Neuroscience
Abstract
Pain emanating from the female reproductive tract is notoriously difficult to be treated and the prevalence of transient pelvic pain has been placed as high as 70-80% in women surveyed. Although sex hormones, especially estrogen, are thought to underlie enhanced pain perception in females, the underlying molecular and cellular mechanisms are not completely understood. Here we show that the pain-initiating TRPA1 channel is required for pain-related behaviors in a mouse model of estrogen-induced uterine pain in ovariectomized female mice. Surprisingly, 2- and 4-hydroxylated estrogen metabolites (HEMs) in the estrogen hydroxylation pathway, but not estrone, estradiol and 16-HEMs, directly increase nociceptor hyperactivity through TRPA1 and TRPV1 channels, and picomolar concentrations of 2- and 4-hydroxylation estrone (OHE1) can sensitize TRPA1 channel function. Moreover, both TRPA1 and TRPV1 are expressed in uterine-innervating primary nociceptors and their expressions are increased in the estrogen-induced uterine pain model. Importantly, pretreatment of 2- or 4-OHE1 recapitulates estrogen-induced uterine pain-like behaviors and intraplantar injections of 2- and 4-OHE1 directly produce a TRPA1-dependent mechanical hypersensitivity. Our findings demonstrate that TRPA1 is critically involved in estrogen-induced uterine pain-like behaviors, which may provide a potential drug target for treating female reproductive tract pain.
Authors
Zili Xie, Jing Feng, Tao Cai, Ronald McCarthy, Mark D. Eschbach II, Yuhui Wang, Yonghui Zhao, Zhihua Yi, Kaikai Zang, Yi Yuan, Xueming Hu, Fengxian Li, Qin Liu, Aditi Das, Sarah K. England, Hongzhen Hu
Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation.
Authors
Mathias Linnerbauer, Lena Lößlein, Oliver Vandrey, Thanos Tsaktanis, Alexander Beer, Ulrike J. Naumann, Franziska Panier, Tobias Beyer, Lucy Nirschl, Joji B. Kuramatsu, Jürgen Winkler, Francisco J. Quintana, Veit Rothhammer
Abstract
BACKGROUND. Potent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression. METHODS. To characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in two populations (opioid-naïve individuals and chronic users of high-dose opioids), the effects of escalating intravenous fentanyl doses with range 0.075-0.35 mg/70kg (opioid-naïve) and 0.25-0.70 mg/70 kg (chronic opioid users) on iso-hypercapnic ventilation at 2-3 background doses of buprenorphine (target plasma concentrations range: 0.2-5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models. RESULTS. Buprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding-dependent reduction of fentanyl-induced respiratory depression in both populations. In chronic opioid users, at buprenorphine plasma concentrations ≥2 ng/mL, a protective effect against high-dose fentanyl was observed. CONCLUSION. Overall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine. TRIAL REGISTRATION. Trialregister.nl, number NL7028 (https://www.trialregister.nl/trial/7028) FUNDING. Indivior Inc., North Chesterfield, VA.
Authors
Erik Olofsen, Marijke Hyke Algera, Laurence Moss, Robert L. Dobbins, Geert J. Groeneveld, Monique van Velzen, Marieke Niesters, Albert Dahan, Celine M. Laffont
Abstract
Spinocerebellar ataxia type1 (SCA1) is an adult-onset neurodegenerative disorder. As disease progresses motor neurons are affected, and their dysfunction contributes towards the inability to maintain proper respiratory function, a major driving force for premature death in SCA1. To investigate the isolated role of motor neurons in SCA1 we created a novel conditional SCA1 (cSCA1) mouse model. This model suppresses expression of the pathogenic SCA1 allele with a floxed stop cassette. cSCA1 mice crossed to a ubiquitous Cre line recapitulate all the major features of the original SCA1 mouse model, except they took twice as long to develop. We found that the cSCA1 mice produce less than half of the pathogenic protein compared to the unmodified SCA1 mice at 3 weeks of age. In contrast, restricted expression of the pathogenic SCA1 allele in motor neurons only leads to a decreased distance traveled of mice in the open field assay and did not affect body weight or survival. We conclude that a fifty percent or greater reduction of the mutant protein has a dramatic effect on disease onset and progression, and that expression of polyglutamine expanded ATXN1 at this level specifically in motor neurons is not sufficient to cause premature lethality.
Authors
James P. Orengo, Larissa Nitschke, Meike E. van der Heijden, Nicholas A. Ciaburri, Harry T. Orr, Huda Y. Zoghbi
Abstract
Understanding the endogenous mechanisms regulating resolution of pain may identify novel targets for treatment of chronic pain. Resolution of chemotherapy-induced peripheral neuropathy (CIPN) after treatment completion depends on CD8+ T cells and on IL-10 produced by other cells. Using Rag2–/– mice lacking T and B cells and adoptive transfer of Il13–/– CD8+ T cells, we showed that CD8+ T cells producing IL-13 were required for resolution of CIPN. Intrathecal administration of anti–IL-13 delayed resolution of CIPN and reduced IL-10 production by dorsal root ganglion macrophages. Depleting local CD206+ macrophages also delayed resolution of CIPN. In vitro, TIM3+CD8+ T cells cultured with cisplatin, apoptotic cells, or phosphatidylserine liposomes produced IL-13, which induced IL-10 in macrophages. In vivo, resolution of CIPN was delayed by intrathecal administration of anti-TIM3. Resolution was also delayed in Rag2–/– mice reconstituted with Havcr2 (TIM3)–/– CD8+ T cells. Our data indicated that cell damage induced by cisplatin activated TIM3 on CD8+ T cells, leading to increased IL-13 production, which in turn induced macrophage IL-10 production and resolution of CIPN. Development of exogenous activators of the IL-13/IL-10 pain resolution pathway may provide a way to treat the underlying cause of chronic pain.
Authors
Susmita K. Singh, Karen Krukowski, Geoffroy O. Laumet, Drew Weis, Jenolyn F. Alexander, Cobi J. Heijnen, Annemieke Kavelaars
Abstract
BACKGROUND After the initial surge in COVID-19 cases, large numbers of patients were discharged from a hospital without assessment of recovery. Now, an increasing number of patients report postacute neurological sequelae, known as “long COVID” — even those without specific neurological manifestations in the acute phase.METHODS Dynamic brain changes are crucial for a better understanding and early prevention of “long COVID.” Here, we explored the cross-sectional and longitudinal consequences of COVID-19 on the brain in 34 discharged patients without neurological manifestations. Gray matter morphology, cerebral blood flow (CBF), and volumes of white matter tracts were investigated using advanced magnetic resonance imaging techniques to explore dynamic brain changes from 3 to 10 months after discharge.RESULTS Overall, the differences of cortical thickness were dynamic and finally returned to the baseline. For cortical CBF, hypoperfusion in severe cases observed at 3 months tended to recover at 10 months. Subcortical nuclei and white matter differences between groups and within subjects showed various trends, including recoverable and long-term unrecovered differences. After a 10-month recovery period, a reduced volume of nuclei in severe cases was still more extensive and profound than that in mild cases.CONCLUSION Our study provides objective neuroimaging evidence for the coexistence of recoverable and long-term unrecovered changes in 10-month effects of COVID-19 on the brain. The remaining potential abnormalities still deserve public attention, which is critically important for a better understanding of “long COVID” and early clinical guidance toward complete recovery.FUNDING National Natural Science Foundation of China.
Authors
Tian Tian, Jinfeng Wu, Tao Chen, Jia Li, Su Yan, Yiran Zhou, Xiaolong Peng, Yuanhao Li, Ning Zheng, Aoling Cai, Qin Ning, Hongbing Xiang, Fuqiang Xu, Yuanyuan Qin, Wenzhen Zhu, Jie Wang
Abstract
BACKGROUND. Paclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. As sensory symptoms are challenging to assess objectively in clinical routine, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as translational surrogate marker for CIPN. METHODS. NFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell-derived sensory neurons (iPSC-DSN) to paclitaxel. Breast and ovarian cancer patients undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced, which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFLs) concentrations were measured at both visits with single molecule array technology (SIMOA). RESULTS. NFL is released from iPSC-DSN upon paclitaxel incubation in a dose- and time-dependent manner and inversely correlates with iPSC-DSN viability. NFLs strongly increased in paclitaxel-treated patients with CIPN, but not in chemotherapy patients without CIPN or controls, resulting in an 86 % sensitivity and 87 % specificity. A NFLs increase of +36 pg/ml from baseline was associated with a predicted CIPN probability of >0.5. CONCLUSION. NFLs correlates with CIPN development and severity, which may guide neurotoxic chemotherapy in the future. TRIAL REGISTRATION. NCT02753036 FUNDING. DFG (EXC 257 NeuroCure), BMBF (01 EO 0801), AnimalFreeResearch Organization, EU Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking (TransBioLine, 821283)
Authors
Petra Huehnchen, Christian Schinke, Nikola Bangemann, Adam D. Dordevic, Johannes Kern, Smilla K. Maierhof, Lois Hew, Luca Nolte, Peter Körtvelyessy, Jens C. Göpfert, Klemens Ruprecht, Christopher J. Somps, Jens-Uwe Blohmer, Jalid Sehouli, Matthias Endres, Wolfgang Boehmerle
Abstract
Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically and pharmacologically validated therapeutic target for prion disease. In order to evaluate PrP concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across six species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varies dramatically between different brain regions in mice, cynomolgus macaques, and humans. PrP expression does not appear to contribute to the known risk factors of age, sex, or common PRNP genetic variants. CSF PrP is lowered in the presence of rare pathogenic PRNP variants, with heterozygous carriers of P102L displaying 55% and of D178N just 31% the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA is reflected in brain parenchyma PrP, and in turn in CSF PrP, validating CSF as a sampling compartment for the effect of PrP-lowering therapy. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs, and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.
Authors
Meredith A. Mortberg, Hien T. Zhao, Andrew G. Reidenbach, Juliana E. Gentile, Eric Kuhn, Jill O'Moore, Patrick M. Dooley, Theresa R. Connors, Curt Mazur, Shona W. Allen, Bianca A. Trombetta, Alison J. McManus, Matthew R. Moore, Jiewu Liu, Deborah E. Cabin, Holly B. Kordasiewicz, Joel Mathews, Steven E. Arnold, Sonia M. Vallabh, Eric Vallabh Minikel
Abstract
Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation for KCNQ2 variants hinders identification of individuals who may benefit from emerging precision therapies. We employed automated patch clamp recording to assess at an unprecedented scale the functional and pharmacological properties of 79 missense and 2 inframe deletion KCNQ2 variants. Among the variants we studied were 18 known pathogenic variants, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. We analyzed electrophysiological data recorded from 9,480 cells. The functional properties of 18 known pathogenic variants largely matched previously published results and validated automated patch clamp for this purpose. Unlike rare population variants, most disease-associated KCNQ2 variants exhibited prominent loss-of-function with dominant-negative effects, providing strong evidence in support of pathogenicity. All variants responded to retigabine, although there were substantial differences in maximal responses. Our study demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine, a proposed precision therapy for KCNQ2 developmental and epileptic encephalopathy.
Authors
Carlos G. Vanoye, Reshma R. Desai, Zhigang Ji, Sneha Adusumilli, Nirvani Jairam, Nora Ghabra, Nishtha Joshi, Eryn Fitch, Katherine L. Helbig, Dianalee McKnight, Amanda S. Lindy, Fanggeng Zou, Ingo Helbig, Edward C. Cooper, Alfred L. George Jr.
Abstract
Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS. Depleting leukocytes with a colony-stimulating factor 1 receptor inhibitor disrupts disease progression, including suppression of CNS lesion formation and a substantial extension of survival. Leukocyte depletion rescues diverse symptoms including seizures, respiratory center function, hyperlactemia, and neurologic sequelae. These data reveal a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement is causal in disease. This work has significant implications for the mechanisms of mitochondrial disease and may lead to novel therapeutic strategies.
Authors
Julia C. Stokes, Rebecca L. Bornstein, Katerina James, Kyung Yeon Park, Kira A. Spencer, Katie Vo, John C. Snell, Brittany M. Johnson, Philip G. Morgan, Margaret M. Sedensky, Nathan A. Baertsch, Simon C. Johnson
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