A selective M1 and M3 receptor antagonist, penehyclidine hydrochloride, prevents postischemic LTP: Involvement of NMDA receptors

Authors

  • Teng-Fei Ma,

    1. Key Laboratory for Brain Disease Bioinformation of Jiangsu Province, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    2. Department of Pharmacology, Key Laboratory of new drugs and clinical application, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    Search for more papers by this author
    • T.-F.M, L.Z, and Y.W contributed equally to this work.

  • Li Zhou,

    1. Key Laboratory for Anesthesiology of Jiangsu Province, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    Search for more papers by this author
  • Yun Wang,

    1. Department of Pharmacology, Key Laboratory of new drugs and clinical application, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    Search for more papers by this author
  • Shou-Jun Qin,

    1. Department of Pharmacology, Key Laboratory of new drugs and clinical application, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    Search for more papers by this author
  • Yuan Zhang,

    1. Department of Pharmacology, Key Laboratory of new drugs and clinical application, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    Search for more papers by this author
  • Bin Hu,

    1. Key Laboratory for Brain Disease Bioinformation of Jiangsu Province, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    Search for more papers by this author
  • Jing-Zhi Yan,

    1. Key Laboratory for Brain Disease Bioinformation of Jiangsu Province, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    Search for more papers by this author
  • Xing Ma,

    1. Department of Pharmacology, Key Laboratory of new drugs and clinical application, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    Search for more papers by this author
  • Cheng-Hua Zhou,

    1. Department of Pharmacology, Key Laboratory of new drugs and clinical application, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    Search for more papers by this author
  • Shu-Ling Gu

    Corresponding author
    1. Department of Pharmacology, Key Laboratory of new drugs and clinical application, XuZhou Medical College, XuZhou, Jiangsu Province, People's Republic of China
    • Correspondence to: Professor Shu-Ling Gu, Department of Pharmacology, XuZhou Medical College, NO. 209, Tong Shan Road, Xu Zhou, Jiangsu Province 221004, People's Republic of China. E-mail:gushling@yahoo.cn

    Search for more papers by this author

ABSTRACT

Our previous and other studies have confirmed that a selective M1 and M3 receptor antagonist, Penehyclidine hydrochloride (PHC), has neuroprotection activity in cerebral ischemia. However, the precise mechanisms of protection of PHC are still elusive. In this study we analyzed PHC-mediated neuroprotection on a model of brain ischemia (oxygen and glucose deprivation), named postischemic LTP (i-LTP). We found that the activation of NMDA receptor was required for the induction of i-LTP. Compared with scopolamine, PHC could prevent it due to selectively blocking M1 receptor, not M2 receptor, to decrease NMDAR activation. Our findings further showed that the inhibition of SK2 channels occluded the prevention of PHC on NMDAR activation. Furthermore, we confirmed that PHC exerted its roles through directly disinhibition of SK2 channels by blocking M1 receptor and subsequent restricting PKC activation. Moreover, our studies further revealed the critical roles of SK2 channels in i-LTP. Thus, the mechanisms of PHC in brain protection may be involved in suppression of NMDAR by regulation of SK2 channels. Our results obtained in effects of PHC on i-LTP further provided a better understanding of the therapy strategy during stroke and identified potential therapeutic targets to prevent development of ischemia. Synapse 67:865–874, 2013. © 2013 Wiley Periodicals, Inc.

Ancillary