Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis. Galantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration). Results indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox). Collectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.

中文翻译：

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加兰他敏可预防和逆转青少年酒精暴露后的神经免疫诱导和成人海马神经发生的丧失

青春期酗酒会减少海马神经发生，尽管禁欲，这种减少仍会持续到整个成年期。这种神经发生的丧失，表现为双皮质素+免疫反应性（DCX+IR）的降低，与海马促炎信号级联反应的增加平行。由于加兰他敏是一种胆碱酯酶抑制剂，具有抗炎作用，我们测试了加兰他敏可以预防（研究 1）或恢复（研究 2）AIE 诱导的海马内促炎信号以及 AIE 诱导的海马神经发生丧失的假设。在青春期间歇性乙醇（AIE；5.0 g/kg 乙醇，2 天开/2 天关，产后第 [P] 25-54 天）期间向 Wistar 大鼠施用加兰他敏（4 mg/kg）或载体（盐水）（研究 1 , 预防）或 AIE 后戒断成熟至成年（研究 2，恢复）。结果表明 AIE 在表达 DCX 的未成熟神经元中降低了 DCX+IR 并诱导了切割的 caspase3 (Casp3)。令人兴奋的是，加兰他敏治疗可以防止和逆转表达 DCX 的神经元中活化的 Casp3 的 AIE 诱导，这也导致了神经发生的预防和恢复 (DCX+IR)。同样，加兰他敏阻止和/或逆转促炎标志物的 AIE 诱导，包括趋化因子（CC 基序）配体 2 (CCL2)、环氧合酶 2 (COX-2) 和高迁移率组框 1 (HMGB1) 蛋白，表明 AIE促炎信号的诱导介导细胞死亡级联和海马神经发生。有趣的是，加兰他敏治疗通常会增加 Ki67+IR，并在 AIE 治疗的大鼠中特异性增加 pan-Trk 表达，但未能逆转 AIE 对 NADPH-氧化酶 (gp91phox) 的诱导。总的来说，我们的研究表明（1）AIE 后神经发生的丧失是由促炎级联反应介导的，促炎级联反应驱动未成熟神经元中细胞死亡机制的激活，（2）加兰他敏可以预防和恢复海马环境环境中的 AIE 破坏然后预防和恢复 AIE 介导的神经发生丧失。