{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:37:13Z","timestamp":1760150233197,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T00:00:00Z","timestamp":1698364800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Excellence Initiative to the Graduate School of Life Sciences, University of W\u00fcrzburg","award":["424778381\u2013TRR 295"],"award-info":[{"award-number":["424778381\u2013TRR 295"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","award":["424778381\u2013TRR 295"],"award-info":[{"award-number":["424778381\u2013TRR 295"]}]},{"name":"Interdisziplinaeres Zentrum fuer Klinische Forschung (IZKF) of the JMU W\u00fcrzburg","award":["424778381\u2013TRR 295"],"award-info":[{"award-number":["424778381\u2013TRR 295"]}]},{"name":"Fondazione Grigioni per il Morbo di Parkinson","award":["424778381\u2013TRR 295"],"award-info":[{"award-number":["424778381\u2013TRR 295"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The pathophysiology of tremor in Parkinson\u2019s disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg\/kg) two weeks prior to reserpine injection (10 mg\/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 \u00b1 0.01 vs. R-group: 0.27 \u00b1 0.04 axons\/um2, p &lt; 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 \u00b1 0.8 vs. R-group: 1.6 \u00b1 0.5; p &lt; 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (% of tremor during 180 s recording), DR-group: 37.9 \u00b1 35.8 vs. R-group: 69.3 \u00b1 29.6; p &lt; 0.05). Akinetic\u2013rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients.<\/jats:p>","DOI":"10.3390\/cells12212529","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T09:42:52Z","timestamp":1698399772000},"page":"2529","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Brain Noradrenergic Innervation Supports the Development of Parkinson\u2019s Tremor: A Study in a Reserpinized Rat Model"],"prefix":"10.3390","volume":"12","author":[{"given":"Nicol\u00f3 Gabriele","family":"Pozzi","sequence":"first","affiliation":[{"name":"Department of Neurology, University Hospital and Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Josef-Schneider-Str. 11, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Bolzoni","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele Eliseo Mario","family":"Biella","sequence":"additional","affiliation":[{"name":"Institute of Molecular Bioimaging and Physiology, CNR, Via Fratelli Cervi 93, 20090 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianni","family":"Pezzoli","sequence":"additional","affiliation":[{"name":"Centro Parkinson e Parkinsonismi, ASST G. Pini-CTO, 20072 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi Wang","family":"Ip","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital and Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Josef-Schneider-Str. 11, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Volkmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital and Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Josef-Schneider-Str. 11, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3160-9030","authenticated-orcid":false,"given":"Paolo","family":"Cavallari","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Human Physiology Section, Universit\u00e0 degli Studi di Milano, via Mangiagalli 32, 20133 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther","family":"Asan","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Koellikerstr 6, 97070 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3552-5144","authenticated-orcid":false,"given":"Ioannis Ugo","family":"Isaias","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital and Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, Josef-Schneider-Str. 11, 97080 W\u00fcrzburg, Germany"},{"name":"Centro Parkinson e Parkinsonismi, ASST G. Pini-CTO, 20072 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s40035-017-0086-4","article-title":"Rest tremor revisited: Parkinson\u2019s disease and other disorders","volume":"6","author":"Chen","year":"2017","journal-title":"Transl. Neurodegener."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"708960","DOI":"10.3389\/fpsyt.2021.708960","article-title":"Stigma and Associated Correlates of Elderly Patients with Parkinson\u2019s Disease","volume":"12","author":"Hou","year":"2021","journal-title":"Front. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"120196","DOI":"10.1016\/j.jns.2022.120196","article-title":"The pathophysiology of Parkinson\u2019s disease tremor","volume":"435","author":"Dirkx","year":"2022","journal-title":"J. Neurol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3389\/fnhum.2011.00179","article-title":"A role for locus coeruleus in Parkinson tremor","volume":"5","author":"Isaias","year":"2012","journal-title":"Front. Hum. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1097\/WNR.0b013e3282ef69f9","article-title":"[123I]FP-CIT striatal binding in early Parkinson\u2019s disease patients with tremor vs. akinetic-rigid onset","volume":"18","author":"Isaias","year":"2007","journal-title":"NeuroReport"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/1531-8257(200005)15:3<503::AID-MDS1013>3.0.CO;2-V","article-title":"Accurate differentiation of parkinsonism and essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: The [123I]-FP-CIT study group","volume":"15","author":"Benamer","year":"2000","journal-title":"Mov. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e1461","DOI":"10.1212\/WNL.0000000000010316","article-title":"Dopamine-responsive and dopamine-resistant resting tremor in Parkinson disease","volume":"95","author":"Zach","year":"2020","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1093\/brain\/awz261","article-title":"Cerebral differences between dopamine-resistant and dopamine-responsive Parkinson\u2019s tremor","volume":"142","author":"Dirkx","year":"2019","journal-title":"Brain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/mds.870131303","article-title":"Consensus Statement of the Movement Disorder Society on Tremor","volume":"13","author":"Deuschl","year":"2008","journal-title":"Mov. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1093\/brain\/awaa083","article-title":"Cognitive load amplifies Parkinson\u2019s tremor through excitatory network influences onto the thalamus","volume":"143","author":"Dirkx","year":"2020","journal-title":"Brain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s11910-021-01157-4","article-title":"The Molecular Neuroimaging of Tremor","volume":"21","author":"Pasquini","year":"2021","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Prange, S., Theis, H., Banwinkler, M., and van Eimeren, T. (2022). Molecular Imaging in Parkinsonian Disorders\u2014What\u2019s New and Hot?. Brain Sci., 12.","DOI":"10.3390\/brainsci12091146"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1097\/00005072-199111000-00006","article-title":"The Neuropathologic Basis of Different Clinical Subgroups of Parkinson\u2019s Disease","volume":"50","author":"Paulus","year":"1991","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s00441-017-2649-1","article-title":"Locus coeruleus","volume":"373","author":"Benarroch","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/j.neuroimage.2010.09.028","article-title":"Parkinson\u2019s disease tremor-related metabolic network: Characterization, progression, and treatment effects","volume":"54","author":"Mure","year":"2011","journal-title":"NeuroImage"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kinnerup, M.B., Sommerauer, M., Damholdt, M.F., Schaldemose, J.L., Ismail, R., Terkelsen, A.J., St\u00e6r, K., Hansen, A., Fedorova, T.D., and Knudsen, K. (2021). Preserved noradrenergic function in Parkinson\u2019s disease patients with rest tremor. Neurobiol. Dis., 152.","DOI":"10.1016\/j.nbd.2021.105295"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1212\/WNL.17.7.711","article-title":"Mechanisms underlying emotional variation in parkinsonian tremor","volume":"17","author":"Marsden","year":"1967","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Jim\u00e9nez-Jim\u00e9nez, F.J., Alonso-Navarro, H., Garc\u00eda-Mart\u00edn, E., and Ag\u00fandez, J.A.G. (2021). Neurochemical Features of Rem Sleep Behaviour Disorder. J. Pers. Med., 11.","DOI":"10.3390\/jpm11090880"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1016\/0028-3908(87)90110-9","article-title":"Pharmacological characteristics of tremor, rigidity and hypokinesia induced by reserpine in rat","volume":"26","author":"Colpaert","year":"1987","journal-title":"Neuropharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1038\/1801200a0","article-title":"3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists","volume":"180","author":"Carlsson","year":"1957","journal-title":"Nature"},{"key":"ref_21","first-page":"490","article-title":"The occurrence, distribution and physiological role of catecholamines in the nervous system","volume":"11","author":"Carlsson","year":"1959","journal-title":"Pharmacol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0014-2999(81)90272-7","article-title":"DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine)\u2014A useful denervation tool for central and peripheral noradrenaline neurons","volume":"72","author":"Jonsson","year":"1981","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1749-6632.1955.tb42462.x","article-title":"Clinical effectiveness of reserpine","volume":"61","author":"Flach","year":"1955","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.bbr.2012.03.008","article-title":"Repeated treatment with a low dose of reserpine as a progressive model of Parkinson\u2019s disease","volume":"231","author":"Fernandes","year":"2012","journal-title":"Behav. Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1007\/BF01291788","article-title":"Animal models of Parkinson\u2019s disease: An empirical comparison with the phenomenology of the disease in man","volume":"103","author":"Gerlach","year":"1996","journal-title":"J. Neural Transm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"a009316","DOI":"10.1101\/cshperspect.a009316","article-title":"A guide to neurotoxic animal models of Parkinson\u2019s disease","volume":"1","author":"Tieu","year":"2011","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.tins.2008.02.010","article-title":"Altered vesicular dopamine storage in Parkinson\u2019s disease: A premature demise","volume":"31","author":"Caudle","year":"2008","journal-title":"Trends Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1152\/physrev.00018.2001","article-title":"Free Radicals in the Physiological Control of Cell Function","volume":"82","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.bbadis.2008.12.006","article-title":"Oxidative and nitrosative stress in Parkinson\u2019s disease","volume":"1792","author":"Tsang","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/0306-4522(89)90364-3","article-title":"Immunohistochemical analysis of the neurotoxic effects of DSP-4 identifies two populations of noradrenergic axon terminals","volume":"30","author":"Fritschy","year":"1989","journal-title":"Neuroscience"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1177\/37.9.2768812","article-title":"Acute action of DSP-4 on central norepinephrine axons: Biochemical and immunohistochemical evidence for differential effects","volume":"37","author":"Grzanna","year":"1989","journal-title":"J. Histochem. Cytochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/0006-8993(90)91474-U","article-title":"Differential effects of DSP-4 on noradrenaline axons in cerebral cortex and hypothalamus may reflect heterogeneity of noradrenaline uptake sites","volume":"522","author":"Zaczek","year":"1990","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.neures.2010.06.003","article-title":"Locomotor response to l-DOPA in reserpine-treated rats following central inhibition of aromatic l-amino acid decarboxylase: Further evidence for non-dopaminergic actions of l-DOPA and its metabolites","volume":"68","author":"Alachkar","year":"2010","journal-title":"Neurosci. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.neuroscience.2011.11.024","article-title":"Effects of noradrenaline and serotonin depletions on the neuronal activity of globus pallidus and substantia nigra pars reticulata in experimental parkinsonism","volume":"202","author":"Delaville","year":"2011","journal-title":"Neuroscience"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0306-4522(03)00211-2","article-title":"Ciliary neurotrophic factor in the olfactory bulb of rats and mice","volume":"120","author":"Asan","year":"2003","journal-title":"Neuroscience"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.neuroscience.2004.11.040","article-title":"The Corticotropin-Releasing Factor (CRF)-system and monoaminergic afferents in the central amygdala: Investigations in different mouse strains and comparison with the rat","volume":"131","author":"Asan","year":"2005","journal-title":"Neuroscience"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/ana.22361","article-title":"Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor","volume":"69","author":"Helmich","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hirano, S., Sugiyama, A., and Arai, K. (2022). Noradrenergic Pathway to the Cerebellum: The Study Must Go on. Cerebellum, Online ahead of print.","DOI":"10.1007\/s12311-022-01479-0"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1093\/brain\/aws360","article-title":"The cerebellum in Parkinson\u2019s disease","volume":"136","author":"Wu","year":"2013","journal-title":"Brain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9844","DOI":"10.1523\/JNEUROSCI.0854-21.2021","article-title":"Subthalamic\u2013Cortical Network Reorganization during Parkinson\u2019s Tremor","volume":"41","author":"Lauro","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1093\/brain\/awab286","article-title":"Dying-back of ascending noradrenergic projections in Parkinson\u2019s disease","volume":"144","author":"Helmich","year":"2021","journal-title":"Brain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2174\/157015908785777229","article-title":"Functional Neuroanatomy of the Noradrenergic Locus Coeruleus: Its Roles in the Regulation of Arousal and Autonomic Function Part I: Principles of Functional Organisation","volume":"6","author":"Samuels","year":"2008","journal-title":"Curr. Neuropharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Isaias, I.U., Marotta, G., Pezzoli, G., Sabri, O., Schwarz, J., Crenna, P., Classen, J., and Cavallari, P. (2011). Enhanced catecholamine transporter binding in the locus coeruleus of patients with early Parkinson disease. BMC Neurol., 11.","DOI":"10.1186\/1471-2377-11-88"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1093\/brain\/awab236","article-title":"Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson\u2019s disease","volume":"144","author":"Doppler","year":"2021","journal-title":"Brain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.neuron.2018.07.028","article-title":"A Cortical Pathogenic Theory of Parkinson\u2019s Disease","volume":"99","author":"Foffani","year":"2018","journal-title":"Neuron"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1093\/brain\/awx376","article-title":"Progression of tremor in early stages of Parkinson\u2019s disease: A clinical and neuroimaging study","volume":"141","author":"Pasquini","year":"2018","journal-title":"Brain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s12640-014-9482-z","article-title":"DSP4, a Selective Neurotoxin for the Locus Coeruleus Noradrenergic System. A Review of Its Mode of Action","volume":"27","author":"Ross","year":"2014","journal-title":"Neurotox. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1162\/08989290152001853","article-title":"Dynamic diaschisis: Anatomically remote and context-sensitive human brain lesions","volume":"13","author":"Price","year":"2001","journal-title":"J. Cogn. Neurosci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/21\/2529\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:12:38Z","timestamp":1760130758000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/21\/2529"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,27]]},"references-count":48,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["cells12212529"],"URL":"https:\/\/doi.org\/10.3390\/cells12212529","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2023,10,27]]}}}