腺苷A1受体激动剂减轻糖尿病并发抑郁症大鼠的认知功能障碍
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摘要
目的观察腺苷A1受体(A1R)激动剂对糖尿病并发抑郁症大鼠学习记忆功能的影响。方法将大鼠分为对照组、模型组、二甲双胍(Met)组[Met组:灌胃给予二甲双胍(0.18 g/kg) 28 d]和二甲双胍联合腺苷A1受体激动剂(Met+CPA)干预组[Met+CPA组:灌胃给予二甲双胍28 d,于第22天开始腹腔注射CPA(1 mg/kg),注射给药7 d]。观察大鼠血糖水平和学习记忆功能;ELISA检测大鼠海马谷氨酸的含量;用免疫组化法和Western blot检测海马谷氨酸转运体GLT-1和脑源性神经营养因子(BDNF)的表达。结果与正常组比较,模型组大鼠血糖含量显著升高(P<0.01);学习和记忆功能明显下降(P<0.01);海马中谷氨酸含量明显升高(P<0.01);而GLT-1和BDNF表达显著下降(P<0.01或P<0.05)。与模型组比较,Met组大鼠仅血糖含量显著下降(P<0.01),其余指标均未见显著变化;而Met+CPA组大鼠血糖含量显著下降(P<0.01),认知功能得到明显的改善(P<0.01),海马中谷氨酸含量显著减少(P<0.01),且GLT-1和BDNF表达显著增加(P<0.01或P<0.05)。结论激活腺苷A1受体可有效改善糖尿病并发抑郁症大鼠的认知功能,这可能与其通过减少谷氨酸释放和增加神经营养作用双途径共同减轻神经元兴奋性毒性有关。
Objective To investigate the effect of adenosine A1 receptor(A1 R) agonist on learning and memory function of diabetic rats with depression. Methods The rats were divided into control group, model group and metformin(Met)group(0.18 g/kg Metformin was given by ig. for 28 days) and metformin plus adenosine A1 receptor agonist(Met+CPA) intervention group(metformin was given by ig, and then the CPA was intraperitoneally injected at 1 mg/kg from day 22 and administered for 7 days). The blood glucose and learning/memory function in rats were observed. Then the concentration of glutamate in hippocampus was detected by ELISA. At last,the expression of GLT-1 and BDNF in hippocampus were detected by immunohistochemistry and Western blot. Results Compared with the normal group,the content of blood glucose and the learning and memory function of the model group were significantly decreased( P<0. 01). In addition,the concentration of glutamate in hippocampus was significantly increased( P<0. 01),while the expressions of GLT-1 and BDNF were significantly decreased( P<0. 01,P<0. 05). Compared with the model group,only the blood glucose level decreased significantly in Met group( P<0. 01) with other indexes did not change significantly. However,there was found that the levels of glucose in blood and glutamate in hippocampus were decreased significantly in Met + CPA group( P<0. 01). Furthermore,the cognitive function was significantly improved and the expression of GLT-1 and BDNF was increased( P<0. 01,P<0. 05). Conclusions Activation of adenosine A1 receptor can effectively improve the cognitive function of diabetic rats with depression,which may be related to its antineurotoxicity by reducing the glutamate release and increasing neuronal nutrition function.
Objective To investigate the effect of adenosine A1 receptor(A1 R) agonist on learning and memory function of diabetic rats with depression. Methods The rats were divided into control group, model group and metformin(Met)group(0.18 g/kg Metformin was given by ig. for 28 days) and metformin plus adenosine A1 receptor agonist(Met+CPA) intervention group(metformin was given by ig, and then the CPA was intraperitoneally injected at 1 mg/kg from day 22 and administered for 7 days). The blood glucose and learning/memory function in rats were observed. Then the concentration of glutamate in hippocampus was detected by ELISA. At last,the expression of GLT-1 and BDNF in hippocampus were detected by immunohistochemistry and Western blot. Results Compared with the normal group,the content of blood glucose and the learning and memory function of the model group were significantly decreased( P<0. 01). In addition,the concentration of glutamate in hippocampus was significantly increased( P<0. 01),while the expressions of GLT-1 and BDNF were significantly decreased( P<0. 01,P<0. 05). Compared with the model group,only the blood glucose level decreased significantly in Met group( P<0. 01) with other indexes did not change significantly. However,there was found that the levels of glucose in blood and glutamate in hippocampus were decreased significantly in Met + CPA group( P<0. 01). Furthermore,the cognitive function was significantly improved and the expression of GLT-1 and BDNF was increased( P<0. 01,P<0. 05). Conclusions Activation of adenosine A1 receptor can effectively improve the cognitive function of diabetic rats with depression,which may be related to its antineurotoxicity by reducing the glutamate release and increasing neuronal nutrition function.
引文
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[4] 蒋东艳. 糖尿病后抑郁症的认知功能特点及神经内分泌相关指标分析[J]. 中国实用神经疾病杂志, 2016,19:117-119.
[5] 贾杰芳, 刘玉美, 陈传刚, 等. 抑郁程度对2型糖尿病共病抑郁患者血糖波动与认知功能影响及机制分析[J]. 精神医学杂志, 2017, 30:45-49.
[6] Zhang DA, Lam V, Chu V, et al. Type 2 diabetes with comorbid depression in relation to cognitive impairment: an opportunity for prevention[J]. Mol Neurobiol, 2018, 55: 85-89.
[7] Atif M, Saleem Q, Scahill S. Depression and mild cognitive impairment among elderly patients with type 2 diabetes mellitus in Pakistan: possible determinants[J]. Int J of Diabetes Dev C, 2017,1:1-9.
[8] 曲向东,徐诚实, 曲智俊, 等. 异氟烷麻醉后老年大鼠学习/记忆功能改变与脑海马 CA1 区谷氨酸水平及受体变化的关系[J]. 中华实验外科杂志, 2016, 33:1811-1813.
[9] Zhang B, Yang LI. Research progress of the antidepres-sants targeting the glutamate receptors[J]. Chinese Pharmacological Bulletin, 2014, 30:1197-2000.
[2] Zhou Q, Zhu S, Guo Y, et al. Adenosine A1 receptors play an important protective role against cognitive impair-ment and long-term potentiation inhibition in a pentylenetetrazol mouse model of epilepsy[J]. Mol Neurobiol, 2018, 55:3316-3327.
[3] Atef RM, Agha AM, Abdel-Rhaman AA, et al. The ying and yang of adenosine A1 and A2A receptors on ERK1/2 activation in a rat model of global cerebral ischemia reperfusion injury[J]. Mol Neurobiol, 2018, 55:1284-1298.
[4] 蒋东艳. 糖尿病后抑郁症的认知功能特点及神经内分泌相关指标分析[J]. 中国实用神经疾病杂志, 2016,19:117-119.
[5] 贾杰芳, 刘玉美, 陈传刚, 等. 抑郁程度对2型糖尿病共病抑郁患者血糖波动与认知功能影响及机制分析[J]. 精神医学杂志, 2017, 30:45-49.
[6] Zhang DA, Lam V, Chu V, et al. Type 2 diabetes with comorbid depression in relation to cognitive impairment: an opportunity for prevention[J]. Mol Neurobiol, 2018, 55: 85-89.
[7] Atif M, Saleem Q, Scahill S. Depression and mild cognitive impairment among elderly patients with type 2 diabetes mellitus in Pakistan: possible determinants[J]. Int J of Diabetes Dev C, 2017,1:1-9.
[8] 曲向东,徐诚实, 曲智俊, 等. 异氟烷麻醉后老年大鼠学习/记忆功能改变与脑海马 CA1 区谷氨酸水平及受体变化的关系[J]. 中华实验外科杂志, 2016, 33:1811-1813.
[9] Zhang B, Yang LI. Research progress of the antidepres-sants targeting the glutamate receptors[J]. Chinese Pharmacological Bulletin, 2014, 30:1197-2000.