如果說在杏仁核體所表現突觸間傳導的長期增益現象是代表著恐懼記憶的形成,那麼杏仁核體所表現長期增益現象的逆轉(就是所謂的去增益現象)對於焦慮以及創傷後的壓力症候群的改善可能是一個相當重要的機轉。我們將5Hz 3分鐘的低頻電刺激給予到external capsule,結果在杏仁核體的側核區(LA)可以將強直性電刺激所誘導的長期增益現象逆轉成去增益現象,此過程需要NMDA接受體的活化與L-型 鈣離子通道的參與,但是與adenosine A1或group II metabotropic glutamate receptors (mGluRII)無關。當直接將去磷酸酶 calcineurin抑制劑灌注到細胞外或是注入細胞內時,去增益現象的表現會被阻斷。相同的低頻電刺激條件參數給予到活體動物的杏仁核體時,也能夠減弱了恐懼記憶的表現及減少恐懼訓練後Akt和MAP kinase磷酸化的程度。由上述的結果可知,低頻電刺激誘發杏仁核體產生去增益現象主要是經由活化calcineurin的訊息傳遞路徑所致。在杏仁核體的LA使用DCG-IV將mGluRII活化也可以成功的將強直性電刺激所誘發的長期增益現象逆轉成去增益現象,此過程中不需要NMDA接受體或是L-型鈣離子通道的活化,去磷酸脢　calcineurin 的活性也沒有涉及在其中,但是需要突觸前的活性以及細胞外Ca++的參與。DCG-IV 誘發杏仁核體LA產生去增益現象會抑制自發性微型興奮性突觸後電流(mEPSC)產生的頻率,但不影響mEPSC的大小，且可以被內生性釋放的glutamate所模倣。DCG-IV能夠抑制4-AP所誘發的glutamate釋放,但沒辦法抑制ionomycin所誘發的glutamate之釋放，這表示DCG-IV的作用並不是經由影響Ca2+進入細胞內的下游所致。透過評估恐懼驚嚇指數的方式,我們將mGluRII的作用劑直接打入杏仁核體，結果發現恐懼記憶的固化會受到抑制。因此，我們確認了DCG-IV誘導去增益現象的性質，並且也發現DCG-IV 在腦切片上所誘發的去增益現象與其減弱恐懼記憶的作用間存在著密切平行的關係。
I6 ，是一個由薑黃素 (Gingerdione) 所衍生的半合成化合物，它具有對抗血癌細胞生長的效果。 目前我們利用MTT代謝分析法來評估I6是否也會影響體外培養的新生鼠大腦皮質神經細胞之存活率，結果發現I6能夠明顯的減少皮質神經細胞的存活率，而且所誘導的皮質神經細胞死亡具有劑量依賴效應。細胞核染劑Hoechst 33323 與 TUNEL呈色反應法的實驗結果顯示I6所誘導的皮質神經細胞的死亡是一種凋亡的現象。我們使用了幾種caspase抑制劑，包括Z-VAD-FMK (能夠滲入細胞內的廣效性caspase 抑制劑) 以及Ac-DMQD-CHO (能夠滲入細胞內的專一興性caspase-3 抑制劑) 來觀察它們對I6誘發神經細胞死亡的影響。結果顯示，10 M 的Z-VAD-FMK並不影響細胞的存活率，只有在高濃度(100 and 200 M)的情況下，Z-VAD-FMK稍微增加細胞的存活率。相較之下Ac-DMQD-CHO對於細胞的存活率並無明顯的影響，這表示caspase-3在I6誘發神經細胞死亡的過程中可能不是主要的調控者。
抗氧化劑維他命E ,glutathione及 N-acetylcysteine (NAC)能夠阻止I6引起的神經細胞死亡，這表示NAC對神經細胞的保護作用至少有一部分是來自它的抗氧化性質。當皮質神經細胞給予NAC處理後會明顯增加p44與p42的磷酸化程度，而NAC對經細胞的保護作用會被MEK抑制劑U0126減弱，這表示NAC所誘發的p44/42磷酸化與它對神經細胞的保護作用存在著平行的關係。NAC也出乎意料之外的增加p38 MAPK的磷酸化而且NAC對神經細胞的保護作用會被專一性的p38 MAPK抑制劑以劑量有關的方式減弱。NAC所誘發的p38 MAPK磷酸化會被U0126 完全阻斷，但是NAC所誘發的ERK磷酸化並不受p38 MAPK抑制劑影響。我們的實驗結果首度證明了NAC能夠連續的活化ERK與p38 MAPK而且ERK與p38 MAPK一起媒介NAC對神經細胞的保護作用。

If fear memory is expressed by a long-term potentiation (LTP) of synaptic transmission in the amygdala, then reversal of LTP (depotentiation) in this area of the brain may provide an important mechanism for amelioration of anxiety and post-traumatic stress disorder. we find that low-frequency stimulation (LFS) of the external capsule elicits a depotentiation in the lateral nucleus of the amygdala. The induction of depotentiation requires activation of N-methyl-D-aspartate receptors and voltage-dependent calcium channels but is independent of adenosine A1 and group II metabotropic glutamate receptors (mGluRII). Extracellular perfusion or loading cells with protein phosphatase(PP) 2B (calcineurin) inhibitors prevents depotentiation. The same stimulating protocol applied to the amygdala in vivo attenuates the expression of fear memory measured with fear-potentiated startle and reduces conditioning-elicited phosphorylation of Akt and mitogen-activated protein kinase (MAPK). This is paralleled by an increase in the activity of calcineurin. In addition, application of calcineurin inhibitor blocks LFS-induced extinction of fear memory and MAPK dephosphorylation. Taken together, this study characterizes the properties of LFS-induced depotentiation in the amygdala and suggests an involvement of calcineurin cascade in synaptic plasticity and memory storage.
Activation of mGluR II with DCG-IV induces depotentiation in the LA. The induction of depotentiation is independent of NMDA receptors, L-type Ca2+ channels and calcineurin activity but requires presynaptic activity and extracellular Ca2+. DCG-IV depotentiation is accompanied by a decrease in the frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and could be mimicked by endogenously released glutamate. DCG-IV inhibited the release of glutamate evoked by 4-AP but not by ionomycin suggesting that the effect of DCG-IV is not mediated by an action downstream of Ca++ entry. Intra-amygdala infusion of mGluR II agonist blocks the consolidation of fear memory measured with fear-potentiated startle. Taken together, the present study characterizes the properties of DCG-IV depotentiation and reveals a close parallel between depotentiation in the amygdala slice and the reduction of conditioned fear in animals.
1-(3,4-Dimethoxyphenyl)-3,5-dodecenedione (I6), a gingerdione derivative, was synthesized in China Medical University laboratory, which has been demonstrated to be an effective anti-tumor agent in leukemia cell line. In the present study, we found that I6 also could induce a concentration-dependent decrease in cortical neuron viability measured by MTT assay . The I6-induced neuronal death exhibits apoptotic features by Hoechst staining and TUNEL reaction. we examine the effects of various caspase inhibitors on I6-induced cell death. These included Z-VAD-FMK, a cell-permeable broad-spectrum caspase inhibitor, and Ac-DMQD-CHO, a cell-permeable caspase-3 inhibitor. The result shows that ZVAD-FMK at 10 M do not affect cell survival . Only at higher concentrations (100 and 200 M) do ZVAD-FMK slightly increase the cell survival . By contrast, cell survival was not significantly affected by Ac-DMQD-CHO , suggesting that caspase-3 may not play a major role in I6 stimulated cell death.
The antioxidants vitamin E, glutathione and N-acetylcysteine (NAC) prevent I6-mediated neuronal death, suggesting that antioxidant activity accounted, at least in part, for the neuroprotective effect of NAC. Treatment of cortical neurons with NAC significantly increased phosphorylated levels of p42 and p44 ERKs. In parallel, MEK inhibitor U0126 completely attenuated neuroprotective effect of NAC. Unexpectedly, NAC also increased phosphorylated level of p38 MAPK and p38 specific inhibitors dose-dependently attenuated neuroprotective effect of NAC. U0126 completely abolished NAC-induced p38 phosphorylation. Conversely, p38 inhibitor did not influence NAC-induced ERK phosphorylation. These results demonstrate for the first time that NAC serially activates ERKs and p38 MAPK, and ERKs and p38 work together to mediate the neuroprotective effect of NAC.

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