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The Neuroprotective Effect of L-Stepholidine on Methamphetamine-Induced Memory Deficits in Mice

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Abstract

Repeated methamphetamine (METH) exposure can cause severe neurotoxicity to the central nervous system, and lead to memory deficits. L-Stepholidine (L-SPD) is a structurally identified alkaloid extract of the Chinese herb Stephania intermedia, which elicits dopamine (DA) D1-type receptors partial agonistic activity and D2-type receptors antagonistic activity. In this study, we investigated the effect of L-SPD on METH-induced memory deficits in mice and its underlying mechanisms. We found that repeated exposure to METH (10 mg/kg, i.p., once per day for 7 consecutive days) impaired memory functions in the novel object recognition experiment. Pretreatment of L-SPD (10 mg/kg, i.p.) significantly improved METH-induced memory deficits in mice. Meanwhile, the protein expression of dopaminergic D2 receptors in hippocampus area was significantly increased by repeated METH exposure, while the protein expression of dopamine transporter (DAT) was significantly reduced. Additionally, the protein expression of phospho-protein kinase A (p-PKA) was significantly increased by repeated METH exposure. The hyperpolarization-activated cyclic-nucleotide-gated non-selective cation 1 (HCN1) channel, which was a key regulator of memory functions and could be regulated by p-PKA, was also significantly increased by repeated METH exposure. These changes caused by METH could be prevented by L-SPD pretreatment. Therefore, our data firstly showed that pretreatment of L-SPD exhibited the protective effect against METH-induced memory deficits, possibly through reducing METH-induced upregulation of dopaminergic pathway and HCN1 channels.

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Funding

This study was performed with the financial support of grants from the Science and Technology Research Project of Hubei Provincial Department of Education (no. B2016294).

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Authors and Affiliations

  1. Wuhan Institutes of Biomedical Sciences, Jianghan University, Triangle Lake Road No.8, Wuhan, 430056, China

    Mei Zhou, Xiaokang Gong, Qin Ru, Qi Xiong, Lin Chen, Huaqiao Xiao & Chaoying Li

  2. Wan Ji Psychiatric Hospital, Wuhan, 430051, China

    Yuanren Si

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  1. Mei Zhou
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  2. Xiaokang Gong
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Correspondence to Chaoying Li.

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Zhou, M., Gong, X., Ru, Q. et al. The Neuroprotective Effect of L-Stepholidine on Methamphetamine-Induced Memory Deficits in Mice. Neurotox Res 36, 376–386 (2019). https://doi.org/10.1007/s12640-019-00069-z

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