Acute and long-term effects of haloperidol on surgery-induced neuroinflammation and cognitive deficits in aged rats
Acute and long-term effects of haloperidol on surgery-induced neuroinflammation and cognitive deficits in aged rats
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DOI：
10.1007/s00540-019-02646-0
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发表时间：
2019-06-01
影响因子：
2.8
通讯作者：
Yokoyama, Masataka
中科院分区：
文献类型：
--
作者：
Nishigaki, Atsushi;Kawano, Takashi;Yokoyama, Masataka
目的神经炎症可能参与了术后谵妄（POD）认知症状及其继发的长期认知功能障碍的发病机制。氟哌啶醇（Haloperidol，HAL）是一种多巴胺受体拮抗剂，被广泛用于治疗POD，而HAL对术后神经炎症和相关认知功能障碍的影响尚未完全确定。（0.5 mg/kg推注，然后0.5 mg/kg/天输注）或高剂量（2.0 mg/kg推注，然后2.0 mg/kg/天输注）HAL。所有治疗均在手术后立即开始，并持续48小时。在术后第2天（早期）或第7天（晚期），所有大鼠在获得痕量恐惧条件反射后测试痕量和背景恐惧记忆保留。认知测试后，促炎细胞因子的水平，以及多巴胺及其代谢产物，在海马和内侧前额叶皮层（mPFC）进行了测量。ResultsIn术后早期，手术引起急性神经炎症沿着与相关的痕迹和上下文记忆功能障碍。海马和mPFC的多巴胺周转增加，而没有观察到与记忆功能的关系。然而，即使在高剂量下，HAL也未能恢复手术引起的神经炎症和相关的认知缺陷。在术后后期，仅在海马中检测到慢性神经炎症，这与上下文相关，但与痕量记忆功能障碍无关。无论是低剂量还是高剂量的HAL都不能防止这些晚期neurocognitive deficits.ConclusionOur研究结果表明，HAL的围手术期给药可能对术后神经炎症和相关的认知障碍没有影响。
PurposeNeuroinflammation may contribute to the pathogenesis of the cognitive symptoms of postoperative delirium (POD) and its subsequent long-term cognitive impairment. Haloperidol (HAL), a dopamine receptor antagonist, is widely used to treat POD, whereas the effects of HAL on postoperative neuroinflammation and related cognitive deficits have been underdetermined.MethodsAged rats underwent sham or abdominal surgery and were subcutaneously treated with either vehicle, low-dose (0.5mg/kg bolus, then 0.5mg/kg/day infusion), or high-dose (2.0mg/kg bolus, then 2.0mg/kg/day infusion) HAL. All treatments were initiated immediately after surgery and continued for 48h. On either postoperative day 2 (early) or 7 (late), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Following the cognitive testing, the levels of pro-inflammatory cytokines, as well as dopamine and its metabolite, in hippocampus and medial prefrontal cortex (mPFC) were measured.ResultsIn the early postoperative period, surgery induced acute neuroinflammation along with related trace and context memory dysfunction. Dopamine turnover was increased in both hippocampus and mPFC, whereas no relationship with memory functions was observed. However, HAL even at high-dose failed to restore the surgery-induced neuroinflammation and related cognitive deficits. In the late postoperative period, chronic neuroinflammation was detected only in hippocampus, which was associated with context, but not trace memory dysfunction. Neither low- nor high-dose HAL could prevent the development of these late-phase neurocognitive deficits.ConclusionOur findings indicate that perioperative administration with HAL may have no effects on postoperative neuroinflammation and related cognitive impairment.