p300/CBP参与神经病理性疼痛的组蛋白乙酰转移酶作用机制
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摘要
目的
观察组蛋白乙酰转移酶p300、CBP、乙酰化底物组蛋白H3的乙酰化水平以及疼痛相关转录因子c-Jun在大鼠坐骨神经慢性压迫性损伤(chronic constriction injury, CCI)模型中的变化规律,采用组蛋白乙酰转移酶p300／CBP的特异性抑制剂姜黄素鞘内注射,观察其对CCI大鼠的镇痛作用,并使用p300 siRNA进行验证,探索p300／CBP参与神经病理性疼痛的表观遗传调控机制。
方法
1.雄性SD大鼠随机分为CCI组和假手术组,CCI组按照Bennett和Xie的方法建立大鼠左侧坐骨神经慢性压迫性损伤模型,假手术组仅暴露左侧坐骨神经不结扎,进行机械痛阈、热痛阈检测后于术后第3、7、14、21天处死取材,行p300、CBP的免疫组化、Western-blot以及RT-PCR测定,采用Western-blot检测乙酰化组蛋白H3(Ac-H3)、总的组蛋白H3、c-Jun的蛋白表达变化。
2.腰段鞘内置管成功的雄性SD大鼠随机分为6组：假手术+生理盐水组、假手术+姜黄素500μg组、CCI+生理盐水组、CCI+DMSO组、CCI+姜黄素100μg组、CCI+姜黄素500μg组。术后第3天开始连续4天鞘内注射高纯度(≥98.5%)姜黄素(溶于50%的DMSO)或50%的DMSO各10μl。于术后7、14、21天各时点测完大鼠痛阈后处死取材进行p300、CBP、Ac-H3、H3、c-Jun的形态学和分子生物学相关检测,并进行大鼠脊髓腰膨大处HE染色以观察有无毒性作用。
3.将腰段鞘内置管成功的雄性SD大鼠随机分为6组：假手术+生理盐水组、CCI+生理盐水组、CCI+转染试剂组、CCI+阴性对照siRNA组、CCI+p300 siRNA组、CCI+阳性对照siRNA组。siRNA经2'Ome修饰,采用聚乙烯亚胺(polyethyleneimine, PEI)体内导入系统,从第3天开始鞘内注射siRNA4μg/天(2μg/次,每天2次),连续4天,转染试剂组鞘内注射同样体积的转染试剂。检测各组大鼠的痛阈变化,并于术后7、14天处死取材进行各观察指标的形态学和分子生物学检测。
结果
1.CCI组与sham组相比,术后第1天痛阈值即明显下降,并于术后第7天降至最低点,持续至第21天仍下降明显。脊髓腰膨大处免疫组化显示p300、CBP阳性细胞以灰质表达为主,并可见于灰质全层均有较多表达,尤其在脊髓背角Ⅰ-Ⅲ层致密表达。阳性颗粒主要位于胞核,胞浆可见少量。CCI组脊髓背角浅层的p300、CBP阳性细胞表达从术后第3天开始明显增多,第7天表达最多,并持续至第14天。p300、CBP的mRNA表达于术后3天明显增高达最大值,并持续至第14天,于第21天恢复至仅略高于假手术组。p300、CBP、Ac-H3以及即早基因c-Jun的蛋白表达也表现出类似的变化,但表达峰值为第7天。
2.姜黄素100μg(0.33-0.40mg／kg)、500μg(1.7-2.0mg／kg)组均能从第5天(注药2天后)开始显著改善CCI大鼠的痛敏现象,术后第7天(注药4天后)达到最大程度的改善,并呈剂量依赖性。姜黄素100μg组的镇痛作用可持续至术后第11天,姜黄素500μg组镇痛作用可持续至术后第14天。到术后第21天时,两个剂量组的姜黄素均已无镇痛作用。姜黄素100μg、500μg在术后第7天均能显著抑制p300、CBP的基因和蛋白表达以及Ac-H3、c-Jun的蛋白表达,并以500μg组更明显。到术后第14天时,仅姜黄素500μg组能降低p300的mRNA水平,对CBP的基因表达已无影响,此时,对各组大鼠指标的蛋白表达的抑制仅见于姜黄素500μg组。第21天时,姜黄素的抑制作用已经消失。在假手术组,姜黄素对大鼠的痛阈和各指标表达均没有明显的影响。HE染色显示鞘注姜黄素组未对大鼠脊髓组织产生明显的损伤。
3.鞘内注射p300siRNA组大鼠从术后第5天(注射2天后)起即表现出痛敏现象的改善,第7天(注射4天后)到达最大缓解,持续至第9天(停止注射2天后),但不能恢复至正常水平。RT-PCR、Western-blot和免疫组化显示p300mRNA和蛋白表达在第7天可以见明显的下调,并且Ac-H3、c-Jun的表达也均被显著抑制。第14天时各指标已经未见明显的下调作用。阳性对照siRNA确认了实验系统的有效性。同时阴性对照siRNA未对p300的高度同源物CBP造成影响,验证了siRNA序列的特异性。各组大鼠未发现明显的毒副作用。
结论
1.神经病理性疼痛大鼠脊髓p300、CBP、Ac-H3和c-Jun表达增加,并与大鼠的疼痛学行为变化相平行。
2.鞘内注射姜黄素能够剂量依赖性的抑制CCI大鼠神经病理性疼痛的发展,并降低脊髓p300、CBP、Ac-H3和c-Jun的表达。其镇痛作用是部分通过抑制组蛋白乙酰转移酶p300／CBP实现的。
3.鞘内注射p300siRNA可减轻CCI大鼠的神经病理性疼痛,并能抑制脊髓p300、Ac-H3和c-Jun的表达,进一步验证了组蛋白乙酰转移酶p300在神经病理性疼痛中的作用。
4.p300／CBP可能通过发挥其组蛋白乙酰转移酶的作用参与神经病理性疼痛的调制。
Objectives:
To investigate the variation regularity of histone acetyltransferase p300、CBP、acetylation level of histone H3 and pain relevant transcription factor c-Jun in a rat modal of chronic constriction injury (CCI). To detect the analgesic effects of intrathecal curcumin, a specific inhibitor of histone acetyltransferase (HAT) p300/CBP and use intrathecal p300 siRNA as a validation in order to search for the epigenetic modulation mechanism of histone acetyltransferase p300/CBP in neuropathic pain.
Methods:
1. Male SD rats were divided randomly into 2 groups. In group CCI, we established a rat modal of chronic constriction injury on the left sciatic nerve according to Bennett and Xie. In group sham rats only underwent surgery of exposing the left sciatic nerve without ligation. After detection of paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) after surgery, rats were sacrified on postoperative day 3、7、14、21 for immunohistochemisty、reverse transciptase polymerase chain reaction (RT-PCR)、western-blot of p300、CBP and western-blot detection of acetylated histone H3 (Ac-H3)、total histone H3、c-Jun.
2. Male SD rats, fitted with intrathecal (i.t.) catheters, were divided randomly into 6 groups:group sham+NS、group sham+curcumin 500μg、group CCI+NS、group CCI+DMSO、group CCI+curcumin 100μg、group CCI+curcumin 500μg. High purity ((?)98.5%) curcumin (dissolved in 50% DMSO) or 50% DMSO 10μl was intrathecally injected beginning from day 3 to day 6 after surgery. On postoperative day 7、14、21, rats were sacrified after pain threshold measurement for morphology molecular biology detection. The lumbar spinal cord was stained with hematoxylin and eosin (HE) to check for toxic action.
3. Male SD rats, fitted with intrathecal (i.t.) catheters, were divided randomly into 6 groups:group sham +NS、group CCI+NS、group CCI+vehie、group CCI+negative control siRN、group CCI+p300 siRNA、group CCI+positive control siRNA.2'Ome modified siRNAs were delivered 4μg/d (2μg, bid) intrathecally by a PEI (polyethyleneimine) system beginning from day 3 to day 6. The same scheme (10μl, bid) of intrathecal transfection agent was used for control. After detecting the pain threshold, rats were sacrified on day 7、14 for indexes detection.
Results:
1. Compared to group sham, the pain threshold in group CCI significantly decreased at all postoperative timepoints, beginning on day 1, reaching a nadir on day 7 and still existing on day 21. Immunonohistochemistry displayed that both p300 and CBP positive cells expressed mainly in the grey matter, abundantly in all layers, especially densely inⅠ-Ⅲlayers of the grey matter. The positive staining was mainly seen in cell nucleus, a small amounts in cytoplasm. In group CCI, p300 and CBP immuno-positive cells in superficial laminae obviously increased from day 3 after surgery, the most on day 7 and lasted to day 14. The mRNA expression of p300、CBP significantly increased and reached the apogee on operative day 3, lasted to day 14 and recovered to a level only slightly higher than group sham on day 21. The protein expression of p300、CBP、Ac-H3 and c-Jun also showed a similar change but with a peak on day 7.
2. Intrathecal curcumin 100μg (0.33-0.4mg/kg)、500μg (1.7-2mg/kg) can both obviously improve the pain-sensitive phenomenon in CCI rats from postoperative day 5(2 days after injection) and reached a greatest improvement on day 7 (4 days after injection) dose dependently. The analgesic effect of curcumin 100μg can last to day 11 (4 days after withdrawal) while curcumin 500μg can last to day 14 (7 days after withdrawal). Neither of the two curcumin groups had analgesic effect on day 21. Curcumin can dose dependently inhibit the mRNA、protein expression of p300、CBP and protein expression of Ac-H3、c-Jun on day 7. When on day 14, only curcumin 500μg can lower the p300 mRNA but not CBP, and only curcumin 500μg had inhibited all the proteins. Curcumin's inhition effect disappeared on postoperative day 21. In group sham, curcumin didn't present anly effect. HE staining showed that intrathecal curcumin didn't produce any overt toxic lesion to the spinal cord.
3. There was an improvement of nociception in group p300 siRNA beginning on day 5(2 days after injection), a maximum relief on day 7 (4 days after injection) and a persistence to day 9 (2 days after withdrawal), but still couldn't recover to the normal level. mRNA and protein expression of p300 were obviously down regulated on day 7 but couldn't be lowered on day 14. The protein expressions of both Ac-H3 and c-Jun were significantly inhibited on day 7. Positive control siRNA affirmed the validity of this essay system. Meanwhile, negative control siRNA had no impaction on CBP, the homology of p300. There were no observed adverse reaction in all the rats.
Conclusions:
1. The expression of p300、CBP、Ac-H3 and c-Jun increased in the spinal cord of CCI rats of neuropathic pain and parallelled with the change of nociceptive behaviors.
2. Intrathecal curcumin can dose dependently inhibit the development of neuropathic pain in CCI rats and depress the expression of p300、CBP、Ac-H3 and c-Jun in spinal cord. The analgesic effect of curcumin was implemented partly via inhibiting the histone acetyltransferase p300/CBP.
3. Intrathecal p300 siRNA can attenuate the neuropathic pain in CCI rats and lower the expression of p300、Ac-H3、c-Jun in spinal cord, further validating the effect of histone acetyltransferase p300 in neuropathic pain.
4. p300/CBP could participate in the modulation of neuropathic pain by the role of histone acetyltransferase.
观察组蛋白乙酰转移酶p300、CBP、乙酰化底物组蛋白H3的乙酰化水平以及疼痛相关转录因子c-Jun在大鼠坐骨神经慢性压迫性损伤(chronic constriction injury, CCI)模型中的变化规律,采用组蛋白乙酰转移酶p300／CBP的特异性抑制剂姜黄素鞘内注射,观察其对CCI大鼠的镇痛作用,并使用p300 siRNA进行验证,探索p300／CBP参与神经病理性疼痛的表观遗传调控机制。
方法
1.雄性SD大鼠随机分为CCI组和假手术组,CCI组按照Bennett和Xie的方法建立大鼠左侧坐骨神经慢性压迫性损伤模型,假手术组仅暴露左侧坐骨神经不结扎,进行机械痛阈、热痛阈检测后于术后第3、7、14、21天处死取材,行p300、CBP的免疫组化、Western-blot以及RT-PCR测定,采用Western-blot检测乙酰化组蛋白H3(Ac-H3)、总的组蛋白H3、c-Jun的蛋白表达变化。
2.腰段鞘内置管成功的雄性SD大鼠随机分为6组：假手术+生理盐水组、假手术+姜黄素500μg组、CCI+生理盐水组、CCI+DMSO组、CCI+姜黄素100μg组、CCI+姜黄素500μg组。术后第3天开始连续4天鞘内注射高纯度(≥98.5%)姜黄素(溶于50%的DMSO)或50%的DMSO各10μl。于术后7、14、21天各时点测完大鼠痛阈后处死取材进行p300、CBP、Ac-H3、H3、c-Jun的形态学和分子生物学相关检测,并进行大鼠脊髓腰膨大处HE染色以观察有无毒性作用。
3.将腰段鞘内置管成功的雄性SD大鼠随机分为6组：假手术+生理盐水组、CCI+生理盐水组、CCI+转染试剂组、CCI+阴性对照siRNA组、CCI+p300 siRNA组、CCI+阳性对照siRNA组。siRNA经2'Ome修饰,采用聚乙烯亚胺(polyethyleneimine, PEI)体内导入系统,从第3天开始鞘内注射siRNA4μg/天(2μg/次,每天2次),连续4天,转染试剂组鞘内注射同样体积的转染试剂。检测各组大鼠的痛阈变化,并于术后7、14天处死取材进行各观察指标的形态学和分子生物学检测。
结果
1.CCI组与sham组相比,术后第1天痛阈值即明显下降,并于术后第7天降至最低点,持续至第21天仍下降明显。脊髓腰膨大处免疫组化显示p300、CBP阳性细胞以灰质表达为主,并可见于灰质全层均有较多表达,尤其在脊髓背角Ⅰ-Ⅲ层致密表达。阳性颗粒主要位于胞核,胞浆可见少量。CCI组脊髓背角浅层的p300、CBP阳性细胞表达从术后第3天开始明显增多,第7天表达最多,并持续至第14天。p300、CBP的mRNA表达于术后3天明显增高达最大值,并持续至第14天,于第21天恢复至仅略高于假手术组。p300、CBP、Ac-H3以及即早基因c-Jun的蛋白表达也表现出类似的变化,但表达峰值为第7天。
2.姜黄素100μg(0.33-0.40mg／kg)、500μg(1.7-2.0mg／kg)组均能从第5天(注药2天后)开始显著改善CCI大鼠的痛敏现象,术后第7天(注药4天后)达到最大程度的改善,并呈剂量依赖性。姜黄素100μg组的镇痛作用可持续至术后第11天,姜黄素500μg组镇痛作用可持续至术后第14天。到术后第21天时,两个剂量组的姜黄素均已无镇痛作用。姜黄素100μg、500μg在术后第7天均能显著抑制p300、CBP的基因和蛋白表达以及Ac-H3、c-Jun的蛋白表达,并以500μg组更明显。到术后第14天时,仅姜黄素500μg组能降低p300的mRNA水平,对CBP的基因表达已无影响,此时,对各组大鼠指标的蛋白表达的抑制仅见于姜黄素500μg组。第21天时,姜黄素的抑制作用已经消失。在假手术组,姜黄素对大鼠的痛阈和各指标表达均没有明显的影响。HE染色显示鞘注姜黄素组未对大鼠脊髓组织产生明显的损伤。
3.鞘内注射p300siRNA组大鼠从术后第5天(注射2天后)起即表现出痛敏现象的改善,第7天(注射4天后)到达最大缓解,持续至第9天(停止注射2天后),但不能恢复至正常水平。RT-PCR、Western-blot和免疫组化显示p300mRNA和蛋白表达在第7天可以见明显的下调,并且Ac-H3、c-Jun的表达也均被显著抑制。第14天时各指标已经未见明显的下调作用。阳性对照siRNA确认了实验系统的有效性。同时阴性对照siRNA未对p300的高度同源物CBP造成影响,验证了siRNA序列的特异性。各组大鼠未发现明显的毒副作用。
结论
1.神经病理性疼痛大鼠脊髓p300、CBP、Ac-H3和c-Jun表达增加,并与大鼠的疼痛学行为变化相平行。
2.鞘内注射姜黄素能够剂量依赖性的抑制CCI大鼠神经病理性疼痛的发展,并降低脊髓p300、CBP、Ac-H3和c-Jun的表达。其镇痛作用是部分通过抑制组蛋白乙酰转移酶p300／CBP实现的。
3.鞘内注射p300siRNA可减轻CCI大鼠的神经病理性疼痛,并能抑制脊髓p300、Ac-H3和c-Jun的表达,进一步验证了组蛋白乙酰转移酶p300在神经病理性疼痛中的作用。
4.p300／CBP可能通过发挥其组蛋白乙酰转移酶的作用参与神经病理性疼痛的调制。
Objectives:
To investigate the variation regularity of histone acetyltransferase p300、CBP、acetylation level of histone H3 and pain relevant transcription factor c-Jun in a rat modal of chronic constriction injury (CCI). To detect the analgesic effects of intrathecal curcumin, a specific inhibitor of histone acetyltransferase (HAT) p300/CBP and use intrathecal p300 siRNA as a validation in order to search for the epigenetic modulation mechanism of histone acetyltransferase p300/CBP in neuropathic pain.
Methods:
1. Male SD rats were divided randomly into 2 groups. In group CCI, we established a rat modal of chronic constriction injury on the left sciatic nerve according to Bennett and Xie. In group sham rats only underwent surgery of exposing the left sciatic nerve without ligation. After detection of paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) after surgery, rats were sacrified on postoperative day 3、7、14、21 for immunohistochemisty、reverse transciptase polymerase chain reaction (RT-PCR)、western-blot of p300、CBP and western-blot detection of acetylated histone H3 (Ac-H3)、total histone H3、c-Jun.
2. Male SD rats, fitted with intrathecal (i.t.) catheters, were divided randomly into 6 groups:group sham+NS、group sham+curcumin 500μg、group CCI+NS、group CCI+DMSO、group CCI+curcumin 100μg、group CCI+curcumin 500μg. High purity ((?)98.5%) curcumin (dissolved in 50% DMSO) or 50% DMSO 10μl was intrathecally injected beginning from day 3 to day 6 after surgery. On postoperative day 7、14、21, rats were sacrified after pain threshold measurement for morphology molecular biology detection. The lumbar spinal cord was stained with hematoxylin and eosin (HE) to check for toxic action.
3. Male SD rats, fitted with intrathecal (i.t.) catheters, were divided randomly into 6 groups:group sham +NS、group CCI+NS、group CCI+vehie、group CCI+negative control siRN、group CCI+p300 siRNA、group CCI+positive control siRNA.2'Ome modified siRNAs were delivered 4μg/d (2μg, bid) intrathecally by a PEI (polyethyleneimine) system beginning from day 3 to day 6. The same scheme (10μl, bid) of intrathecal transfection agent was used for control. After detecting the pain threshold, rats were sacrified on day 7、14 for indexes detection.
Results:
1. Compared to group sham, the pain threshold in group CCI significantly decreased at all postoperative timepoints, beginning on day 1, reaching a nadir on day 7 and still existing on day 21. Immunonohistochemistry displayed that both p300 and CBP positive cells expressed mainly in the grey matter, abundantly in all layers, especially densely inⅠ-Ⅲlayers of the grey matter. The positive staining was mainly seen in cell nucleus, a small amounts in cytoplasm. In group CCI, p300 and CBP immuno-positive cells in superficial laminae obviously increased from day 3 after surgery, the most on day 7 and lasted to day 14. The mRNA expression of p300、CBP significantly increased and reached the apogee on operative day 3, lasted to day 14 and recovered to a level only slightly higher than group sham on day 21. The protein expression of p300、CBP、Ac-H3 and c-Jun also showed a similar change but with a peak on day 7.
2. Intrathecal curcumin 100μg (0.33-0.4mg/kg)、500μg (1.7-2mg/kg) can both obviously improve the pain-sensitive phenomenon in CCI rats from postoperative day 5(2 days after injection) and reached a greatest improvement on day 7 (4 days after injection) dose dependently. The analgesic effect of curcumin 100μg can last to day 11 (4 days after withdrawal) while curcumin 500μg can last to day 14 (7 days after withdrawal). Neither of the two curcumin groups had analgesic effect on day 21. Curcumin can dose dependently inhibit the mRNA、protein expression of p300、CBP and protein expression of Ac-H3、c-Jun on day 7. When on day 14, only curcumin 500μg can lower the p300 mRNA but not CBP, and only curcumin 500μg had inhibited all the proteins. Curcumin's inhition effect disappeared on postoperative day 21. In group sham, curcumin didn't present anly effect. HE staining showed that intrathecal curcumin didn't produce any overt toxic lesion to the spinal cord.
3. There was an improvement of nociception in group p300 siRNA beginning on day 5(2 days after injection), a maximum relief on day 7 (4 days after injection) and a persistence to day 9 (2 days after withdrawal), but still couldn't recover to the normal level. mRNA and protein expression of p300 were obviously down regulated on day 7 but couldn't be lowered on day 14. The protein expressions of both Ac-H3 and c-Jun were significantly inhibited on day 7. Positive control siRNA affirmed the validity of this essay system. Meanwhile, negative control siRNA had no impaction on CBP, the homology of p300. There were no observed adverse reaction in all the rats.
Conclusions:
1. The expression of p300、CBP、Ac-H3 and c-Jun increased in the spinal cord of CCI rats of neuropathic pain and parallelled with the change of nociceptive behaviors.
2. Intrathecal curcumin can dose dependently inhibit the development of neuropathic pain in CCI rats and depress the expression of p300、CBP、Ac-H3 and c-Jun in spinal cord. The analgesic effect of curcumin was implemented partly via inhibiting the histone acetyltransferase p300/CBP.
3. Intrathecal p300 siRNA can attenuate the neuropathic pain in CCI rats and lower the expression of p300、Ac-H3、c-Jun in spinal cord, further validating the effect of histone acetyltransferase p300 in neuropathic pain.
4. p300/CBP could participate in the modulation of neuropathic pain by the role of histone acetyltransferase.
引文
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