Neuroprotection by propofol in acute mechanical injury: Role of GABAergic inhibition
Neuroprotection by propofol in acute mechanical injury: Role of GABAergic inhibition
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DOI：
10.1152/jn.1996.76.4.2412
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发表时间：
1996-10-01
影响因子：
2.5
通讯作者：
Soltesz, I
中科院分区：
文献类型：
--
作者：
Hollrigel, GS;Toth, K;Soltesz, I
1.在400 μ m厚的成年大鼠脑片上，采用全细胞膜片钳和细胞外野记录技术，观察了静脉注射麻醉剂2，6-二异丙基苯酚的作用异丙酚对树突切断后急性神经元存活和突触完整性的保护作用（树枝切断术），并确定γ-氨基丁酸-A（GABA（A））-受体介导的抑制在丙泊酚的神经保护作用中的作用。比较异丙酚与另一种广泛使用的静脉全身麻醉药5-乙基-5-[1-甲基丁基]-2-硫代巴比妥酸（硫喷妥钠）的作用.丙泊酚（10 μ M）增加了在对照神经元中记录的微型抑制性突触后电流（mIPSC）的频率（对照：5.9 +/- 0.9 Hz，平均值+/- SE;丙泊酚：10.5 +/- 1.3 Hz）和单指数衰减时间常数（tau（D））（对照：4.5 +/- 0.2 ms;丙泊酚：15.3 +/- 1.5 ms）。硫喷妥钠（25 μ M）也增加了mISPC的tau（D）（14.3 +/- 0.9 ms），但对mIPSC频率没有影响。两种麻醉剂在低浓度下（丙泊酚：5 μ M;硫喷妥钠：1 μ M）均增强mIPSC。丙泊酚和硫喷妥钠不改变mIPSC的峰值振幅和上升时间。异丙酚（10 μ M）能够抑制控制颗粒细胞的兴奋性，确定减少的幅度的顺向人口尖峰。GABA（A）受体拮抗剂荷包牡丹碱（50 μ M）可以阻止这种抑制，表明丙泊酚通过GABA（A）受体功能降低兴奋性.异丙酚和硫喷妥钠是神经保护剂（通过损伤后2-5小时的逆向群体反应进行评估），如果存在于颗粒细胞树突截肢之前和期间。保护作用是剂量依赖性的，在高剂量（丙泊酚：200 μ M;硫喷妥钠：400 μ M）的麻醉剂是作为神经保护2-氨基-5-磷酸戊酸（APV）和6-氰基-7-硝基喹喔啉-2，3-二酮（CNQX）对神经元切断诱导的细胞死亡。麻醉剂的保护作用被GABA（A）受体拮抗剂印防己毒素或荷包牡丹碱完全阻断，并被GABA（A）受体激动剂蝇蕈醇（100 μ M）模拟。与APV和CNQX相反，丙泊酚不能阻止树枝切除术诱导的mIPSC衰减动力学中的Ca 2+依赖性和持久的变化（双指数延长衰减的出现）。麻醉剂和APV及CNQX对神经元存活的保护作用在神经元切断后应用时不显著，表明在没有神经保护剂的情况下从索马体进行150-200 μ m的神经元切断可迅速诱导大多数受损神经元的不可逆急性变性。未能从树枝切断诱导的损伤中拯救细胞不是由于GABA（A）受体对麻醉剂的敏感性降低，因为麻醉剂对来自对照和树枝切断的神经元的mIPSC的增强作用没有差异。这些数据表明，丙泊酚增强突触前和突触后的突触抑制，并且，当存在于树枝切断术期间时，它可以通过增强GABAA受体功能保护神经元免于急性机械损伤诱导的细胞死亡。然而，异丙酚不能提供神经保护，对神经树切断术诱导的突触生理学的变化。
1. Whole cell patch-clamp and extracellular field recordings were obtained from granule cells of the dentate gyrus in 400-mu m-thick brain slices of the adult rat to determine the actions of the intravenous general anesthetic 2,6-diisopropylphenol (propofol) on acute neuronal survival and preservation of synaptic integrity after amputation of dendrites (dendrotomy), and to determine the role of gamma-aminobutyric acid-A (GABA(A))-receptor-mediated inhibition in the neuroprotective effects of propofol. The actions of propofol were compared with those exerted by another widely used intravenous general anesthetic, 5-ethyl-5-[1-methylbutyl]-2-thiobarbituric acid (thiopental).2. Propofol (10 mu M) increased the frequency (control: 5.9 +/- 0.9 Hz, mean +/- SE; propofol: 10.5 +/- 1.3 Hz) and the single-exponential decay time constant (tau(D)) (control: 4.5 +/- 0.2 ms; propofol: 15.3 +/- 1.5 ms) of miniature inhibitory postsynaptic currents (mIPSCs) recorded in control neurons. Thiopental (25 mu M) also increased the tau(D) (14.3 +/- 0.9 ms) Of mISPCs, but had no effect on mIPSC frequency. Both anesthetics potentiated mIPSCs at low concentrations (propofol: 5 mu M; thiopental: 1 mu M) Propofol and thiopental did not change the peak amplitude and rise times of mIPSCs.3. Propofol (10 mu M) was able to depress the excitability of control granule cells, as determined by the reduction in the amplitude of the orthodromic population spikes. This depression could be prevented by the GABA(A) receptor antagonist bicuculline (50 mu M), indicating that propofol reduces excitability via GABA(A) receptor functions.4. Propofol and thiopental were neuroprotectant (assessed by antidromic population responses 2-5 h after injury) if present before and during the amputation of the granule cell dendrites. The protective actions were dose dependent, and at high doses (propofol: 200 mu M; thiopental: 400 mu M) the anesthetics were as neuroprotective against dendrotomy-induced cell death as 2-amino-5-phosphovaleric acid (APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The protective effects of the anesthetics were completely blocked with the GABA(A) receptor antagonists picrotoxin or bicuculline, and were mimicked by the GABA(A) receptor agonist muscimol (100 mu M).5. Propofol, in contrast to APV and CNQX, could not prevent the dendrotomy-induced Ca2+ dependent and long-lasting changes in mIPSC decay kinetics (appearance of a double-exponential, prolonged decay).6. The protective effects of the anesthetics and those of APV and CNQX on neuronal survival were not significant when the drugs were applied after dendrotomy, indicating that dendrotomy carried out 150-200 mu m from the soma without neuroprotective agents rapidly induces irreversible acute degeneration in most injured neurons. The failure to rescue cells from dendrotomy-induced injury did not result from a decreased sensitivity of the GABA(A) receptors to the anesthetics, because the potentiating effects of the anesthetics on mIPSCs from control and dendrotomized neurons were not different.7. These data indicate that propofol potentiates synaptic inhibition pre- and postsynaptically, and, when present during dendrotomy, it can protect neurons from acute mechanical-injury-induced cell death via potentiation of GABAA receptor functions. However, propofol fails to provide neuroprotection against dendrotomy-induced changes in synaptic physiology.