{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T02:23:11Z","timestamp":1784600591319,"version":"3.55.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>\n                    Protein kinase C (PKC) plays a key role in modulating the activities of the innate immune cells of the central nervous system (CNS). A delicate balance between pro-inflammatory and regenerative activities by microglia and CNS-associated macrophages is necessary for the proper functioning of the CNS. Thus, a maladaptive activation of these CNS innate immune cells results in neurodegeneration and demyelination associated with various neurologic disorders, such as multiple sclerosis (MS) and Alzheimer\u2019s disease. Prior studies have demonstrated that modulation of PKC activity by bryostatin-1 (bryo-1) and its analogs (bryologs) attenuates the pro-inflammatory processes by microglia\/CNS macrophages and alleviates the neurologic symptoms in experimental autoimmune encephalomyelitis (EAE), an MS animal model. Here, we demonstrate that (2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB), a structurally distinct PKC modulator, has a similar effect to bryo-1 on CNS innate immune cells both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , attenuating neuroinflammation and resulting in CNS regeneration and repair. This study identifies a new structural class of PKC modulators, which can therapeutically target CNS innate immunity as a strategy to treat neuroinflammatory and neurodegenerative disorders.\n                  <\/jats:p>","DOI":"10.3389\/fncel.2024.1373557","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:52:46Z","timestamp":1716339166000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis"],"prefix":"10.3389","volume":"18","author":[{"given":"Shruthi","family":"Shanmukha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley H.","family":"Godfrey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payam","family":"Gharibani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy J.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Wender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Kornberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.chembiol.2020.12.015","article-title":"Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation","volume":"28","author":"Abramson","year":"2021","journal-title":"Cell Chem. Biol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1038\/s41593-020-0650-6","article-title":"Alzheimer\u2019s-associated PLC\u03b32 is a signaling node required for both TREM2 function and the inflammatory response in human microglia","volume":"23","author":"Andreone","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/nm.3489","article-title":"New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo","volume":"20","author":"Bullen","year":"2014","journal-title":"Nat. Med."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1186\/1471-2407-14-90","article-title":"Protein kinase C-delta inactivation inhibits the proliferation and survival of cancer stem cells in culture and in vivo","volume":"14","author":"Chen","year":"2014","journal-title":"BMC Cancer"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1097\/00001813-200208000-00001","article-title":"The clinical development of the bryostatins","volume":"13","author":"Clamp","year":"2002","journal-title":"Anti Cancer Drugs"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"194.e13","DOI":"10.1016\/j.neurobiolaging.2017.01.015","article-title":"A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature","volume":"53","author":"Dardiotis","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"12108","DOI":"10.1021\/cr300481j","article-title":"C1 domains: structure and ligand-binding properties","volume":"114","author":"Das","year":"2014","journal-title":"Chem. Rev."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1038\/s41573-019-0035-2","article-title":"Progressive multiple sclerosis: from pathophysiology to therapeutic strategies","volume":"18","author":"Faissner","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"555","DOI":"10.3233\/JAD-180759","article-title":"A randomized, double-blind, placebo-controlled, phase II study assessing safety, tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe Alzheimer\u2019s disease","volume":"67","author":"Farlow","year":"2019","journal-title":"J. Alzheimers Disease"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1189\/jlb.0805438","article-title":"Role of PKC isoforms in the Fc\u03b3R-mediated inhibition of LPS-stimulated IL-12 secretion by macrophages","volume":"79","author":"Fronhofer","year":"2006","journal-title":"J. Leukoc. Biol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/2023.08.28.555084","article-title":"PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination","author":"Gharibani","year":"2023","journal-title":"bioRxiv"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"979659","DOI":"10.3389\/fneur.2022.979659","article-title":"Therapeutic potential of blocking GAPDH Nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis","volume":"13","author":"Godfrey","year":"2023","journal-title":"Front. Neuro"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1097\/QAD.0000000000001064","article-title":"Bryostatin-1 for latent virus reactivation in HIV-infected patients on antiretroviral therapy","volume":"30","author":"Guti\u00e9rrez","year":"2016","journal-title":"AIDS"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1038\/s41467-020-15742-7","article-title":"Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy","volume":"11","author":"Hardman","year":"2020","journal-title":"Nat. Commun."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1038\/s41593-018-0242-x","article-title":"Microglia in neurodegeneration","volume":"21","author":"Hickman","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1523\/JNEUROSCI.5209-10.2011","article-title":"PKC \u03b5 activation prevents synaptic loss, A\u03b2 elevation, and cognitive deficits in Alzheimer\u2019s disease transgenic mice","volume":"31","author":"Hongpaisan","year":"2011","journal-title":"J. Neurosci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/0014-5793(93)80078-9","article-title":"Phorbol esters induce nitric oxide synthase and increase arginine influx in cultured peritoneal macrophages","volume":"320","author":"Hortelano","year":"1993","journal-title":"FEBS Lett."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.2174\/1381612043384907","article-title":"Indolactam and Benzolactam compounds as new medicinal leads with binding selectivity for C1 domains of protein kinase C isozymes","volume":"10","author":"Irie","year":"2005","journal-title":"Curr. Pharm. Des."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"2695","DOI":"10.1038\/S41467-022-30389-2","article-title":"Structural anatomy of protein kinase C C1 domain interactions with diacylglycerol and other agonists","volume":"13","author":"Katti","year":"2022","journal-title":"Nat. Commun."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/J.COPH.2021.11.008","article-title":"Targeting PKC in microglia to promote remyelination and repair in the CNS","volume":"62","author":"Kim","year":"2022","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s40478-015-0223-1","article-title":"Trichuris suis induces human non-classical patrolling monocytes via the mannose receptor and PKC: implications for multiple sclerosis","volume":"3","author":"Kooij","year":"2015","journal-title":"Acta Neuropathol. Commun."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2186","DOI":"10.1073\/pnas.1719902115","article-title":"Bryostatin-1 alleviates experimental multiple sclerosis","volume":"115","author":"Kornberg","year":"2018","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1021\/jm960875h","article-title":"Modeling, chemistry, and biology of the benzolactam analogues of indolactam V (ILV). 2. Identification of the binding site of the benzolactams in the CRD2 activator-binding domain of PKC\u03b4 and discovery of an ILV analogue of improved isozyme selectivity","volume":"40","author":"Kozikowski","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/B978-0-444-52001-2.00002-9","article-title":"Pathology of multiple sclerosis and related inflammatory demyelinating diseases","volume":"122","author":"Kutzelnigg","year":"2014","journal-title":"Handb Clin Neurol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1172\/JCI80142","article-title":"Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations","volume":"125","author":"Laird","year":"2015","journal-title":"J. Clin. Invest."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1111\/imm.12510","article-title":"Protein kinase C in the immune system: from signalling to chromatin regulation","volume":"146","author":"Lim","year":"2015","journal-title":"Immunology"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"3678","DOI":"10.1021\/jacs.5b00886","article-title":"Toward a biorelevant structure of protein kinase C bound modulators: design, synthesis, and evaluation of labeled bryostatin analogues for analysis with rotational echo double resonance NMR spectroscopy","volume":"137","author":"Loy","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/S1474-4422(14)70256-X","article-title":"Pathological mechanisms in progressive multiple sclerosis","volume":"14","author":"Mahad","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1080\/10409238.2018.1442408","article-title":"Protein kinase C: perfectly balanced","volume":"53","author":"Newton","year":"2018","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"14226","DOI":"10.1074\/jbc.M111.308841","article-title":"Protein kinase C \u03b4 (PKC\u03b4)-extracellular signal-regulated kinase 1\/2 (ERK1\/2) signaling Cascade regulates glycogen synthase Kinase-3 (GSK-3) inhibition-mediated Interleukin-10 (IL-10) expression in lipopolysaccharide (LPS)-induced endotoxemia","volume":"287","author":"Noh","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1016\/S0006-2952(03)00449-0","article-title":"Involvement of protein kinase C\u03b4 and extracellular signal-regulated kinase-2 in the suppression of microglial inducible nitric oxide synthase expression by N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast)","volume":"66","author":"Platten","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1056\/NEJMra1401483","article-title":"Multiple Sclerosis","volume":"378","author":"Reich","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e56322","DOI":"10.3791\/56322","article-title":"In vitro phagocytosis of myelin debris by bone marrow-derived macrophages","volume":"130","author":"Rolfe","year":"2017","journal-title":"J. Visual. Exp."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"10688","DOI":"10.1073\/pnas.1919408117","article-title":"Prodrugs of PKC modulators show enhanced HIV latency reversal and an expanded therapeutic window","volume":"117","author":"Sloane","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1023\/a:1022478005243","article-title":"Effects of phorbol myristate acetate (PMA) on functions of macrophages and microglia in vitro","volume":"23","author":"Smith","year":"1998","journal-title":"Neurochem. Res."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1527-3458.2006.00001.x","article-title":"Bryostatin-1: pharmacology and therapeutic potential as a CNS drug","volume":"12","author":"Sun","year":"2006","journal-title":"CNS Drug Rev."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1046\/j.1440-1789.2000.00297.x","article-title":"Nasu-Hakola disease: a review of its leukoencephalopathic and membranolipodystrophic features","volume":"20","author":"Tanaka","year":"2000","journal-title":"Neuropathology"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1038\/s41582-018-0072-1","article-title":"TREM2 \u2014 a key player in microglial biology and Alzheimer disease","volume":"14","author":"Ulland","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.molmed.2018.11.005","article-title":"Microglia in central nervous system inflammation and multiple sclerosis pathology","volume":"25","author":"Voet","year":"2018","journal-title":"Trends Mol. Med."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"4153","DOI":"10.1016\/J.CELL.2022.09.033","article-title":"TREM2 drives microglia response to amyloid-\u03b2 via SYK-dependent and -independent pathways","volume":"185","author":"Wang","year":"2022","journal-title":"Cell"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"7197","DOI":"10.1073\/pnas.85.19.7197","article-title":"Modeling of the bryostatins to the phorbol ester pharmacophore on protein kinase C","volume":"85","author":"Wender","year":"1988","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"4214","DOI":"10.1073\/pnas.83.12.4214","article-title":"Analysis of the phorbol ester pharmacophore on protein kinase C as a guide to the rational design of new classes of analogs","volume":"83","author":"Wender","year":"1986","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/s41593-021-00975-6","article-title":"TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration","volume":"25","author":"Xie","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1007\/s12031-012-9816-3","article-title":"Bryostatin-1 vs. TPPB: dose-dependent APP processing and PKC-\u03b1, \u2212\u03b4, and -\u03b5 isoform activation in SH-SY5Y neuronal cells","volume":"48","author":"Yi","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"12042","DOI":"10.1016\/s0021-9258(19)49803-7","article-title":"Immunoglobulin-mediated phagocytosis by human monocytes requires protein kinase C activation. Evidence for protein kinase C translocation to phagosomes","volume":"267","author":"Zheleznyak","year":"1992","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2024.1373557\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:52:49Z","timestamp":1716339169000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2024.1373557\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,22]]},"references-count":45,"alternative-id":["10.3389\/fncel.2024.1373557"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2024.1373557","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.02.02.578637","asserted-by":"object"}]},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,22]]},"article-number":"1373557"}}