Intestinal dysmotility and enteric neurochemical changes in a Parkinson's disease rat model
Intestinal dysmotility and enteric neurochemical changes in a Parkinson's disease rat model
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DOI：
10.1016/j.autneu.2012.04.005
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发表时间：
2012-08-16
影响因子：
2.7
通讯作者：
Tonini, Marcello
中科院分区：
文献类型：
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作者：
Colucci, Mario;Cervio, Marila;Tonini, Marcello
胃肠道疾病，特别是便秘，是影响帕金森病（PD）患者最常见的非运动功能障碍。我们以前曾报道过，大鼠轴承单侧黑质纹状体病变所造成的6-羟基多巴胺（6-OHDA）立体定位注射发展严重便秘连同区域特异性减少的神经元一氧化氮合酶（nNOS）的肠神经元下肠道。在这里，我们将这些观察扩展到其他肠神经元亚群，还研究了分离的结肠标本的推进活动。4周后6-OHDA注射，损伤大鼠表现出血管活性肠多肽（VIP）的显着增加，伴随着在远端回肠和近端结肠的肌间神经丛的nNOS的表达减少：特别是VIP增加的神经元的亚群积极表达nNOS。另一方面，胆碱乙酰转移酶（ChAT）没有修改的任何肠段分析。有趣的是，我们发现在6-OHDA损伤的大鼠中，近端（-66.8%）和远端（-54.5%）结肠中多巴胺受体2型（D2 R）的表达减少，以及蠕动效率降低（管腔内压力和蠕动事件频率降低）。多巴胺能黑质纹状体神经元的选择性耗竭与肠抑制性神经递质的表达变化以及肠道特定区域中D2 R的表达变化相关。此外，6-OHDA损伤大鼠表现出结肠推进活动的改变与D2 R的减少有关。我们的研究结果揭示了肠道神经化学可塑性事件引起的破坏正常的脑-肠串扰的微妙机制，给出了一个特殊的观点严重便秘的病理生理学，经常影响PD患者。(C)2012爱思唯尔有限公司版权所有。
Gastrointestinal disorders, constipation in particular, are the most common non-motor dysfunctions affecting Parkinson's disease (PD) patients. We have previously reported that rats bearing unilateral nigrostriatal lesion caused by 6-hydroxydopamine (6-OHDA) stereotaxic injection develop severe constipation together with a region-specific decrease of neuronal nitric oxide synthase (nNOS) in enteric neurons of the lower intestinal tract. Here, we extend these observations on other enteric neuronal subpopulations, investigating also the propulsive activity of isolated colonic specimens. Four weeks post 6-OHDA injection, lesioned rats showed a significant increase of vasoactive intestinal polypeptide (VIP) concomitant with the reduced expression of nNOS in the myenteric plexus of distal ileum and proximal colon: in particular VIP increased in a subpopulation of neurons actively expressing nNOS. On the other hand, choline acetyltransferase (ChAT) was not modified in any of the intestinal segments analyzed. Interestingly, we found a reduced expression of dopamine receptor type 2 (D2R) in proximal (-66.8%) and distal (-54.5%) colon, together with reduced peristalsis efficiency (decrease in intraluminal pressure and frequency of peristaltic events) in the 6-OHDA-lesioned rats. The selective depletion of dopaminergic nigrostriatal neurons is associated with changes in the expression of enteric inhibitory neurotransmitters, as well as of the D2R in intestinal specific regions. Moreover, 6-OHDA-lesioned rats demonstrated altered colon propulsive activity referable to the D2R decrease. Our findings unveil subtle mechanisms underlying the enteric neurochemical plasticity events evoked by disruption of the normal brain-gut cross-talk, giving a peculiar point of view on the pathophysiology of the severe constipation that frequently affects PD patients. (C) 2012 Elsevier B.V. All rights reserved.