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Effect of ARA 290 on cold allodynia. A. Effect of spared nerve injury and treatment with vehicle or different doses of ARA 290 on cold allodynia scores. Animals were sham-operated (grey) or received spared nerve injury and 5 doses of vehicle (red), 3 μg/kg ARA 290 (yellow), 10 μg/kg ARA 290 (green), 30 μg/kg ARA 290 (marine blue), or 60 μg/kg ARA 290 (dark blue) administered on days 1, 3, 6, 8 and 10 post-surgery (for each treatment p < 0.0001 compared to vehicle). Scoring of cold allodynia is described in the Methods Section. B. Correlation of ARA 290 treatment dose and the relief of cold allodynia, calculated by the difference in area under the curves (AUC) of the cold allodynia score on day 1 vs. day 140. The adjusted R2 is 0.78. C. Survival analysis showing the cold allodynia-free proportion of animals in time either sham-operated, or receiving spared nerve injury and treated with vehicle or different doses of ARA 290. Log-Rank p < 0.001.
Source publication
Neuropathic pain is a difficult to treat disorder arising from central or peripheral nervous system lesions. The etiology of neuropathic pain consists of several overlapping pathways converging into an exaggerated pain state with symptoms such as allodynia and hyperalgesia. One of these pathways involves activation of spinal cord microglia and astr...
Contexts in source publication
Context 1
... of treatment, all SNI groups dif- fered significantly from sham-operated animals (p < 0.001 for all groups). Animals treated with ARA 290 showed a dose-dependent relief of allodynia ( Figure 2A, treat- ment effect p < 0.001). Post hoc analysis showed that at all doses allodynia was significantly less compared to vehicle (p < 0.001). ...Context 2
... hoc analysis showed that at all doses allodynia was significantly less compared to vehicle (p < 0.001). A linear ARA 290 dose-response relationship was observed with an adjusted R 2 of 0.78 ( Figure 2B). Higher doses of ARA 290 resulted in lower AUCs corresponding to animals responding less vigorously to the application of acetone and hence less thermal allodynia. ...Context 3
... doses of ARA 290 resulted in lower AUCs corresponding to animals responding less vigorously to the application of acetone and hence less thermal allodynia. Survival analysis indicates that a more persisting effect was obtained at higher ARA 290 doses ( Figure 2C, Log-Rank p < 0.001). ...Similar publications
More than a decade ago the novel concept that glial cells are major players in the modulation of pain mechanisms in the spinal cord has started a prolific series of work addressing the modalities of neuron-glia communication. Mike Salter with Kazuhide Inoue laboratories introduced ATP as pivotal mediator for such communication via activation of P2X...
Chronic neuroinflammation plays an important role in the development and maintenance of neuropathic pain. The compound flexibilide, which can be obtained from cultured soft coral, possesses anti-inflammatory and analgesic effects in the rat carrageenan peripheral inflammation model. In the present study, we investigated the antinociceptive properti...
Neuropathic pain is caused by nerve injury. Yokukansan (Yi-Gan San), a traditional Japanese (Kampo) medicine, has been widely used for neuropathic pain control. However, the analgesic mechanisms remain unknown. In this study, we investigated the analgesic mechanisms of yokukansan in a mouse model of neuropathic pain. Partial sciatic nerve ligation...
Background
Optogenetic tools enable cell selective and temporally precise control of neuronal activity; yet, difficulties in delivering sufficient light to the spinal cord of freely behaving animals have hampered the use of spinal optogenetic approaches to produce analgesia. We describe an epidural optic fiber designed for chronic spinal optogeneti...
Neuropathic pain is a global clinical problem; nevertheless, nerve injury treatment methods remain limited. Olanzapine has antinociceptive and anti-nueropathic properties; however, its preventive effects have not been assessed in nerve injury models.
We prepared a partial sciatic nerve ligation (Seltzer model) or sham-operated model in male Sprague...
Citations
... The β-common-receptor acts in conjunction with the EPO receptor to form a heterocomplex that is rapidly up-regulated locally following tissue injury (21), initiating a local anti-inflammatory response, inhibition of death signals and anti-apoptosis that aids in the prevention of tissue damage. Chronic treatment with ARA290 reduces systemic inflammation by decreasing susceptibility to diet-induced insulin resistance, neuropathic pain in patients with type 2 diabetes and sarcoidosis associated small nerve loss (22)(23)(24)(25). Additionally, ARA290 administration to rats improves survival following myocardial infarction, reduces organ dysfunction in mice during hemorrhagic shock, and suppresses development of atherosclerosis in hyperlipidemic rabbits (26-28). ...
Background:
Aging is associated with increased levels of reactive oxygen species and inflammation that disrupt proteostasis and mitochondrial function and leads to organism-wide frailty later in life. ARA290 (cibinetide), an 11-aa non-hematopoietic peptide sequence within the cardioprotective domain of erythropoietin, mediates tissue protection by reducing inflammation and fibrosis. Age-associated cardiac inflammation is linked to structural and functional changes in the heart, including mitochondrial dysfunction, impaired proteostasis, hypertrophic cardiac remodeling, and contractile dysfunction. Can ARA290 ameliorate these age-associated cardiac changes and the severity of frailty in advanced age?
Methods:
We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline. Serial echocardiography, tail blood pressure and body weight were evaluated repeatedly at 4-month intervals. A frailty index was calculated at the final timepoint (33 months of age). Tissues were harvested at 4-month intervals to define inflammatory markers and left ventricular tissue remodeling. Mitochondrial and myocardial cell health was assessed in isolated left ventricular myocytes. Kaplan-Meier survival curves were established. Mixed ANOVA tests and linear mixed regression analysis were employed to determine the effects of age, treatment, and age-treatment interactions.
Results:
Chronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines, total NF-κB, and p-NF-κB. Additionally, ARA290 treatment enhanced cardiomyocyte autophagy flux and reduced cellular accumulation of lipofuscin. The cardiomyocyte mitochondrial permeability transition pore response to oxidant stress was desensitized following chronic ARA290 treatment. Concurrently, ARA290 significantly blunted the age-associated elevation in blood pressure and preserved the LV ejection fraction. Finally, ARA290 preserved body weight and significantly reduced other markers of organism-wide frailty at the end of life.
Conclusion:
Administration of ARA290 reduces cell and tissue inflammation, mitigates structural and functional changes within the cardiovascular system leading to amelioration of frailty and preserved healthspan.
... In the case of neuropathy, ARA290 has been demonstrated to attenuate small nerve fiber loss and neuritis caused by type 2 diabetes (McVicar et al., 2011;Dahan et al., 2013;Dahan et al., 2016), autoimmunity Huang et al., 2018), or localized peripheral nerve inflammation (Pulman et al., 2013). In the central nervous system, intraperitoneal injection of 30 μg/kg of ARA290 once a day on days 1, 3, 6, 8, and 10 after spared nerve injury was reported to suppress the spinal microglia response and thereby produce long-term relief of neuropathic pain (Swartjes et al., 2014). Intraperitoneal injection of 0.7 nmol/kg ARA290 once a week for 5 weeks decelerates Alzheimer's disease-like pathology progression with more monocyte progenitors in the bone marrow and the accumulation of Ly6C low patrolling monocyte subset in the brain, which are implicated in clearing Aβ from the cerebral vasculature (Al-Onaizi et al., 2022). ...
... Therefore, it is reasonable to propose that ARA290 also has such effects. This work is the first to suggest that ARA290 induces microglial polarization toward M2 even though previous studies have demonstrated that ARA290 inhibits microglia/macrophage activation Swartjes et al., 2014;Watanabe et al., 2016;Huang et al., 2018). ...
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder. But the treatment of depression remains challenging. Anti-inflammatory treatments frequently produce antidepressant effects. EPO-derived helix-B peptide ARA290 has been reported to retain the anti-inflammatory and tissue-protective functions of EPO without erythropoiesis-stimulating effects. The effects of ARA290 on MDD remain elusive. This study established chronic unpredictable mild stress and chronic social defeat stress mouse models. Daily administration of ARA290 during chronic stress induction in two mouse models ameliorated depression-like behavior, similar to fluoxetine. With marginal effects on peripheral blood hemoglobin and red cells, ARA290 and fluoxetine reversed chronic stress-induced increased frequencies and/or numbers of CD11b+Ly6Ghi neutrophils and CD11b+Ly6Chi monocytes in the bone marrow and meninges. Furthermore, both drugs reversed chronic stress-induced microglia activation. Thus, ARA290 ameliorated chronic stress-induced depression-like behavior in mice through, at least partially, its anti-inflammatory effects.
... Evidence suggests that EPO binding to EPOR/CD131 heterodimers can mediate some of EPO's nonerythropoietic effects, including those involved in tissue and immune homeostasis and repair (15,(21)(22)(23). ARA290 is a nonerythropoietic EPO derivative that specifically ligates the EPOR/CD131 heterodimer with high affinity; it does not bind to or signal via the EPOR homodimer (24,25). We administered ARA290 at 0.5 mg/kg 3 times a week to CTLA4-Ig-treated EPOR fl/fl and EPOR fl/fl LysM-Cre recipients of BALB/c heart grafts, a dose previously shown to be effective in vivo in other murine models (refs. ...
Erythropoietin (EPO) has multiple non-erythropoietic functions including immune modulation, but EPO's effects in transplantation remain incompletely understood. We tested the mechanisms linking EPO administration to prolongation of murine heterotopic heart transplantation using wild type (WT) and conditional EPO receptor (EPOR) knockout mice as recipients. In WT controls, peri-transplant administration of EPO synergized with CTLA4-Ig to prolong allograft survival (P < 0.001), reduce frequencies of donor-reactive effector CD8+ T cells in the spleen (P < 0.001) and in the graft (P < 0.05), and increase frequencies and total numbers of donor-reactive regulatory T cells (TREG, P < 0.01 for each) vs. CTLA4-Ig alone. Studies performed in conditional EPOR knockout recipients showed that each of these differences required EPOR expression in myeloid cells, but not in T cells. Analysis of mRNA isolated from spleen monocytes showed that EPO/EPOR ligation upregulated macrophage-expressed, anti-inflammatory, regulatory and pro-efferocytosis genes, and downregulated selected pro-inflammatory genes. Together, the data support the conclusion that EPO promotes TREG-dependent murine cardiac allograft survival by crucially altering the phenotype and function of macrophages. Coupled with our previous documentation that EPO promotes TREG expansion in humans, the data support the need for testing the addition of EPO to costimulatory blockade-containing immunosuppression regimens in an effort to prolong human transplant survival.
... Experimental designs revealed that ARA 290 is able to prevent tissue injury and cell apoptosis, to reduce inflammation and to protect from neural tissue damage, inflammatory environment and neuritis Chen et al., 2014;Schmidt et al., 2011;Zhang et al., 2016). In agreement, data from preclinical studies Dahan et al., 2013;Heij et al., 2012;Swartjes et al., 2011Swartjes et al., , 2014) not only demonstrated its safety but also indicated that specific activation of the heterodimeric EpoR-βcR may result in the protection of different nonhematopoietic tissues. ...
Erythropoietin (Epo), the main erythropoiesis-stimulating factor widely prescribed to overcome anemia, is also known nowadays for its cytoprotective action on non-hematopoietic tissues. In this context, Epo showed not only its ability to cross the blood-brain barrier, but also its expression in the brain of mammals. In clinical trials, recombinant Epo treatment has been shown to stimulate neurogenesis, improve cognition and activate antiapoptotic, antioxidant and anti-inflammatory signaling pathways. These mechanisms, proposed to characterize a neuroprotective property, opened new perspectives on the Epo pharmacological potencies. However, many questions arise about a possible physiological role of Epo in the central nervous system (CNS) and the factors or environmental conditions that induce its expression.
Although Epo may be considered a strong candidate to be used against neuronal damage, long-term treatments, particularly when high Epo doses are needed, may induce thromboembolic complications associated with increases in hematocrit and blood viscosity. To avoid these adverse effects, different Epo analogs without erythropoietic activity but maintaining neuroprotection ability are currently being investigated. Carbamylated erythropoietin, as well as alternative molecules like Epo fusion proteins and partial peptides of Epo, seems to match this profile.
This review will focus on the discussion of experimental evidence reported in recent years linking erythropoietin and CNS function through investigations aimed at finding benefits in the treatment of neurodegenerative diseases. In addition, it will review the proposed mechanisms for novel derivatives which may clarify and, eventually, improve the neuroprotective action of Epo.
... 90 In preclinical models of neuropathy, ARA290 alleviated neuropathic pain by reducing inflammation and stimulating axonal repair. 91 A trial of daily subcutaneous ARA290 for 28 days compared with placebo in patients with sarcoidosis-associated small fiber neuropathy showed an improvement in symptoms, cutaneous temperature sensitivity, increased exercise capacity, and corneal nerve fiber density. 92 Another Phase IIA trial 93 in patients with painful DPN found that daily subcutaneous ARA290 for 28 days resulted in an improvement in HbA 1c , lipids, neuropathic symptoms, and CNFD compared with placebo, with surprisingly greater benefits in subjects with a lower baseline CNFD. ...
Purpose:
Diagnosing early diabetic peripheral neuropathy remains a challenge due to deficiencies in currently advocated end points. The cornea is densely innervated with small sensory fibers, which are structurally and functionally comparable to intraepidermal nerve fibers. Corneal confocal microscopy is a method for rapid, noninvasive scanning of the living cornea with high resolution and magnification.
Methods:
This narrative review presents the framework for the development of biomarkers and the literature on the use and adoption of corneal confocal microscopy as an objective, diagnostic biomarker in experimental and clinical studies of diabetic peripheral neuropathy. A search was performed on PubMed and Google Scholar based on the terms "corneal confocal microscopy," "diabetic neuropathy," "corneal sensitivity," and "clinical trials."
Findings:
A substantial body of evidence underpins the thesis that corneal nerve loss predicts incident neuropathy and progresses with the severity of diabetic peripheral neuropathy. Corneal confocal microscopy also identifies early corneal nerve regeneration, strongly arguing for its inclusion as a surrogate end point in clinical trials of disease-modifying therapies.
Implications:
There are sufficient diagnostic and prospective validation studies to fulfill the US Food and Drug Administration criteria for a biomarker to support the inclusion of corneal confocal microscopy as a primary end point in clinical trials of disease-modifying therapies in diabetic neuropathy.
... non-erythropoeitic peptide engineered from EPO (ARA 290, trade name Cibinetide) to find that patients receiving this compound for treatment of diabetic neuropathy had significant improvement of neuropathic symptoms in type 2 diabetics [40]. Furthermore, recent studies have demonstrated analgesic effects of ARA 290 against neuropathic pain in animal models by regulation of the transient receptor potential cation channel subfamily V member 1 channel and by microglia activation [41,42]. ARA 290 has also been shown to reduce neuropathic symptoms in patients with sarcoidosis and small fiber neuropathy [43]. ...
Erythropoietin (EPO) is an exciting neurotherapeutic option. Despite its potential, concerns exist regarding the potential for thrombosis and adverse events with EPO administration in normonemic adults. Systematic review of literature using PRISMA guidelines to examine the application and risks of EPO as a treatment option for neuroprotection in normonemic adults. Independent, systematic searches were performed in July 2019. PubMed (1960–2019) and the Cochrane Controlled Trials Register (1960–2019) were screened. Search terms included erythropoietin, neuroprotection, and humans. The PubMed search resulted in the following search strategy: (“erythropoietin” [MeSH Terms] OR “erythropoietin” [All Fields] OR “epoetin alfa” [MeSH Terms] OR (“epoetin” [All Fields] AND “alfa” [All Fields]) OR “epoetin alfa” [All Fields]) AND (“neuroprotection” [MeSH Terms] OR “neuroprotection” [All Fields]) AND “humans” [MeSH Terms]. PubMed, Cochrane Controlled Trials Register, and articles based on prior searches yielded 388 citations. 50 studies were included, comprising of 4351 patients. There were 13 studies that noted adverse effects from EPO. Three attributed serious adverse effects to EPO and complications were statistically significant. Two of these studies related the adverse events to the co-administration of EPO with tPA. Minor adverse effects associated with the EPO group included nausea, pyrexia, headache, generalized weakness and superficial phlebitis. Most published studies focus on spinal cord injury, peri-surgical outcomes and central effects of EPO. We found no studies to date evaluating the role of EPO in post-operative pain. Future trials could evaluate this application in persistent post-surgical pain and in the peri-operative period.
... Shepherd et al. 26 observed unabated mechanical allodynia in female C57BL/6 mice at 120 days after surgery. Swartjes et al. 28 observed maximal allodynia in female Sprague-Dawley rats at 140 days after SNI. Hubbard et al. 9 observed SNI allodynia in female Sprague-Dawley rats at 19-week point after injury, although visual inspection (see Fig. 3A in Hubbard et al.) suggests that remission may have been in the process of occurring. ...
Introduction:. Increasing attention is being paid to the effects of organismic factors like age on pain sensitivity. However, very little data exist on this topic using modern algesiometric assays and measures in laboratory rodents.
Objectives:. We investigated the effect of age and duration of nerve injury on baseline mechanical thresholds, neuropathic allodynia, and the antiallodynic and analgesic efficacy of 4 systemically administered analgesics: amitriptyline, diclofenac, morphine, and pregabalin.
Methods:. Mice of both sexes and 3 conditions were compared: Young-Young, in which baseline testing (von Frey thresholds), the injury producing neuropathic pain (spared nerve injury [SNI]) and subsequent drug testing occurred while mice were young (8–10 weeks); Young-Old, in which mice received the nerve injury while young but were tested for drug efficacy over 10 months later; and Old-Old, in which both the nerve injury and drug testing occurred at approximately 1 year of age.
Results:. Old-Old mice were found to display higher baseline mechanical sensitivity than other groups. No group differences were seen in SNI-induced allodynia in males; female Young-Old mice were found to display greatly reduced allodynia. With respect to drug efficacy, no differences among conditions were observed for amitriptyline, diclofenac, or morphine. For pregabalin, however, Young-Old mice displayed significantly reduced antiallodynia, and the drug was completely ineffective in Old-Old mice.
Conclusion:. Novel findings include the apparent remission of SNI-induced allodynia in female mice 10 months after injury and reduced pregabalin antiallodynic effects produced by both the passage of time after nerve injury and aging.
... Other studies have demonstrated that the βc receptor is involved in the induction of nitric oxide upon EPO stimulation 16,22,23 . Several groups have thereafter studied EPO derivatives such as ARA290, a peptide derived from helix B of EPO 24 , that could potentially activate the proposed IRR but not the EPOR homodimer. These derivatives would help in tissue repair and protection in pathological conditions without affecting physiological haematopoiesis [24][25][26][27] , as has been demonstrated by several studies demonstrating the protective effects of these EPO derivatives [28][29][30] . ...
... Several groups have thereafter studied EPO derivatives such as ARA290, a peptide derived from helix B of EPO 24 , that could potentially activate the proposed IRR but not the EPOR homodimer. These derivatives would help in tissue repair and protection in pathological conditions without affecting physiological haematopoiesis [24][25][26][27] , as has been demonstrated by several studies demonstrating the protective effects of these EPO derivatives [28][29][30] . ...
... Lastly, we tested whether the peptide ARA290 could bring the extracellular domains of EPOR and the βc receptor together 28 . ARA290 has been reported to preferentially bind to the proposed IRR heteroreceptor and not to the EPOR homodimer 24,[26][27][28]47 . We first carried out pull down assays where EPOR-His was immobilised on resin before being incubated with ARA290 or βc + ARA290. ...
A direct interaction between the erythropoietin (EPOR) and the beta-common (βc) receptors to form an Innate Repair Receptor (IRR) is controversial. On one hand, studies have shown a functional link between EPOR and βc receptor in tissue protection while others have shown no involvement of the βc receptor in tissue repair. To date there is no biophysical evidence to confirm a direct association of the two receptors either in vitro or in vivo. We investigated the existence of an interaction between the extracellular regions of EPOR and the βc receptor in silico and in vitro (either in the presence or absence of EPO or EPO-derived peptide ARA290). Although a possible interaction between EPOR and βc was suggested by our computational and genomic studies, our in vitro biophysical analysis demonstrates that the extracellular regions of the two receptors do not specifically associate. We also explored the involvement of the βc receptor gene (Csf2rb) under anaemic stress conditions and found no requirement for the βc receptor in mice. In light of these studies, we conclude that the extracellular regions of the EPOR and the βc receptor do not directly interact and that the IRR is not involved in anaemic stress.
... The results showed that treatment with HBSP prevented the development of mechanical allodynia caused by neuritis but not afect heat hyperalgesia [48]. In another study, HBSP treatment could reduce allodynia coupled to the suppression of spinal microglia response in a dose-dependent manner, which may result from HBSP-induced suppression of inlammation in central nervous system [49]. In the study on the therapeutic efects of HBSP in experimental autoimmune encephalomyelitis (EAE), the administration of HBSP to EAE rats signiicantly reduced the severity and shortened the duration of injury, reduced the iniltration of proinlammatory cells and suppressed expression of pro-inlammatory cytokines such as IL-1β, IL-17, TNF-α, IFN-γ. ...
... Produced by cells under stress, erythropoietin (EPO) is known to antagonize the production of proinflammatory molecules and as a consequence promotes tissue regeneration. 93,94 In experimental models, EPO is known to ameliorate DPN, but its use in humans is precluded by tendency to cause thrombosis. ARA290 is a nonhematopoietic peptide synthesized from EPO, which selectively targets the innate repair receptor, downregulating inflammation, without the procoagulant effects of EPO. ...
Saad Javed,1,2 Uazman Alam,3–5 Rayaz A Malik1,2,6 1Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK; 2Manchester University Hospital, Manchester, UK; 3Diabetes and Endocrinology Research, Department of Eye and Vision Sciences and Pain Research Institute, Institute of Ageing and Chronic Disease, University of Liverpool and Aintree University Hospital NHS Foundation Trust, Liverpool, UK; 4Department of Diabetes and Endocrinology, Royal Liverpool and Broadgreen University NHS Hospital Trust, Liverpool, UK; 5Division of Endocrinology, Diabetes and Gastroenterology, University of Manchester, Manchester, UK; 6Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar Abstract: There are currently no approved disease-modifying therapies for diabetic neuropathy, and there are only 3 US Food and Drug Administration-approved therapies (pregabalin, duloxetine, and tapentadol) for painful diabetic neuropathy. They each have moderate efficacy with adverse effects limiting optimal dose titration. There is a considerable need for new therapies for the management of painful diabetic neuropathy. We reviewed the potential role of mirogabalin, which like gabapentin and pregabalin modulates the alpha-2/delta-1 subunit of the voltage-gated calcium channel, allowing the influx of calcium and release of neurotransmitters at the synaptic cleft in the central nervous system and spinal cord. It has shown efficacy and good tolerability in a Phase II study in diabetic painful neuropathy and based on the results of two Phase III clinical trials in diabetic painful neuropathy and post-herpetic neuralgia, Daiichi Sankyo submitted a marketing application for neuropathic pain in Japan in February 2018. We have also reviewed potential new therapies, currently in Phase II clinical trials that may modify disease and/or relieve neuropathic pain through novel modes of action. Keywords: diabetic neuropathy, painful diabetic neuropathy, treatment, mirogabalin
