Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071.
Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071.
复制标题
DOI：
10.1007/s00213-021-05822-x
复制
发表时间：
2021-07
影响因子：
3.4
通讯作者：
Sarter M
中科院分区：
文献类型：
--
作者：
Kucinski A;Sarter M
除了疾病定义的运动症状外，帕金森病（PD）患者还表现出步态功能障碍、姿势不稳定和福尔斯倾向。这些多巴胺（DA）抵抗症状部分归因于基底前脑（BF）胆碱能神经元的损失，并且与纹状体多巴胺（DA）损失相互作用，导致平衡和复杂运动的注意力控制中断。具有双重胆碱能-DA损失的大鼠（"DL大鼠"）先前被证明可以模拟PD福尔斯以及步态和平衡的相关损伤。我们之前发现，毒蕈碱M1阳性变构调节剂（PAM）TAK-071可改善BF胆碱能损失大鼠的注意力表现。在此，我们检验了TAK-071降低DL大鼠跌倒率的假设。在DL手术之前，训练雌性大鼠穿过旋转直杆以及具有两个Z字形节段的杆。使DL大鼠在手术后重新熟悉这种穿越，并在日益苛刻的测试条件下测试7天。TAK-071（0.1、0.3 mg/kg，p.o.）在这7天期间的每日测试阶段之前施用。和以前一样，DL大鼠比假手术对照组大鼠更频繁地跌倒。TAK-071给药DL大鼠可减少旋转棒和旋转之字形棒的福尔斯跌落，特别是当进入时之字形节段的成角部分处于陡峭、接近垂直的角度时。TAK-071可能有利于复杂的运动控制，特别是在破坏向前运动模式并需要认知和运动功能之间相互作用的情况下，以根据动态表面状态、平衡和步态信息修改运动。
In addition to the disease-defining motor symptoms, patients with Parkinson’s disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. These dopamine (DA) replacement-resistant symptoms in part have been attributed to loss of basal forebrain (BF) cholinergic neurons and, in interaction with striatal dopamine (DA) loss, to the resulting disruption of the attentional control of balance and complex movements. Rats with dual cholinergic-DA losses (“DL rats”) were previously demonstrated to model PD falls and associated impairments of gait and balance. We previously found that the muscarinic M1-positive allosteric modulator (PAM) TAK-071 improved the attentional performance of rats with BF cholinergic losses. Here, we tested the hypotheses that TAK-071 reduces fall rates in DL rats. Prior to DL surgery, female rats were trained to traverse a rotating straight rod as well as a rod with two zigzag segments. DL rats were refamiliarized with such traversals post-surgery and tested over 7 days on increasingly demanding testing conditions. TAK-071 (0.1, 0.3 mg/kg, p.o.) was administered prior to daily test sessions over this 7-day period. As before, DL rats fell more frequently than sham-operated control rats. Treatment of DL rats with TAK-071 reduced falls from the rotating rod and the rotating zigzag rod, specifically when the angled part of the zigzag segment, upon entering, was at a steep, near vertical angle. TAK-071 may benefit complex movement control, specifically in situations which disrupt the patterning of forward movement and require the interplay between cognitive and motor functions to modify movement based on information about the state of dynamic surfaces, balance, and gait.
登录
查看更多内容
影响因子：
3.2
作者：
Berry AS;Demeter E;Sabhapathy S;English BA;Blakely RD;Sarter M;Lustig C
通讯作者：
Lustig C
影响因子：
5
作者：
Gould RW;Dencker D;Grannan M;Bubser M;Zhan X;Wess J;Xiang Z;Locuson C;Lindsley CW;Conn PJ;Jones CK
通讯作者：
Jones CK
影响因子：
64.8
作者：
Herrero, J. L.;Roberts, M. J.;Delicato, L. S.;Gieselmann, M. A.;Dayan, P.;Thiele, A.
通讯作者：
Thiele, A.
DOI：
10.1093/gerona/51a.3.m116
发表时间：
1996-05-01
影响因子：
5.1
作者：
Chen, HC;Schultz, AB;Guire, KE
通讯作者：
Guire, KE
影响因子：
11.2
作者：
Bohnen, Nicolaas, I;Kanel, Prabesh;Mueller, Martijn L. T. M.
通讯作者：
Mueller, Martijn L. T. M.