{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:56:33Z","timestamp":1788965793256,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T00:00:00Z","timestamp":1636070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82001373"],"award-info":[{"award-number":["82001373"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Epileptogenesis may be responsible for both of recurrent seizures and comorbid depression in epilepsy. Disease-modifying treatments targeting the latent period before spontaneous recurrent seizures may contribute to the remission of seizures and comorbid depression. We hypothesized that pre-treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase (sEH) inhibitor, which has anti-inflammatory and neuroprotective effects might rescue status epilepticus (SE)-induced dendritic spine loss and alleviate depressive behaviours. Rats were either pre-treated with TPPU (0.1 mg\/kg\/d) intragastrically or with vehicle (40% polyethylene glycol 400) from 7 days before to 7 days after SE that was induced with lithium chloride and pilocarpine intraperitoneally. Rats in the Control group were given saline instead. The forced swim test (FST) was performed on the 8th day after SE to evaluate the depression-like behaviours in rats. The results showed that seizures severity during SE was significantly decreased, and the immobility time during FST was significantly increased through TPPU pre-treatment. Moreover, pre-treatment with TPPU attenuated inflammations including microglial gliosis and the level of proinflammatory cytokine IL-1\u03b2 in the hippocampus; in addition, neuronal and dendritic spine loss in the subfields of hippocampus was selectively rescued, and the expression of NR1 subunit of N-methyl-D-aspartate (NMDA) receptor, ERK1\/2, CREB, and their phosphorylated forms involved in the dendritic spine development were all significantly increased. We concluded that pre-treatment with TPPU attenuated seizures severity during SE and depressive behaviours during the period of epileptogenesis probably by rescuing dendritic spine loss in the hippocampus.<\/jats:p>","DOI":"10.3390\/brainsci11111465","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T10:33:09Z","timestamp":1636108389000},"page":"1465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["TPPU Pre-Treatment Rescues Dendritic Spine Loss and Alleviates Depressive Behaviours during the Latent Period in the Lithium Chloride-Pilocarpine-Induced Status Epilepticus Rat Model"],"prefix":"10.3390","volume":"11","author":[{"given":"Weifeng","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Neurology, Zhongshan Hospital, Fudan University, Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijun","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Zhongshan Hospital, Fudan University, Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Zhongshan Hospital, Fudan University, Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Neurology, Zhongshan Hospital, Fudan University, Fenglin Road, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Zhongshan Hospital, Fudan University, Fenglin Road, Shanghai 200032, China"},{"name":"Department of The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S1474-4422(18)30031-0","article-title":"The roles of surgery and technology in understanding focal epilepsy and its comorbidities","volume":"17","author":"Spencer","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1001\/jamaneurol.2017.3949","article-title":"Treatment Outcomes in Patients With Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs: A 30-Year Longitudinal Cohort Study","volume":"75","author":"Chen","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"78","DOI":"10.5698\/1535-7511.17.2.78","article-title":"The Contribution of Cognitive Networks to Depression in Epilepsy","volume":"17","author":"Rayner","year":"2017","journal-title":"Epilepsy Curr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.euroneuro.2012.10.011","article-title":"Brain, networks, depression, and more","volume":"23","author":"Leistedt","year":"2013","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0920-1211(02)00195-X","article-title":"Suggestive evidence for association of two potassium channel genes with different idiopathic generalised epilepsy syndromes","volume":"52","author":"Chioza","year":"2002","journal-title":"Epilepsy Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"re12","DOI":"10.1126\/stke.3562006re12","article-title":"Molecular Signaling Mechanisms Underlying Epileptogenesis","volume":"2006","author":"McNamara","year":"2006","journal-title":"Sci. STKE"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.neuropharm.2012.04.004","article-title":"The role of inflammation in epileptogenesis","volume":"69","author":"Vezzani","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/epi.13785","article-title":"Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy","volume":"58","author":"White","year":"2017","journal-title":"Epilepsia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.nbd.2018.04.005","article-title":"Chronic agomelatine treatment prevents comorbid depression in the post-status epilepticus model of acquired epilepsy through suppression of inflammatory signaling","volume":"115","author":"Tchekalarova","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E1944","DOI":"10.1073\/pnas.1601532113","article-title":"Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress","volume":"113","author":"Ren","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1021\/acs.jmedchem.0c01886","article-title":"Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative","volume":"64","author":"Hammock","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.prostaglandins.2009.06.004","article-title":"Epoxyeicosanoid signaling in CNS function and disease","volume":"91","author":"Iliff","year":"2010","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.bbi.2019.07.014","article-title":"Anti-inflammatory treatment with a soluble epoxide hydrolase inhibitor attenuates seizures and epilepsy-associated depression in the LiCl-pilocarpine post-status epilepticus rat model","volume":"81","author":"Shen","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1111\/j.1528-1167.2008.01616.x","article-title":"A cellular mechanism for dendritic spine loss in the pilocarpine model of status epilepticus","volume":"49","author":"Kurz","year":"2008","journal-title":"Epilepsia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1111\/epi.12195","article-title":"Remodeling of dendrites and spines in the C1q knockout model of genetic epilepsy","volume":"54","author":"Ma","year":"2013","journal-title":"Epilepsia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1146\/annurev.neuro.31.060407.125646","article-title":"Balancing Structure and Function at Hippocampal Dendritic Spines","volume":"31","author":"Bourne","year":"2008","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.neuron.2012.04.031","article-title":"Activity-Dependent Growth of New Dendritic Spines Is Regulated by the Proteasome","volume":"74","author":"Hamilton","year":"2012","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.neuron.2005.03.015","article-title":"Spine-Neck Geometry Determines NMDA Receptor-Dependent Ca2+ Signaling in Dendrites","volume":"46","author":"Noguchi","year":"2005","journal-title":"Neuron"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Franchini, L., Carrano, N., Di Luca, M., and Gardoni, F. (2020). Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041538"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1126\/science.1245622","article-title":"Long-Distance Integration of Nuclear ERK Signaling Triggered by Activation of a Few Dendritic Spines","volume":"342","author":"Zhai","year":"2013","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nrn2911","article-title":"Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerative disorders","volume":"11","author":"Hardingham","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_22","first-page":"6436","article-title":"Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation","volume":"364","author":"Murdock","year":"2019","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.eplepsyres.2015.09.013","article-title":"N-methyl-d-aspartate receptor NR2B subunit involved in depression-like behaviours in lithium chloride-pilocarpine chronic rat epilepsy model","volume":"119","author":"Peng","year":"2016","journal-title":"Epilepsy Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0013-4694(72)90177-0","article-title":"Modification of seizure activity by electrical stimulation: II. Motor seizure","volume":"32","author":"Racine","year":"1972","journal-title":"Electroencephalogr. Clin. Neurophysiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/BF02245592","article-title":"Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants","volume":"121","author":"Detke","year":"1995","journal-title":"Psychopharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.wneu.2016.12.074","article-title":"Prevalence and Incidence of Drug-Resistant Mesial Temporal Lobe Epilepsy in the United States","volume":"99","author":"Stewart","year":"2017","journal-title":"World Neurosurg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/nan.12451","article-title":"Review: Animal models of acquired epilepsy: Insights into mechanisms of human epileptogenesis","volume":"44","author":"Becker","year":"2018","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.expneurol.2007.03.008","article-title":"Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat","volume":"205","author":"Goffin","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"107359","DOI":"10.1016\/j.yebeh.2020.107359","article-title":"A prospective pilot study of cognitive impairment and mood in adults with first seizure, new-onset epilepsy, and newly diagnosed epilepsy at time of initial seizure presentation","volume":"112","author":"Whatley","year":"2020","journal-title":"Epilepsy Behav."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1001\/jamaneurol.2016.5042","article-title":"Association of Depression and Treated Depression with Epilepsy and Seizure Outcomes: A Multicohort Analysis","volume":"74","author":"Josephson","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1002\/ana.25561","article-title":"A Trial of Sertraline or Cognitive Behavior Therapy for Depression in Epilepsy","volume":"86","author":"Gilliam","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.eplepsyres.2009.10.015","article-title":"Cyto-, axo- and dendro-architectonic changes of neurons in the limbic system in the mouse pilocarpine model of temporal lobe epilepsy","volume":"89","author":"Tang","year":"2010","journal-title":"Epilepsy Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1111\/j.1528-1157.2000.tb01550.x","article-title":"Remodeling Dendritic Spines of Dentate Granule Cells in Temporal Lobe Epilepsy Patients and the Rat Pilocarpine Model","volume":"41","author":"Isokawa","year":"2000","journal-title":"Epilepsia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3073","DOI":"10.1021\/acs.biomac.5b00999","article-title":"Dendritic Polyglycerol Sulfate Inhibits Microglial Activation and Reduces Hippocampal CA1 Dendritic Spine Morphology Deficits","volume":"16","author":"Maysinger","year":"2015","journal-title":"Biomacromolecules"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nm.4340","article-title":"CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-\u03b1","volume":"23","author":"Silva","year":"2017","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s00401-017-1803-x","article-title":"Glia-to-neuron transfer of miRNAs via extracellular vesicles: A new mechanism underlying inflammation-induced synaptic alterations","volume":"135","author":"Prada","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nature25013","article-title":"Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy","volume":"552","author":"Hu","year":"2017","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.neubiorev.2018.01.010","article-title":"Metabolic\/inflammatory\/vascular comorbidity in psychiatric disorders; soluble epoxide hydrolase (sEH) as a possible new target","volume":"87","author":"Swardfager","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.prostaglandins.2018.07.002","article-title":"Neuroprotective effects of epoxyeicosatrienoic acids","volume":"138","author":"Wang","year":"2018","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1021\/jm201468j","article-title":"Discovery of Inhibitors of Soluble Epoxide Hydrolase: A Target with Multiple Potential Therapeutic Indications","volume":"55","author":"Shen","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Inceoglu, B., Zolkowska, D., Yoo, H.J., Wagner, K.M., Yang, J., Hackett, E., Hwang, S.H., Lee, K.S.S., Rogawski, M., and Morisseau, C. (2013). Epoxy Fatty Acids and Inhibition of the Soluble Epoxide Hydrolase Selectively Modulate GABA Mediated Neurotransmission to Delay Onset of Seizures. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080922"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.neuropharm.2017.05.013","article-title":"11,12-Epoxyeicosatrienoic acid (11,12 EET) reduces excitability and excitatory transmission in the hippocampus","volume":"123","author":"Mule","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.nbd.2013.07.015","article-title":"Pharmacological blockade of IL-1beta\/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy","volume":"59","author":"Noe","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/nrn3504","article-title":"NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease","volume":"14","author":"Paoletti","year":"2013","journal-title":"Nat. Rev. Neurosci."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/11\/1465\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:26:23Z","timestamp":1760167583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/11\/1465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,5]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["brainsci11111465"],"URL":"https:\/\/doi.org\/10.3390\/brainsci11111465","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,5]]}}}