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Early changes in M2 muscarinic acetylcholine receptors (mAChRs) induced by sarin intoxication may be linked to long lasting neurological effects
NeuroToxicology ( IF 3.4 ) Pub Date : 2017-11-08 , DOI: 10.1016/j.neuro.2017.11.002
Zipora Pittel , Shlomi Lazar , Rellie Gez , Shira Chapman

The effect of sarin on the binding parameters (KD & Bmax) of M2 muscarinic acetylcholine receptor (mAChR) was studied 24 h and 1 week post exposure. Male & female Sprague-Daweley rats were poisoned with 1XLD50 sarin (80 μg/kg, im) followed by treatment of trimedoxime bromide and atropine (7.5:5 mg/kg, im) 1 min later. Brains were removed and analyzed for M2 mAChR binding, using [3H]AFDX384, an M2 selective antagonist. A significant increase in KD of M2 mAChR was found in the cortex 24 h post poisoning, displaying elevation from 4.65 ± 1.16 to 8.45 ± 1.06 nM and 5.24 ± 0.93 to 9.29 ± 1.56 nM in male and female rats, respectively. A rise in KD was also noted 1 week following exposure from 5.04 ± 1.20 to 11.75 ± 2.78 and from 5.37 ± 1.02 to 11.66 ± 1.73 nM, presenting an added increase of 51 and 40% (compared to 24 h) in males and females, respectively. Analysis of M2 receptor density (Bmax) revealed a significant reduction of 68% in males and insignificant reduction of 22% in females, 24 h after sarin exposure which was followed by 37% recovery in males and 100% recovery in females, 1 week later. These results indicate that sarin induces a long-term decreased affinity in M2 mAChR (elevated KDs) and a transient effect on the number of this receptor subtype (Bmax). We hypothesize that the reduced affinity of the M2 receptors (negative auto-regulatory receptors) may cause long-term brain deficits by impairing the normal regulation release of ACh into the synaptic cleft.



中文翻译:

沙林毒素中毒引起的M2毒蕈碱型乙酰胆碱受体(mAChRs)的早期变化可能与长期的神经系统作用有关

暴露后24小时和1周研究了沙林蛋白对M2毒蕈碱型乙酰胆碱受体(mAChR)的结合参数(KD和Bmax)的影响。将雄性和雌性Sprague-Daweley大鼠分别用1XLD50沙林(80μg/ kg,im)中毒,然后在1分钟后用溴化三甲肟和阿托品(7.5:5 mg / kg,im)进行中毒。移出大脑,并使用[ 3H] AFDX384,一种M2选择性拮抗剂。中毒后24 h,皮质中发现M2 mAChR的KD显着增加,雄性和雌性大鼠分别从4.65±1.16升至8.45±1.06 nM和5.24±0.93至9.29±1.56 nM。暴露1周后KD也升高,从5.04±1.20增至11.75±2.78和从5.37±1.02增至11.66±1.73 nM,男性和女性的增加分别为51%和40%(与24小时相比),分别。M2受体密度(Bmax)的分析显示,沙林暴露24小时后,雄性显着降低68%,雌性显着降低22%,随后1周后雄性恢复37%,雌性恢复100% 。这些结果表明,沙林蛋白在M2 mAChR(升高的KD)中诱导长期降低的亲和力,并对该受体亚型(Bmax)的数量产生短暂影响。我们假设,M2受体(负的自动调节受体)亲和力降低可能会通过损害ACh进入突触间隙的正常调节释放而导致长期脑功能不全。

更新日期:2017-11-08
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