Tacrolimus (TAC) is a common cause of neurotoxicity in clinical settings, yet its precise mechanisms and protective interventions remain elusive. This study aimed to elucidate TAC-induced neurotoxicity and evaluate the neuroprotective effects of ibudilast (IBU), a drug initially used for asthma, as a potential drug repositioning candidate.
In vitro experiments using SH-SY5Y cells demonstrated dose-dependent apoptotic cell death induced by TAC, which was mitigated by IBU treatment. Subsequently, in vivo experiments were performed by subcutaneous administration of TAC (2.5 or 5.0 mg/kg/day) for 14 days to Wistar rats, and administrating IBU (7.5 mg/kg/day) intraperitoneally once daily, commencing 2 days prior to TAC. Neurotoxic behavior was scored from 0 to 3 according to the severity of tremors, seizures, or irritability at pre-treatment, day 8, and day 15. Results revealed significant chronic neurotoxicity in the TAC (5 mg/kg/day) group on day 15, which was ameliorated by IBU administration. A histopathological assay of excised brains using Nissl and TUNEL staining demonstrated neuronal damage primarily in the cerebral cortex and CA1 region of the hippocampus, with sparing of the CA3 region, dendrite gyrus, and cerebellum. Co-administration of IBU notably attenuated these neuronal cell death. In conclusion, our findings suggest that TAC penetration into the brain and subsequent neuronal damage in the cortex and CA1 region underlie TAC-induced neurotoxicity. Furthermore, IBU emerges as a promising protective agent against this adverse event.
"},{"@language":"ja","@value":"免疫抑制薬タクロリムス(TAC)の有害事象として、振戦等の神経障害が知られているが、その発生機序は未だ解明されておらず、臨床的な対策も取られていない。本研究はTAC誘発性神経障害の機序解明および、気管支喘息に対する既承認薬で神経保護作用を有する非選択的ホスホジエステラーゼ阻害薬であるイブジラストの神経保護効果を評価し、ドラッグリポジショニングの可能性の探索を目的とした。
ヒト神経芽細胞腫SH-SY5Y細胞を用いたin vitro実験では、TACが用量依存的にアポトーシス細胞死を誘導し、イブジラストはTACによる細胞死を軽減した。TAC誘発性神経障害を解剖学的、行動学的に評価するため、WistarラットにTAC（2.5または5.0mg/kg/日）を１日1回14日間皮下投与した動物モデルを作成した。またイブジラスト(7.5mg/kg/日)はTAC（5mg/kg/日）投与の2日前から1日1回腹腔内に投与した。神経障害は、投与前、8日目、および15日目に評価し以下に従いスコアを算出した：スコア0（神経障害の徴候なし）、スコア1（震え、軽度の発作、または過敏性）、スコア2（明確な震え、発作、または極度の過敏性）、スコア3（重度の発作または暴力的行動）。結果、TAC（5mg/kg/日）投与群では投与開始15日目で慢性神経毒性が認められ、これはイブジラストにより有意に減少した。脳摘出後の解析から、TACの脳内移行が認められ、脳中TAC濃度は神経毒性スコアと相関していた。イブジラスト投与は脳中TAC濃度にはは影響を及ぼさなかった。Nissl染色とTUNEL染色を用いた病理組織学的評価では、TAC投与群において大脳皮質と海馬CA1領域に神経細胞損傷が多く、CA3領域、歯状回、小脳には細胞損傷は見られなかった。イブジラストの併用により、これらの病理組織学的変化は顕著に抑制された。
結論として、TAC誘発性神経障害はTACの脳内移行とそれに続く大脳皮質とCA1領域における神経細胞障害に起因することが考えられ、さらにイブジラストはこの有害事象に対する有望な保護薬であることが示された。
"}],"abstractLicenseFlag":"disallow"}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1410301319807339523","@type":"Researcher","foaf:name":[{"@language":"en","@value":"MATSUKANE Ryosuke"},{"@language":"ja","@value":"松金 良祐"}],"jpcoar:affiliationName":[{"@language":"en","@value":"Kyushu University Hospital, Department of Pharmacy"},{"@language":"ja","@value":"九州大学病院 薬剤部"}]},{"@id":"https://cir.nii.ac.jp/crid/1410301319807339520","@type":"Researcher","foaf:name":[{"@language":"en","@value":"SUETSUGU Kimitaka"},{"@language":"ja","@value":"末次 王卓"}],"jpcoar:affiliationName":[{"@language":"en","@value":"Kyushu University Hospital, Department of Pharmacy"},{"@language":"ja","@value":"九州大学病院 薬剤部"}]},{"@id":"https://cir.nii.ac.jp/crid/1410301319807339522","@type":"Researcher","foaf:name":[{"@language":"en","@value":"ZHANG Wei"},{"@language":"ja","@value":"Wei ZHANG"}],"jpcoar:affiliationName":[{"@language":"ja","@value":"九州大学病院 薬剤部"},{"@language":"en","@value":"Kyushu University Hospital, Department of Pharmacy"}]},{"@id":"https://cir.nii.ac.jp/crid/1410301319807339524","@type":"Researcher","foaf:name":[{"@language":"en","@value":"IEIRI Ichiro"},{"@language":"ja","@value":"家入 一郎"}],"jpcoar:affiliationName":[{"@language":"ja","@value":"九州大学病院 薬剤部"},{"@language":"en","@value":"Kyushu University Hospital, Department of Pharmacy"}]},{"@id":"https://cir.nii.ac.jp/crid/1410301319807339521","@type":"Researcher","foaf:name":[{"@language":"en","@value":"HIROTA Takeshi"},{"@language":"ja","@value":"廣田 豪"}],"jpcoar:affiliationName":[{"@language":"en","@value":"Kyushu University Hospital, Department of Pharmacy"},{"@language":"ja","@value":"九州大学病院 薬剤部"}]}],"publication":{"prism:publicationName":[{"@language":"en","@value":"Annual Meeting of the Japanese Society of Toxicology"},{"@language":"ja","@value":"日本毒性学会学術年会"}],"dc:publisher":[{"@language":"en","@value":"The Japanese Society of Toxicology"},{"@language":"ja","@value":"日本毒性学会"}],"prism:publicationDate":"2024","prism:volume":"51.1","prism:number":"0","prism:startingPage":"P-263"},"jpcoar:conferenceName":"第51回日本毒性学会学術年会","availableAt":"2024","dataSourceIdentifier":[{"@type":"JALC","@value":"oai:japanlinkcenter.org:2013337527"}]}