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オランザピンは成体ラットでの術後認知機能障害を軽減する

田地, 慶太郎 筑波大学 DOI:10.15068/0002005351

2022.11.16

概要

【目的】術後認知機能障害(POCD: postoperative cognitive dysfunction)は就労困難や生活の質の低下の原因となる。そのため高齢の患者よりも中年世代の患者でのPOCDの影響は大きい。中枢神経系の炎症(neuroinflammation)はPOCDの主因と考えられている。オランザピンはこれまで統合失調症患者での認知機能を改善することが報告されてきた。我々はオランザピンのPOCDに対する有効性とそのメカニズムを6ヶ月齢のラットを用いて検討した。

【対象と方法】6ヶ月齢のSprague Dawleyラット63匹を用いた。バーンズ迷路のトレーニングを行った1週間後にラットを次の3群に割り付けた。LPS群:全身麻酔下の開腹操作+リポポリサッカライド(LPS: lipopolysaccharide)の腹腔内投与(n=12)、OLA群;全身麻酔下の開腹操作+オランザピンとLPSの腹腔内投与(n=12)、CON群:全身麻酔のみ(n=12)。手術翌日にバーンズ迷路による認知機能評価を行った。ゴールまでに要した時間と距離の基準をそれぞれ20秒以内、2.2m以内とし、基準を満たした場合を成功とした。ゴールまでに要した時間と距離に関して成功率を比較した。また、同様のモデルを作成し、免疫染色(Iba-1)による海馬のミクログリア活性化状態の検討(n=12)及び血液と海馬におけるインターロイキン1β(IL-1β: interleukin-1β)と腫瘍壊死因子α(TNF-α: tumor necrosis factor-α)の定量評価(n=15)を行った。

【結果】LPS群と比較しOLA群ではバーンズ迷路におけるゴールまでの時間(33.3% vs 52.8%, P<0.05)、距離(38.9% vs 69.4%, P<0.05)の成功率が有意に高く認知機能の低下が軽度であった。CON群との比較ではOLA群はバーンズ迷路のゴールまでの時間における成績は劣っていたが(63.9% vs 52.8%, P<0.05)、ゴールするまでの移動距離は同等であった。活性型ミクログリアの割合を示すIba-1染色領域は、CON群と比較してLPS群(11.6±5.2% vs 31.5±6.0%, P<0.05)とOLA群(11.6±5.2% vs 22.1±6.6%, P<0.05)で有意に広範囲であった。LPS群と比較するとOLA群では染色領域が有意に小さかった(31.5±6.0% vs 22.1±6.6%, P<0.05)。血中のIL-1βはCON群と比較しLPS群(48.9±9pg/mlvs142.0±28.4pg/ml, P<0.05)とOLA群(48.9±2.9pg/mlvs140.8±26.0pg/ml, P<0.05)で有意な上昇を認めた一方で、LPS群とOLA群での比較では有意差を認めなかった。海馬のIL-1βと血中および海馬のTNF-αは3群間に有意差がなかった。

【結語】オランザピンは手術とLPSの腹腔内投与による認知機能障害と海馬でのミクログリアの活性化を減弱した。この効果は血中・海馬内のIL-1β、TNF-αの濃度とは関連せず、IL-1β、TNF-αを介さないメカニズムによることが推測された。

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