γ-Secretase modulation inhibits amyloid plaque formation and growth and stimulates plaque regression in amyloid precursor protein/presenilin-1 mice
(2025) Journal of Pharmacology and Experimental Therapeutics, 392 (4), art. no. 103400, .
Nordvall, G.a b c , Yan, P.d , Agholme, L.e , Lundkvist, J.b c f , Sandin, J.a b c , Biverstål, H.g , Winblad, B.c h , Zetterberg, H.e i j k l m , Klintenberg, R.b , Ferm, M.b , Cirrito, J.R.d , Lee, J.-M.d
a AlzeCure Pharma AB, Huddinge, Sweden
b Former AstraZeneca R&D, CNS & Pain Innovative Medicines, Södertälje, Sweden
c Division of Neurogeriatrics, Care Sciences and Society, Department of Neurobiology, Karolinska Institutet, Solna, Sweden
d Department of Neurology, Washington University, School of Medicine, St. Louis, Missouri, United States
e Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
f AlzeCure Foundation, Huddinge, Sweden
g The Biosciences and Nutrition Unit (BioNut) at the Department of Medicine, Karolinska Institutet, Huddinge, Sweden
h Theme Inflammation & Aging, Karolinska University Hospital, Huddinge, Sweden
i Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
j Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
k UK Dementia Research Institute at UCL, London, United Kingdom
l Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong
m Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
Abstract
γ-Secretase modulators (GSMs) represent an emerging oral therapy for preventing and targeting Aβ-amyloidosis in Alzheimer disease. Aβ is a family of peptides of varying lengths where both the total and relative amounts of the individual Aβ peptides affect the process of amyloidosis. In contrast to inhibitors of Aβ synthesis, GSMs do not affect the total amount of Aβ peptides generated but decrease longer more amyloidogenic Aβ species while increasing the production of shorter less amyloidogenic Aβ peptides. In this study, we investigated how this modulation of Aβ production affects Aβ plaque dynamics in the brains of APP/PS1dE9 transgenic mice. Similar to studies with different inhibitors of Aβ synthesis, we found that 28 days of once-daily oral treatment with the GSM AZ4126 (100 μmol/kg) resulted in a strong reduction in plaque formation and plaque growth. In addition, and in contrast to Aβ production inhibitors, the GSM AZ4126 caused a significant reduction in the size of established Aβ plaques. Moreover, the antiamyloidogenic activity was accompanied by a marked reduction in brain interstitial fluid Aβ40 and Aβ42 and an increase in Aβ37. Treatment of induced pluripotent stem cell-derived cortical neurons with the GSM AZ4126 reduced secreted Aβ40 and Aβ42 dose-dependently and with a complementary increase in Aβ37 and Aβ38. These studies unravel a previously unknown antiamyloidogenic effect of GSMs, suggesting that they promote the clearance of already established Aβ pathology in addition to their inhibition of Aβ amyloid formation. Significance Statement: Immunotherapies promoting Aβ-amyloid clearance have shown efficacy in early Alzheimer disease, but complementary Aβ targeting therapeutic approaches are needed. γ-Secretase modulators (GSMs) target Aβ production with an effective and tolerable mechanism. This study demonstrates that a GSM not only inhibits Aβ-amyloid formation but also promotes Aβ-plaque clearance in experiments conducted in an Aβ-amyloidosis mouse model and supports further development of GSMs as an effective oral treatment for Alzheimer disease. © 2025 The Authors
Author Keywords
2-Photon; Abeta; Alzheimer’s disease; Amyloid; Gamma-secretase modulator; Microdialysis
Funding details
Alzheimer’s AssociationAA
Erling-Perssons Stiftelse
Horizon 2020 Framework ProgrammeH2020
VINNOVA
Olav Thon Stiftelsen
Cure Alzheimer’s FundCAF
Horizon 2020
22HLT07
UK Dementia Research InstituteUK DRI02905/EC 643417, 643417, UKDRI-1003
UK Dementia Research InstituteUK DRI
EU Joint Programme – Neurodegenerative Disease ResearchJPNDJPND2021-00694
EU Joint Programme – Neurodegenerative Disease ResearchJPND
Alzheimer’s Drug Discovery FoundationADDF201809-2016862
Alzheimer’s Drug Discovery FoundationADDF
#FO2022-0270
-71320, 101053962
VetenskapsrådetVR2022-01018, 2019-02397, 2023-00356
VetenskapsrådetVR
H2020 Marie Skłodowska-Curie ActionsMSCA860197
H2020 Marie Skłodowska-Curie ActionsMSCA
Document Type: Article
Publication Stage: Final
Source: Scopus
Optimism in inclusion body myositis: a double-blind randomised controlled phase III trial investigating the effect of sirolimus on disease progression in patients with IBM as measured by the IBM Functional Rating Scale
(2025) Clinical and Experimental Rheumatology, 43 (2), pp. 316-325.
Badrising, U.A.a , Henderson, R.b c , Reddel, S.d , Corbett, A.e , Liang, C.f g h , Reardon, K.i j , Ghaoui, R.k l , Bulsara, M.m , Brady, S.n , Brusch, A.o p q , Chan, D.r , Coudert, J.D.p s t , Fairchild, T.s u v , Jain, G.i w , Kiernan, M.C.x y , Leonard, D.z , Lloyd, T.aa ab ac , Schmidt, J.ad ae af , McDermot, M.P.ag , Sanders, L.i , Lowe, C.ah , van der Kooi, A.J.ai , Weihl, C.aj , Mohassel, P.aa , Simpson, M.w , Carrol, A.ak , Cooper, I.p s , Beer, K.p s , Hiscock, K.al , Walters, S.p , Panicker, A.p s , Doverty, A.p s , Heim, A.J.am , van Heur-Neuman, M.a , Benveniste, O.an ao , Dimachki, M.M.b , Needham, M.p s t ap
a Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
b Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, Australia
c Centre for Clinical Research, University of Queensland, Brisbane, Australia
d Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia
e Department of Neurology, Concord Repatriation Hospital, Concord, NSW, Australia
f Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
g Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia
h Neuroscience Research Australia, Sydney, NSW, Australia
i Department of Neurology, St Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia
j The University of Melbourne, Victoria, Australia
k Department of Neurology, Central Adelaide Local Health Network, Royal Adelaide Hospital, Adelaide, SA, Australia
l Adelaide Medical School, University of AdelaideSA, Australia
m Institute for Health Research, The University of Notre Dame Australia, Fremantle, WA, Australia
n Oxford Adult Muscle Service, John Radcliffe Hospital, Oxford University Hospital Trust, Oxford, United Kingdom
o Department of Clinical Immunology, Sir Charles Gairdner Hospital, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia
p Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
q Centre for Neuromuscular and Neurological Disorders, University of Western Australia Medical School, Perth, WA, Australia
r Department of Renal Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
s Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA, Australia
t University of Notre Dame Australia, School of Medicine, Fremantle, WA, Australia
u School of Allied Health (Exercise Science), Murdoch University, Murdoch, WA, Australia
v Centre for Healthy Aging, Murdoch University, Murdoch, WA, Australia
w Department of Neurology, Austin Hospital, Austin Health, Heidelberg, VIC, Australia
x Neuroscience Research Australia, University of New South Wales, Sydney, NSW, Australia
y Neurology Department, South Eastern Sydney Local Health District, Sydney, NSW, Australia
z Department of Medical Sciences, University of Uppsala, Sweden
aa Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
ab Department of Neurology, Baylor College of Medicine, Houston, TX, United States
ac Department of Clinical Research, Imricor Medical Systems, Burnsville, MN, United States
ad Klinik für Neurologie, Universitätsmedizin Göttingen, Germany
ae Abteilung für Neurologie und Schmerztherapie, Neuromuskuläres Zentrum, Zentrum für Translationale Medizin, Immanuel Klinik Rüdersdorf, Universitätsklinikum der Medizinischen Hochschule Brandenburg, Rüdersdorf, Berlin, Germany
af Fakultät für Gesundheitswissenschaften Brandenburg, Medizinische Hochschule Brandenburg Theodor Fontane, Rüdersdorf, Berlin, Germany
ag Department of Biostatistics and Computational Biology, Department of Neurology, University of Rochester Medical Center, Rochester, NY, United States
ah The Myositis Association – Australia Inc, Berry, NSW, Australia
ai Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, Netherlands
aj Neuromuscular Division, Washington University School of Medicine, Saint Louis, United States
ak Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Department of Neurology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
al Affinity Clinical Research, Nedlands, WA, Australia
am Department of Neurology, University of Kansas Medical Center, Kansas City, United States
an Sorbonne University, AP-HP, Paris, France
ao Department of Internal Medicine and Clinical Immunology, National Reference Centre for Inflammatory Myopathies, Hôpital Pitié-Salpêtrière, Paris, France
ap Fiona Stanley Hospital, Murdoch, WA, Australia
Abstract
Objective Inclusion body myositis (IBM) is a complex inflammatory muscle disease in adults over 40, with histological features of autoinflammation, cell stress and autophagic abnormalities, and marked clinically by relentless progression with no effective disease-modifying therapy. Sirolimus (rapamycin) may help maintain function by inhibiting T effector cells, preserving T regulatory cells, inducing autophagy, and improving mitochondrial function. This international trial follows a phase II pilot study. Methods This phase IIb/III double-blind, randomised, controlled trial (RCT) of sirolimus involves 140 IBM patients randomly assigned with equal allocation to sirolimus (2 mg) or matching placebo. This RCT aims to assess the efficacy of sirolimus compared to placebo in slowing or stabilising IBM progression, as measured by the mean change in patient function using the IBM Functional Rating Scale (IBM-FRS) from Baseline to Week 84. Secondary outcomes will evaluate efficacy and safety to inform future clinical trial design. Results Ethical approval has been granted in Australia (St Vincent’s Hospital Melbourne HREC-D 311/20) and the USA (University of Kansas Medical Center Human Research Protection Program FWA no. 00003411), with European approval pending. The protocol is version 3.0 (02-Dec-2022). Trial registration: ANZCTR: ACTRN12620001226998p, ClinicalTrials.gov: NCT04789070, UTN: U1111-1258-1354, and EU CT 2024-514575-17-00. Conclusion This phase IIb/III trial builds on prior findings to assess sirolimus’s potential in slowing or halting IBM progression, preserving patient function and independence, and advancing IBM therapeutic strategies and trial design. © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2025.
Author Keywords
clinical trials; inclusion body myositis; international; investigator-inititated
Funding details
Texas Medical AssociationTMA
Perron Institute for Neurological and Translational Science
Deutsche ForschungsgemeinschaftDFG
Muscular Dystrophy UKMDUK
National Health and Medical Research CouncilNHMRC
AFM-Téléthon
Association Française contre les MyopathiesAFM
Pfizer
Document Type: Article
Publication Stage: Final
Source: Scopus
Associations of Cerebrospinal Fluid Orexin-A, Alzheimer Disease Biomarkers, and Cognitive Performance
(2025) Annals of Clinical and Translational Neurology, .
Lu, R.a , Shah, K.b , Toedebusch, C.D.b , Hess, A.b , Richardson, R.b , Mignot, E.c , Schindler, S.E.b d e , Benzinger, T.L.S.d e f , Flores, S.f , Hassenstab, J.b , Xiong, C.a , Morris, J.C.b d e , Holtzman, D.M.b d e , Lucey, B.P.b e
a Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, United States
d Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
f Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
Abstract
Objective: Cerebrospinal fluid (CSF) orexin-A has been suggested to be a biomarker of Alzheimer disease (AD). In both cognitively unimpaired healthy older adults and individuals with symptomatic AD, CSF orexin-A is positively associated with CSF Aβ42, p-tau181, and total tau (t-tau) concentrations. However, a recent systematic review and meta-analysis did not support differences in orexin-A between AD and controls. In this study, we tested the association between CSF orexin-A concentrations, AD biomarkers, and cognitive performance in older adults with and without symptomatic AD. Methods: Two hundred and seventy community-dwelling older adults underwent standardized cognitive assessments, sleep monitoring with a single-channel electroencephalography test, one night of home sleep apnea testing, biofluid and imaging AD biomarker measurement within 1 year of sleep monitoring, and APOE genotyping. Plasma and CSF AD biomarkers were measured by immunoassay or mass spectrometry. CSF orexin-A was measured by radioimmunoassay. Results: CSF orexin-A levels did not differ by amyloid positivity, cognitive status, or AD stage. However, CSF AD biomarkers (Aβ40, Aβ42, and t-tau) were positively associated with CSF orexin-A levels even after correction for multiple comparisons. CSF orexin-A was not associated with any measure of cognitive performance. Interpretation: This study showed that CSF orexin-A is associated with multiple CSF AD biomarkers, but not with AD pathology or cognitive performance. We hypothesize that this is due to similar mechanisms of production/release of these proteins with sleep–wake activity. Future studies measuring other forms of orexin peptides, such as orexin-B, may provide evidence for orexin as a marker for AD. © 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Institutes of HealthNIH
Eisai
National Institute on AgingNIAP01 AG026276, P30 AG066444, P01 AG03991
National Institute on AgingNIA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Aberrant homeodomain–DNA cooperative dimerization underlies distinct developmental defects in two dominant CRX retinopathy models
(2025) Genome Research, 35 (2), pp. 242-256.
Zheng, Y.a b , Stormo, G.D.c , Chen, S.b d
a Molecular Genetics and Genomics Graduate Program, Division of Biology & Biomedical Sciences, Washington University in St. Louis, St. Louis, MO 63110, United States
b Department of Ophthalmology and Visual Sciences, Washington University in St Louis, Saint Louis, MO 63110, United States
c Department of Genetics, Washington University in St Louis, Saint Louis, MO 63110, United States
d Department of Developmental Biology, Washington University in St Louis, Saint Louis, MO 63110, United States
Abstract
Paired-class homeodomain (HD) transcription factors (TFs) play essential roles in vertebrate development, and their mutations are linked to human diseases. One unique feature of a paired-class HD is cooperative dimerization on specific palindrome DNA sequences. Yet, the functional significance of HD cooperative dimerization in animal development and its dysregulation in diseases remains elusive. Using the retinal TF cone-rod homeobox (CRX) as a model, we have studied how blindness-causing mutations in the paired HD, p.E80A and p.K88N, alter CRX’s cooperative dimerization, leading to gene misexpression and photoreceptor developmental deficits in dominant manners. CRXE80A maintains binding at monomeric WT CRX motifs but is deficient in cooperative binding at dimeric motifs. CRXE80A’s cooperativity defect impacts the exponential increase of photoreceptor gene expression in terminal differentiation and produces immature, nonfunctional photoreceptors in the CrxE80A retinas. CRXK88N is highly cooperative and localizes to ectopic genomic sites with strong enrichment of dimeric HD motifs. CRXK88N’s altered biochemical properties disrupt CRX’s ability to direct dynamic chromatin remodeling during development to activate photoreceptor differentiation programs and silence progenitor programs. Our study provides in vitro and in vivo molecular evidence that paired-class HD cooperative dimerization regulates neuronal development and that dysregulation of cooperative binding contributes to severe dominant blinding retinopathies. © 2025 Zheng et al.
Funding details
Research to Prevent BlindnessRPB
Genome Technology Access CenterGTAC
National Institutes of HealthNIHEY012543, EY032136, EY027784, EY002687
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Assessing the clinical meaningfulness of slowing CDR-SB progression with disease-modifying therapies for Alzheimer’s disease
(2025) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 11 (1), art. no. e70033, .
Hartz, S.M.a , Schindler, S.E.b , Streitz, M.L.b , Moulder, K.L.b , Mozersky, J.c , Wang, G.b d , Xiong, C.d , Morris, J.C.b
a Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Division of Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
INTRODUCTION: For many patients and caregivers, a major goal of disease-modifying treatments (DMTs) for Alzheimer’s disease (AD) dementia is to extend independence in instrumental and basic activities of daily living (IADLs and BADLs). The goal of this study was to estimate the effect of treatments on the time remaining independent in IADLs and BADLs. METHODS: Participants at the Knight Alzheimer Disease Research Center (Knight ADRC) who met eligibility criteria for recent DMT trials were studied: age ≥60 years at baseline, clinical diagnosis of very mild or mild AD dementia (global Clinical Dementia Rating [CDR] score 0.5 or 1), biomarker confirmation of amyloid pathology, and at least one follow-up CDR assessment within 5 years. For IADLs, a subset of the Functional Assessment Questionnaire (FAQ) was examined that rated the degree of independence in the following: paying bills, driving, remembering medications and appointments, and preparing meals. For BADLs, the Personal Care domain of the CDR was used. Mixed-effects logistic and ordinal regression models were used to examine the relationship between CDR Sum of Boxes (CDR-SB) and the individual functional outcomes and their components. The change in CDR-SB over time was estimated with linear mixed-effects models. RESULTS: A total of 282 participants were followed for an average of 2.9 years (standard deviation [SD] 1.3 years). For 50% of individuals, loss of independence in IADLs occurred at CDR-SB >4.5 and in BADLs at CDR-SB >11.5. For individuals with a baseline CDR-SB = 2, treatment with lecanemab would extend independence in IADLs for 10 months (95% confidence interval [CI] 4–18 months) and treatment with donanemab in the low/medium tau group would extend independence in IADLs by 13 months (95% CI 6–24 months). DISCUSSION: Independence in ADLs can be related to CDR-SB and used to demonstrate the effect of AD treatments in extending the time of independent function, a meaningful outcome for patients and their families. Highlights: We estimated time to loss of independence for people with AD dementia Estimating time to loss of independence can help with clinical decision-making Disease-modifying treatments for AD dementia can extend independence. © 2025 The Author(s). Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
AD dementia; clinical meaningfulness; functional independence
Funding details
National Institutes of HealthNIHP01 AG026276, U01 AA008401, R01 AG065234, P01 AG003991, R01 AG067505, P30 AG066444, R01 AG070941, R01 AA029308, UL1 TR002345
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Mechanistic basis of activation and inhibition of protein disulfide isomerase by allosteric antithrombotic compounds
(2025) Journal of Thrombosis and Haemostasis, 23 (2), pp. 577-587.
Ponzar, N.a , Chinnaraj, M.a , Pagotto, A.b , De Filippis, V.b , Flaumenhaft, R.c , Pozzi, N.a
a Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, United States
b Department of Pharmaceutical and Pharmacological Sciences, School of Medicine, University of Padova, Padua, Italy
c Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
Abstract
Background: Protein disulfide isomerase (PDI) is a promising target for combating thrombosis. Extensive research over the past decade has identified numerous PDI-targeting compounds. However, limited information exists regarding how these compounds control PDI activity, which complicates further development. Objectives: To define the mechanism of action of 2 allosteric antithrombotic compounds of therapeutic interest, quercetin-3-O-rutinoside and bepristat-2a. Methods: A multipronged approach that integrates single-molecule spectroscopy, steady-state kinetics, single-turnover kinetics, and site-specific mutagenesis. Results: PDI is a thiol isomerase consisting of 2 catalytic a domains and 2 inactive b domains arranged in the order a-b-b’-a’. The active sites CGHC are located in the a and a’ domains. The binding site of quercetin-3-O-rutinoside and bepristat-2a is in the b’ domain. Using a library of 9 Förster resonance energy transfer sensors, we showed that quercetin-3-O-rutinoside and bepristat-2a globally alter PDI structure and dynamics, leading to ligand-specific modifications of its shape and reorientation of the active sites. Combined with enzyme kinetics and mutagenesis of the active sites, Förster resonance energy transfer data reveal that binding of quercetin-3-O-rutinoside results in a twisted enzyme with reduced affinity for the substrate. In contrast, bepristat-2a promotes a more compact conformation of PDI, in which a greater enzymatic activity is achieved by accelerating the nucleophilic step of the a domain, leading to faster formation of the covalent enzyme–substrate complex. Conclusion: This work reveals the mechanistic basis underlying PDI regulation by antithrombotic compounds quercetin-3-O-rutinoside and bepristat-2a and points to novel strategies for furthering the development of PDI-targeting compounds into drugs. © 2024 International Society on Thrombosis and Haemostasis
Author Keywords
blood clotting; drug discovery; enzymology; protein disulfide-isomerases; single-molecule imaging
Funding details
Ministero dell’Istruzione, dell’Università e della RicercaMIURPRIN-2022ZSA2JP
Ministero dell’Istruzione, dell’Università e della RicercaMIUR
Document Type: Article
Publication Stage: Final
Source: Scopus
The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance
(2025) Pain, 166 (2), pp. 376-387.
Martin, L.F.a b c , Almuslim, M.a d , Ismail, K.A.b , Ibrahim, M.M.a b c , Moutal, A.e , Cheng, K.a , Stratton, H.J.a , Price, T.J.f , Vanderah, T.W.a b c , Olivera, B.M.g , Khanna, R.h i , Patwardhan, A.j k
a Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States
b Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States
c Comprehensive Center for Pain and Addiction, College of Medicine, The University of Arizona, Tucson, AZ, United States
d Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
e Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States
f Department of Neuroscience, Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States
g Department of Biology, University of Utah, Salt Lake City, UT, United States
h Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL, United States
i Pain and Addiction Therapeutics (PATH) Collaboratory, College of Medicine, University of Florida, Gainesville, FL, United States
j Department of Anesthesiology and Pain Management, University of Texas, Southwestern Medical Center, Dallas, TX, United States
k Peter o’Donnell Jr. Brain Institute, Dallas, TX, United States
Abstract
As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway. However, the efficacy and side effect profile of CGX have never been assessed in CIBP. Here, we evaluated CGX’s antinociceptive potential in a rodent model of CIBP. We hypothesized that CGX engages the NTSR2 pathway, providing pain relief with minimal tolerance and motor side effects. Our results demonstrated that CGX intrathecal injection in mice with CIBP attenuated both spontaneous pain behaviors and evoked mechanical hypersensitivity, regardless of their sex. Furthermore, the antinociceptive effect of CGX was dependent upon expression of NTSR2 and the R-type voltage-gated calcium channel (Cav2.3); gene editing of these targets abolished CGX antinociception without affecting morphine antinociception. Examination of the side effect profile of CGX demonstrated that, unlike morphine, chronic intrathecal infusion maintained antinociception with reduced tolerance in rats with CIBP. Moreover, at antinociceptive doses, CGX had no impact on motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting analysis revealed expression of NTSR2 in both dorsal and ventral horns, while Cav2.3 was minimally expressed in the ventral horn, possibly explaining the sensory selectivity of CGX. Together, these findings support advancing CGX as a potential therapeutic for cancer pain. © 2024 International Association for the Study of Pain.
Author Keywords
Cancer-induced bone pain; Cav2.3; Conotoxins; Motor deficits; NTSR2; Tolerance
Funding details
National Institute of Neurological Disorders and StrokeNINDSR01 NS116694, K08 NS104272
National Institute of Neurological Disorders and StrokeNINDS
National Center for Complementary and Integrative HealthNCCIHR01AT009716
National Center for Complementary and Integrative HealthNCCIH
Document Type: Article
Publication Stage: Final
Source: Scopus