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In recent years, many non-intravenous routes of administration of benzodiazepines have been developed for seizure control, with intranasal administration being an attractive route of choice. However, for such a route of administration, there is a lack of evidence on the choice of the epilepsy drug. This study aims to compare the intranasal formulations of three first-line drugs for seizure control, namely midazolam, diazepam, and lorazepam, via an ideal intranasal treatment.\u00a0A pilocarpine-induced seizure model in mice was used to compare drug efficacy. The three drugs were administered intranasally to 36 C57 mice at a single dose of 1\u00a0mg\/kg, followed by inducing the seizures via intraperitoneal injection of pilocarpine. The subsequent seizure scores were observed for either 10\u2013100\u00a0min. After sacrificing the mice at 10\/100 minutes post-dosing, whole brain tissue and plasma were collected to analyze the drug concentrations as well as brain-to-plasma concentration ratios. In addition, effects of these intranasally delivered drugs on neuroinflammation-associated molecules were monitored and compared via the mRNA levels and\/or protein expression of GABAR\u03b11, TNF-\u03b1, and IL-1\u03b2 in the cortex and hippocampus. Additionally, drug bindings to plasma and brain tissue obtained using the ultrafiltration method were compared, and drug binding affinities towards the GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor, as determined via the computer docking technique, were also compared.\u00a0Among the three tested drugs, our results suggested that intranasal diazepam, with the highest brain-to-plasma ratio, was the best in seizure control at 10\u00a0min. Although all three drugs showed good stability, similar brain binding and receptor binding affinity, diazepam demonstrated the greatest efficacy in reducing TNF-\u03b1 mRNA and protein levels, and lowest plasma protein binding, which could contribute to its higher brain-to-plasma ratio and better acute epilepsy control compared to the other two drugs.\u00a0Our pilot in vivo experiments in the pilocarpine-induced mice seizure model for the first time demonstrated that intranasally administered benzodiazepines are effective for seizure control at the early stage, with intranasally delivered diazepam being the most potent one.\n                  <\/jats:p>","DOI":"10.1007\/s11064-026-04720-y","type":"journal-article","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T10:18:10Z","timestamp":1772705890000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intranasal Diazepam Outperforms Midazolam and Lorazepam in Early Seizure Control in Pilocarpine-Induced Mice Model"],"prefix":"10.1007","volume":"51","author":[{"given":"Anson Hei-Ka","family":"Tong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiajia","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahao","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weikang","family":"Ban","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rilla Jiansu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuning","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"4720_CR1","volume-title":"Status Epilepticus","author":"T Wylie","year":"2025","unstructured":"Wylie T, Sandhu DS, Murr NI (2025) Status Epilepticus. 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