PDF(Pubmed)
Abstract：
Preclinical studies have reported that, compared to the muscarinic receptor (mAChR) antagonist atropine, (R,S)-trihexyphenidyl (THP) more effectively counters the cholinergic crisis, seizures, and neuropathology triggered by organophosphorus (OP)-induced acetylcholinesterase (AChE) inhibition. The greater effectiveness of THP was attributed to its ability to block mAChRs and N-methyl-d-aspartate-type glutamatergic receptors (NMDARs) in the brain. However, THP also inhibits α7 nicotinic receptors (nAChRs). The present study examined whether THP-induced inhibition of mAChRs, α7 nAChRs, and NMDARs is required to suppress glutamatergic synaptic transmission, whose overstimulation sustains OP-induced seizures. In primary hippocampal cultures, THP (1-30 μM) suppressed the frequency of excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs, respectively) recorded from neurons in nominally Mg2+-free solution. A single sigmoidal function adequately fit the overlapping concentration-response relationships for THP-induced suppression of IPSC and EPSC frequencies yielding an IC50 of 6.3 ± 1.3 μM. Atropine (1 μM), the NMDAR antagonist d,l-2-amino-5-phosphonopentanoic acid (D,L-AP5, 50 μM), and the α7 nAChR antagonist methyllycaconitine (MLA, 10 nM) did not prevent THP-induced inhibition of synaptic transmission. THP (10 μM) did not affect the probability of transmitter release because it had no effect on the frequency of miniature IPSCs and EPSCs recorded in the presence of tetrodotoxin. Additionally, THP had no effect on the amplitudes and decay-time constants of miniature IPSCs and EPSCs; therefore, it did not affect the activity of postsynaptic GABAA and glutamate receptors. This study provides the first demonstration that THP can suppress action potential-dependent synaptic transmission via a mechanism independent of NMDAR, mAChR, and α7 nAChR inhibition.
摘要：
临床前研究报告说，与毒蕈碱受体（mAChR）拮抗剂阿托品相比，(R,S）-己基苯基（THP）更有效地对抗胆碱能危象，癫痫发作,和由有机磷（OP）诱导的乙酰胆碱酯酶（AChE）抑制触发的神经病理学。THP的更高有效性归因于其阻断大脑中的mAChRs和N-甲基-d-天冬氨酸型谷氨酸能受体（NMDARs）的能力。然而,THP还抑制α7烟碱受体(nAChRs)。本研究检查了THP是否诱导了对mAChRs的抑制，α7nAChRs,NMDAR是抑制谷氨酸能突触传递所必需的，其过度刺激维持OP诱导的癫痫发作。在原代海马培养物中,THP（1-30μM）抑制兴奋性和抑制性突触后电流的频率（EPSCs和IPSCs，分别）从标称无Mg2的溶液中记录神经元。单个S形函数充分拟合了THP诱导的IPSC和EPSC频率抑制的重叠浓度-响应关系，IC50为6.3±1.3μM。阿托品（1μM），NMDAR拮抗剂d，1-2-氨基-5-膦戊酸(D，L-AP5,50μM),和α7nAChR拮抗剂甲基云杉碱（MLA，10nM)不阻止THP诱导的突触传递抑制。THP（10μM）不影响发射器释放的可能性，因为它对在河豚毒素存在下记录的微型IPSC和EPSC的频率没有影响。此外,THP对微型IPSC和EPSC的振幅和衰减时间常数没有影响；因此，它不影响突触后GABAA和谷氨酸受体的活性。这项研究首次证明THP可以通过独立于NMDAR的机制抑制动作电位依赖性突触传递，mAChR,和α7nAChR抑制。
