in the hearts of GPR22(-/-) mice had no apparent effect on normal heart structure or function; however, these mice displayed increased susceptibility to functional decompensation following aortic banding. Thus, we described, for the first time, the expression pattern and signaling for GPR22 and identified a protective role for GPR22 in response to hemodynamic stress resulting from increased afterload.

5-Hydroxytryptamine (5-HT)(2C) receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT(2C) full agonist. Lorcaserin bound to human and rat 5-HT(2C) receptors with high affinity (K(i) = 15 +/- 1 nM, 29 +/- 7 nM, respectively), and it was a full agonist for the human 5-HT(2C) receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT(2A) and 5-HT(2B) receptors, respectively. Lorcaserin was also highly selective for human 5-HT(2C) over other human 5-HT receptors (5-HT(1A), 5-HT(3), 5-HT(4C), 5-HT5(5A), 5-HT(6), and 5-HT(7)), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT(2A) agonist (+/-)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT(2A) agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT(2C)-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT(2A) antagonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT(2C) receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT(2C) receptor, with potential for the treatment of obesity.

The prevalence of obesity and type 2 diabetes, two strongly correlated disorders, is increasing worldwide. Weight loss can reduce the risk of developing type 2 diabetes and the pharmacological treatments normally required to manage this disorder. Even though dietary and lifestyle changes may eventually reduce obesity for some individuals, new safe and more efficacious drugs are required for successful weight reduction and treatment of type 2 diabetes in a large proportion of obese individuals. In addition to targeting known G protein-coupled receptors (GPCRs), several orphan GPCRs expressed in central nervous system areas known to regulate feeding may provide new targets for the treatment of obesity. Similarly, the pancreas contains numerous islet GPCRs as well as an abundance of orphan GPCRs that potentially could emerge as targets for future antidiabetic compounds. One of the major challenges facing the pharmaceutical industry is how to rapidly establish the function and therapeutic relevance of orphan GPCRs, some of which may represent novel targets for the discovery of the next generation of drugs to effectively treat obesity and type 2 diabetes. This review will focus on the significant potential of known and orphan GPCRs as targets for the discovery of new drugs to successfully treat these serious disorders.

Constitutive activity of wild-type and mutant forms of human beta(1)- and beta(2)-adrenoceptors was measured by guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding assays using fusion proteins between these receptors and G(s)alpha. Constitutive activity of the beta(1)-adrenoceptor is enhanced by mutation of Leu(322). The ability of ligands to suppress receptor instability and produce up-regulation is often associated with constitutively active mutants. Leu(322)Lysbeta(1)-adrenoceptor, but not wild type, was up-regulated by exposure to the beta(1)-adrenoceptor selective blocker betaxolol. More extensive sequence alterations of the beta(1)-adrenoceptor were generated to mimic the initially described constitutively active mutant (CAM) of the beta(2)-adrenoceptor that is up-regulated strongly by betaxolol. Substitution of amino acids 316 to 324 of the beta(1)-adrenoceptor with the equivalent alpha(1b)-adrenoceptor sequence did not result in up-regulation by betaxolol. However, these forms of both beta(1)- and beta(2)-adrenoceptors displayed substantial and equivalent constitutive activity. The addition of the Leu(322)Lys mutation into the alpha(1b)-adrenoceptor substituted beta(1)-adrenoceptor to produce the CAMKbeta(1)-adrenoceptor allowed substantially greater levels of up-regulation by betaxolol without enhancement of constitutive [(35)S]GTPgammaS binding. Arg(156)Alabeta(1)-adrenoceptor was up-regulated strongly by betaxolol but displayed lower constitutive activity than did other mutants. Binding of [(35)S]GTPgammaS binding to all the fusion proteins was increased substantially by isoprenaline. Despite the ability of betaxolol to cause up-regulation of many mutants, only for the CAMbeta(2)-adrenoceptor-G(s)alpha and CAMKbeta(1)-adrenoceptor-G(s)alpha fusion proteins was the basal binding of [(35)S]GTPgammaS decreased by betaxolol. Clear resolution between receptor constitutive activity and ligand suppression of receptor instability can be obtained for mutant beta-adrenoceptors, and potential inverse agonists do not function equally at phenotypically apparently equivalent CAM receptors.

Several lines of evidence over the last decade have established that G protein-coupled receptors (GPCRs) can signal in the absence of their natural ligand which results in ligand-independent or constitutive activity. Natural genetic mutation, overexpression and site-directed mutagenesis all result in constitutive activation of GPCRs. Of the 100 leading pharmaceutical products in 2000, 39, wholly or in part, acted through a GPCR-mediated mechanism, a fact that underlines the extreme importance of GPCRs as pharmaceutical drug targets. In addition, the sequencing of the human genome and database mining has revealed that there are hundreds of putative orphan GPCRs for which the natural ligands have not been identified. These orphan GPCRs have largely been inaccessible to drug discovery because traditional methods have mainly relied on ligand-dependent binding assays to discover and pharmacologically characterize potential drug candidates from this receptor class. In the absence of ligand identification, constitutively active receptors allow for a logical and direct way forward through the drug discovery pathway by providing the tool necessary to find modulators of this receptor class in a ligand-independent fashion.

Insulin-like growth factors I and II (IGF-I and IGF-II) play an important role in normal growth and brain development and protect brain cells from several forms of injury. The effects of IGFs are mediated by type-I and type-II receptors and modulated by potentially six specific binding proteins that form high-affinity complexes with IGFs in blood and cerebrospinal fluid (CSF) and under most circumstances inactivate them. Because brain injury is commonly associated with increases in IGFs and their associated binding proteins, we hypothesized that displacement of this large "pool" of endogenous IGF from the binding proteins would elevate "free" IGF levels to elicit neuroprotective effects comparable to those produced by administration of exogenous IGF. A human IGF-I analog [(Leu24, 59, 60, Ala31)hIGF-I] with high affinity to IGF-binding proteins (Ki = 0.3-3.9 nM) and no biological activity at the IGF receptors (Ki = >10,000 nM) increased the levels of "free, bioavailable" IGF-I in the CSF. Intracerebroventricular administration of this analog up to 1h after an ischemic insult to the rat brain had a potent neuroprotective action comparable to IGF-I. This novel strategy for increasing "free" IGF levels in the brain may be useful for the treatment of stroke and other neurodegenerative diseases.