{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:40:19Z","timestamp":1789418419987,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T00:00:00Z","timestamp":1724716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science","award":["23K05531"],"award-info":[{"award-number":["23K05531"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Epilepsy is a chronic neurological disorder characterized by recurrent seizures that affects over 70 million people worldwide. Although many antiepileptic drugs that block seizures are available, they have little effect on preventing and curing epilepsy, and their side effects sometimes lead to serious morbidity. Therefore, prophylactic agents with anticonvulsant properties and no adverse effects need to be identified. Recent studies on probiotic administration have reported a variety of beneficial effects on the central nervous system via the microbiota\u2013gut\u2013brain axis. In this study, we investigated the effects of the oral administration of Bifidobacterium breve strain A1 [MCC1274] (B. breve A1) on tonic\u2013clonic seizure in a pentylenetetrazole (PTZ)-induced kindling mouse (KD mouse) model. We found that the oral administration of B. breve A1 every other day for 15 days significantly reduced the seizure score, which gradually increased with repetitive injections of PTZ in KD mice. The administration of B. breve A1, but not saline, to KD mice significantly increased the level of Akt Ser473 phosphorylation (p-Akt) in the hippocampus; this increase was maintained for a minimum of 24 h after PTZ administration. Treatment of B. breve A1-administered KD mice with the selective inhibitor of integrin-linked kinase (ILK) Cpd22 significantly increased the seizure score and blocked the antiepileptic effect of B. breve A1. Moreover, Cpd22 blocked the B. breve A1-induced increase in hippocampal p-Akt levels. These results suggest that the ILK-induced phosphorylation of Akt Ser473 in the hippocampus might be involved in the antiepileptic effect of B. breve A1.<\/jats:p>","DOI":"10.3390\/ijms25179259","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T09:26:51Z","timestamp":1724750811000},"page":"9259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Oral Administration of Probiotic Bifidobacterium breve Ameliorates Tonic\u2013Clonic Seizure in a Pentylenetetrazole-Induced Kindling Mouse Model via Integrin-Linked Kinase Signaling"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6431-3263","authenticated-orcid":false,"given":"Toshiaki","family":"Ishii","sequence":"first","affiliation":[{"name":"Department of Basic Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motohiro","family":"Kaya","sequence":"additional","affiliation":[{"name":"Center for Industry-University Collaboration, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikage","family":"Muroi","sequence":"additional","affiliation":[{"name":"Department of Basic Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S0140-6736(18)32596-0","article-title":"Epilepsy in adults","volume":"393","author":"Thijs","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/S1474-4422(07)70215-6","article-title":"Development of new antiepileptic drugs: Challenges, incentives, and recent advances","volume":"6","author":"Perucca","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1528-1167.2008.02005.x","article-title":"Preventing and treating posttraumatic seizures: The human experience","volume":"50","author":"Temkin","year":"2009","journal-title":"Epilepsia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/j.1528-1167.2006.00684.x","article-title":"Effects of antiepileptic drugs on mood and behavior","volume":"47","author":"Schmitz","year":"2006","journal-title":"Epilepsia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1740-0929.2009.00645.x","article-title":"Health-benefical effects of probiotics: Its mode of action","volume":"80","author":"Ohashi","year":"2009","journal-title":"Anim. Sci. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.chom.2015.04.011","article-title":"Review control of brain development, function, and behavior by the microbiome","volume":"17","author":"Sampson","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2515690X20957225","DOI":"10.1177\/2515690X20957225","article-title":"Dysfunction of the microbiota-gut-brain axis in neurodegenerative disease: The promise of therapeutic modulation with prebiotics, medicinal herbs, probiotics, and synbiotics","volume":"25","author":"Peterson","year":"2020","journal-title":"J. Evid. Based. Integr. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"628","DOI":"10.4103\/1673-5374.295270","article-title":"The emerging role of probiotics in neurodegenerative diseases: New hope of Parkinson\u2019s disease?","volume":"16","author":"Castelli","year":"2021","journal-title":"Neural. Regen. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3565","DOI":"10.3748\/wjg.v23.i19.3565","article-title":"Fecal microbiota transplantation cured epilepsy in a case with Grohn\u2019s Disease: The first report","volume":"23","author":"He","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Riva, A., Sahin, E., Volpedo, G., Petretto, A., Lavarello, C., Sapia, R.D., Barbarossa, D., Zaniani, N.R., Craparotta, I., and Barbera, M.C. (2024). Identification of an epilepsy-linked gut microbiota signature in a pediatric rat model of acquired epilepsy. Neurobiol. Dis., 194.","DOI":"10.1016\/j.nbd.2024.106469"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ishii, T., Furuoka, H., Kaya, M., and Kuhara, T. (2021). Oral administration of probiotic Bifidobacterium breve improves facilitation of hippocampal memory extinction via restoration of aberrant higher induction of neuropsin in an MPTP-induced mouse model of Parkinson\u2019s disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020167"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kobayashi, Y., Sugahara, H., Shimada, K., Mitsuyama, E., Kuhara, T., Yasuoka, A., Kondo, T., Abe, K., and Xiao, J.Z. (2017). Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer\u2019s disease. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-13368-2"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"139","DOI":"10.3233\/JAD-200488","article-title":"Probiotic Bifidobacterium breve in improving cognitive functions of older adults with suspected mild cognitive impairment: A randomized, double-blind, placebo-controlled trial","volume":"77","author":"Xiao","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.seizure.2017.02.017","article-title":"Epilepsy and cognition\u2014A bidirectional relationship?","volume":"49","author":"Helmstaedter","year":"2017","journal-title":"Seizure"},{"key":"ref_15","first-page":"56573","article-title":"Pentylenetetrazole-induced kindling mouse model","volume":"136","author":"Shimada","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_16","first-page":"267","article-title":"Changes in seizure susceptibility in rats following chronic administration of pentylenetetrazol","volume":"46","author":"Schmidt","year":"1987","journal-title":"Biomed. Biochim. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0304-3940(91)90302-A","article-title":"Changes in seizure latency correlate with alterations in A1 adenosine receptor binding during daily repeated pentylenetetrazol-induced convulsions in different mouse brain area","volume":"132","author":"Angelatou","year":"1991","journal-title":"Neurosci. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12963","DOI":"10.1523\/JNEUROSCI.3118-11.2011","article-title":"Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetrtrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus","volume":"31","author":"Mizoguchi","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/35081571","article-title":"Metalloproteinases in biology, pathology of the nervous system","volume":"2","author":"Yong","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1523\/JNEUROSCI.4359-05.2006","article-title":"Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory","volume":"15","author":"Nagy","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.nbd.2009.07.008","article-title":"The role of MMP-9 in integrin-mediated hippocampal cell death after pilocarpine-induced status epilepticus","volume":"36","author":"Kim","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1046\/j.1460-9568.2003.02876.x","article-title":"Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainite","volume":"18","author":"Jourquin","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Jareo-Basulto, J., Gasca-Mart\u00ednez, Y., Rivera-Cervantes, M.C., Ure\u00f1a-Guerrero, M.E., Ferina-Velasco, A.I., and Beas-Zarate, C. (2018). Interactions between epilepsy and plasticity. Pharmaceuticals, 11.","DOI":"10.3390\/ph11010017"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1177\/107385840200800211","article-title":"Epilepsy as an example of neural plasticity","volume":"8","author":"Scharfman","year":"2002","journal-title":"Neuroscientist"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8924634","DOI":"10.1155\/2019\/8924634","article-title":"Alteration of extracellular matrix molecules and perineuronal nets in the hippocampus of pentylenetetrazol-kindled mice","volume":"2019","author":"Ueno","year":"2019","journal-title":"Neural Plast."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jchemneu.2011.05.014","article-title":"Neuropsin-A possible modulator of synaptic plasticity","volume":"42","author":"Shiosaka","year":"2011","journal-title":"J. Chem. Neuroanat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1046\/j.1471-4159.2003.01579.x","article-title":"Essential role for integrin linked kinase in Akt-mediated integrin survival signaling in hippocampal neurons","volume":"84","author":"Gary","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/bies.950140705","article-title":"The matrix-degrading metalloproteinases","volume":"14","author":"Matrisian","year":"1992","journal-title":"Bioessays"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11211","DOI":"10.1073\/pnas.95.19.11211","article-title":"Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B\/AKT by the integrin-linked kinase","volume":"95","author":"Delcommenne","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27462","DOI":"10.1074\/jbc.M102940200","article-title":"Regulation of protein\/Akt-serine 473 phosphorylation by integrin-linked kinase","volume":"276","author":"Persad","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6364","DOI":"10.1021\/jm2007744","article-title":"Identification and characterization of a novel integrin-linked kinase inhibitor","volume":"54","author":"Lee","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bonaz, B., Bazin, T., and Pellissier, S. (2018). The vagus nerve at the interface of the microbiota-gut-brain axis. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00049"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1007\/s11910-017-0802-6","article-title":"Microbiota-brain-gut axis and neurodegenerative diseases","volume":"17","author":"Quigley","year":"2017","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1083\/jcb.200708213","article-title":"Important role of matorix metalloproteinase-9 in epileptogenesis","volume":"10180","author":"Wilczynski","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.neuro.2020.05.005","article-title":"Anti-epileptic activity of daidzin in PTZ-induced mice model by targeting oxidative stress and BDNF\/VEGF signaling","volume":"79","author":"Kazmi","year":"2020","journal-title":"Neurotoxicology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.neuint.2015.07.009","article-title":"Curcumin attenuates inflammatory response and cognitive deficits in experimental model of chronic epilepsy","volume":"89","author":"Kaur","year":"2015","journal-title":"Neurochem. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.advms.2016.11.011","article-title":"Tangeretin alters neuronal apoptosis and ameliorates the severity of seizures in experimental epilepsy-induced rats by modulating apoptotic protein expressions, regulating matrix metalloproteinases, and activating the PI3K\/Akt cell survival pathway","volume":"62","author":"Guo","year":"2017","journal-title":"Adv. Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0962-8924(99)01612-8","article-title":"Integrin-linked kinase (ILK): A regulator of integrin and growth-factor signalling","volume":"9","author":"Dedhar","year":"1999","journal-title":"Trends Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nrc1524","article-title":"Integrin-linked kinase: A cancer therapeutic target unique among its ILK","volume":"5","author":"Hannigan","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_40","first-page":"4784","article-title":"CB2R induces a protective response for epileptic seizure via the PI3K 100\u03b1-AKT signaling pathway","volume":"16","author":"Cao","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.eplepsyres.2019.05.007","article-title":"Anticonvulsant and anti-apoptosis effects of salvianolic acid B on pentylenetetrazole-kindled rats via AKT\/CREB\/BDNF signaling","volume":"154","author":"Yu","year":"2019","journal-title":"Epilepsy Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"McDonald, P.C., and Dedhar, S. (2022). New perspectives on the role of integrin-linked kinase (ILK) signaling in cancer metastasis. Cancers, 14.","DOI":"10.3390\/cancers14133209"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0166-2236(97)01169-7","article-title":"Matrix metalloproteinases and disease of the CNS","volume":"21","author":"Yong","year":"1998","journal-title":"Trends Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nrn1807","article-title":"Metalloproteinase mediators of pathology and regeneration in CNS","volume":"6","author":"Yong","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15337","DOI":"10.1523\/JNEUROSCI.3467-10.2010","article-title":"Metzincin proteases and their inhibitors, foes or friends in nervous system physiology","volume":"30","author":"Rivera","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR aand the 2\u2212\u0394\u0394Ct method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9259\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:43:12Z","timestamp":1760110992000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9259"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,27]]},"references-count":46,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25179259"],"URL":"https:\/\/doi.org\/10.3390\/ijms25179259","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,27]]}}}