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Bucladesine Attenuates Spatial Learning and Hippocampal Mitochondrial Impairments Induced by 3, 4-Methylenedioxymethamphetamine (MDMA)

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Abstract

Neurotoxic effects of systemic administration of 3, 4- methylenedioxymethamphetamine (MDMA) has been attributed to MDMA and its metabolites. However, the role of the parent compound in MDMA-induced mitochondrial and memory impairment has not yet been investigated. Moreover, it is not yet studied that analogs of 3′, 5′-cyclic adenosine monophosphate (cAMP) could decrease these neurotoxic effects of MDMA. We wished to investigate the effects of the central administration of MDMA on spatial memory and mitochondrial function as well as the effects of bucladesine, a membrane-permeable analog of cAMP, on these effects of MDMA. We assessed the effects of pre-training bilateral intrahippocampal infusion of MDMA (0.01, 0.1, 0.5, and 1 μg/side), bucladesine (10 and 100 μM) or combination of them on spatial memory, and different parameters of hippocampal mitochondrial function including the level of reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, the amount of cytochrome c release as well as hippocampal ADP/ATP ratio. The results showed that MDMA caused spatial memory impairments as well as mitochondrial dysfunction as evidenced by the marked increase in hippocampal ADP/ATP ratio, ROS level, the collapse of MMP, mitochondrial swelling, and mitochondrial outer membrane damage leading to cytochrome c release from the mitochondria. The current study also found that bucladesine markedly reduced the destructive effects of MDMA. These results provide evidence of the role of the parent compound (MDMA) in MDMA-induced memory impairments through mitochondrial dysfunction. This study highlights the role of cAMP/PKA signaling in MDMA-induced memory and mitochondrial defects.

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Acknowledgments

This work was supported by Tehran University of Medical Sciences.

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Authors and Affiliations

  1. Rehabilitation Research Center, Department of Occupational Therapy, School of Rehabilitation Sciences, Iran University of Medical Sciences, Tehran, Iran

    Ghorban Taghizadeh

  2. Department of Neurosciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Hajar Mehdizadeh & Mohammad Sharifzadeh

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Jalal Pourahmad

  4. Toxicology and Disease group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran

    Alireza Foroumadi & Shokoufeh Hassani

  5. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran

    Shokoufeh Hassani, Marzieh Noruzi, Homayoon Behmadi & Mohammad Sharifzadeh

  6. Faculty of Pharmacy, Islamic Azad University of Medical Sciences, Tehran, Iran

    Zahra Halvaei Khankahdani

  7. Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Hoda Lavasani & Mohammad Reza Rouini

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  1. Ghorban Taghizadeh
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Taghizadeh, G., Mehdizadeh, H., Pourahmad, J. et al. Bucladesine Attenuates Spatial Learning and Hippocampal Mitochondrial Impairments Induced by 3, 4-Methylenedioxymethamphetamine (MDMA). Neurotox Res 38, 38–49 (2020). https://doi.org/10.1007/s12640-020-00183-3

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