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International Journal of Biomedical Science
18(1) 14-23
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© 2005 Master Publishing Group
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ORIGINAL ARTICLE
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Activation of Cannabinoid Receptor 2 Protects Rat Hippocampal Neurons against Chronic, Oligomeric A_-induced Neuronal Hyperexcitation |
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Yudan Zhang1, Jingfu Zhao1, Lin Sun1, Shuangtao Li2, Menzheng Wang1, Wei Liu1, Zhegang Ma1, Jie Wu1, 2 |
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1 Institute of Brain Science and Disorders, Qingdao University, Qingdao, China;
2 Brain Function and Disease Laboratory, Shantou University Medical College, Xin-Ling Road #22, Shantou 515041, China
Corresponding Author: Jie Wu, MD, PhD, Professor, Institute of Brain Science and Disorders, Qingdao University, Qingdao, China; Brain Function and Disease Laboratory, Shantou University Medical College, Xin-Ling Road #22, Shantou 515041, China. E-mail: jiewu2@qdu.edu.cn or jiewubni@gmail.com.
Running title: CB2R-MEDIATED A REDUCTION OF OAβ-INDUCED NEURONAL HYPEREXCITATION
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Amyloid beta-peptide; Cannabinoid receptor 2; Hippocampal neurons; AD, Alzheimer's disease; Neuronal hyperexcitation; Neuronal toxicity |
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There is a significantly elevated incidence of epilepsy in Alzheimer’s disease (AD). Burgeoning evidence indicates that soluble beta-amyloid peptides oligomers (oAβ) are vital players in driving neuronal hyperactivity in AD. It is well known that the modulations of the cannabinoid system exhibit neuroprotective effects in various neurological diseases, including AD. However, a consensus is yet to emerge as to the impact of hippocampal cannabinoid receptor 2 (CB2R) in protecting hippocampal neurons against Aβ-induced neuronal hyperexcitation. Here, we report that chronic treatment of primary hippocampal neuronal cultures with 100 nM Aβ1–42 oligomers for 7 days results in a neuronal hyperexcitation. Further, pre-treatments of CB2R agonist (JWH133, 1 μM with Aβ1–42 for 7 days) significantly protect hippocampal neurons against Aβ-increased hyperexcitation, including prolonged action potential (AP) initiation, enhanced after hyperpolarization (AHP), and decreased AP numbers. These effects are eliminated by a selective CB2R antagonist, AM630. Furthermore, when the oAβ-increased neuronal hyperexcitation has already formed (pretreated with oAβ1–42 for 5 days), the addition of JWH133 also abolishes the Aβ’s effects. Collectively, our results suggest that the selective activation of hippocampal CB2Rs not only prevents Aβ-increased neuronal hyperexcitation, but also abolishes the established neuronal hyperexcitation, which underlies our recent findings that CB2Rs play a critical role in protection of hippocampal neurons against the Aβ-induced neuronal toxicity and degeneration. This novel finding suggests a potentially therapeutic strategy for the treatment of AD using CB2R agonists.
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