Korean J Physiol Pharmacol.  2019 Nov;23(6):483-491. 10.4196/kjpp.2019.23.6.483.

Cordycepin protects against β-amyloid and ibotenic acid-induced hippocampal CA1 pyramidal neuronal hyperactivity

• Yao LH
• Wang J
• Liu C
• Wei S
• Li G
• Wang S
• Meng W
• Liu ZB
• Huang LP

• KMID: 2461041
• DOI: http://doi.org/10.4196/kjpp.2019.23.6.483

Abstract

Cordycepin exerts neuroprotective effects against excitotoxic neuronal death. However, its direct electrophysiological evidence in Alzheimer's disease (AD) remains unclear. This study aimed to explore the electrophysiological mechanisms underlying the protective effect of cordycepin against the excitotoxic neuronal insult in AD using whole-cell patch clamp techniques. β-Amyloid (Aβ) and ibotenic acid (IBO)-induced injury model in cultured hippocampal neurons was used for the purpose. The results revealed that cordycepin significantly delayed Aβ+ IBO-induced excessive neuronal membrane depolarization. It increased the onset time/latency, extended the duration, and reduced the slope in both slow and rapid depolarization. Additionally, cordycepin reversed the neuronal hyperactivity in Aβ+ IBO-induced evoked action potential (AP) firing, including increase in repetitive firing frequency, shortening of evoked AP latency, decrease in the amplitude of fast afterhyperpolarization, and increase in membrane depolarization. Further, the suppressive effect of cordycepin against Aβ+ IBO-induced excessive neuronal membrane depolarization and neuronal hyperactivity was blocked by DPCPX (8-cyclopentyl-1,3-dipropylxanthine, an adenosine A₁ receptor-specific blocker). Collectively, these results revealed the suppressive effect of cordycepin against the Aβ+ IBO-induced excitotoxic neuronal insult by attenuating excessive neuronal activity and membrane depolarization, and the mechanism through the activation of A₁R is strongly recommended, thus highlighting the therapeutic potential of cordycepin in AD.

Keyword

Adenosine A₁ receptor; Alzheimer disease; Cordycepin; Excitotoxicity; Neuroprotection

MeSH Terms

Action Potentials
Adenosine
Alzheimer Disease
Fires
Ibotenic Acid
Membranes
Neurons
Neuroprotection
Neuroprotective Agents
Patch-Clamp Techniques
Pyramidal Cells*
Adenosine
Ibotenic Acid
Neuroprotective Agents

Figure

• 

  Fig. 1 Effects of cordycepin on neuronal membrane potentials before and after drug application. (A) A representative trace in the control group subjected to no treatment. (B) A representative trace subjected to β-amyloid (Aβ) + ibotenic acid (IBO). (C) A representative trace subjected to cordycepin (Cor) + Aβ + IBO. (D) A representative trace pretreated with DPCPX and then subjected to Cor + Aβ + IBO. (E) A representative trace pretreated with caffeine and then subjected to Cor + Aβ + IBO.

• 

  Fig. 2 Effects of cordycepin on action potential (AP) firing in primary hippocampal neurons evoked by a depolarization stimulus of 20 pA amplitude for the 600-ms duration. (A) Sample traces showed that cordycepin reversed the increase in β-amyloid (Aβ) + ibotenic acid (IBO)-induced firing frequency. (B) Comparison of membrane potential before and after drug application. (C) Comparison of firing frequency among different drug application groups. (D) Comparison of evoked AP latency among different drug application groups. **p < 0.01, compared with the Aβ + IBO group; ##p < 0.01, compared with the cordycepin (Cor) + Aβ + IBO group.

• 

  Fig. 3 Effects of cordycepin on action potential (AP) firing evoked by a depolarizing ramp stimulus in primary hippocampal neurons treated with β-amyloid (Aβ) + ibotenic acid (IBO). (A) Sample traces of AP firing evoked by a ramp current in different groups (control, Aβ + IBO, cordycepin [Cor] + Aβ + IBO, and DPCPX + Cor + Aβ + IBO). (B) Comparison of membrane potential before and after drug application. (C) Comparison of evoked AP latency among different drug application groups. **p < 0.01, compared with the Aβ + IBO group; ##p < 0.01, compared with the Cor + Aβ + IBO group.

• 

  Fig. 4 Effects of cordycepin on the evoked action potential (AP) properties of primary hippocampal neurons treated with β-amyloid (Aβ) + ibotenic acid (IBO). (A) Representative AP recording in different groups (control, Aβ + IBO, cordycepin [Cor] + Aβ + IBO, and DPCPX + Cor + Aβ + IBO). (B) AP spike width had no significant difference among different drug application groups. (C) Comparison of the fast afterhyperpolarization (fAHP) amplitude among different drug application groups. **p < 0.01, compared with the Aβ + IBO group; ##p < 0.01, compared with the Cor + Aβ + IBO group.

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