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Influence of Hemantane on Changes in Ca2+ and Na+ Caused by Activation of NMDA Channels in Cultured Rat Brain Neurons

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Abstract—One of the leading mechanisms of neurodegeneration in Parkinson’s disease is excitotoxicity of glutamate, the main excitatory brain neurotransmitter. Excitotoxicity develops as a result of excessive stimulation of ionotropic NMDA glutamate receptors. Drugs reversibly inhibiting NMDA receptors are considered as promising pharmacological agents that prevent the death of neurons and slow down neurodegeneration. In this work, we studied the effect of N-(2-adamantyl)-hexamethyleneimine hydrochloride (hemantane) on changes in the intracellular concentration of Ca2+ ([Ca2+]i), Na+ ([Na+]i) and mitochondrial potential (ΔΨm) induced by NMDA in cultured neurons. Cultures were prepared from the cerebral cortex of 1-2-day-old Wistar rats. Experiments with animals were performed in accordance with the ethical principles and regulatory documents recommended by the European Convention on the Protection of Vertebrate Animals. The measurements of [Ca2+]i, [Na+]i and ΔΨm were taken using a fluorescence microscopy system based on an Olympus IX-71 inverted microscope with a Sutter Lambda 10-2 multi-wavelength illumination system and a cooled CoolSnap HQ CCD camera. The system was controlled using the MetaFluor software. It was shown that short-term subtoxic doses of NMDA (2–3 min, 10 μM) cause a rapid rise in [Ca2+]i, which is reversibly inhibited by high concentrations of Mg2+ (10 mM) and hemantane (100 μM). Prolonged administration of the neurotoxic NMDA concentration (20 min, 500 μM) caused the development of delayed calcium deregulation (DCD), a steady rise in [Na+]i and a profound drop in ΔΨm. Hemantane (100 μM) reduced [Ca2+]i elevation, postponed the development of DCD, reduced mitochondrial depolarization, and helped to restore the initial values of [Ca2+]i, [Na+]i and ΔΨm after NMDA washout. Unlike hemantane, the high-affinity non-competitive inhibitor of NMDA channels MK-801 irreversibly blocked changes in [Ca2+]i and ΔΨm, even at a high NMDA concentration (500 μM). Obviously, hemantane exhibits neuroprotective properties due to a decrease in Ca2+ and Na+ fluxes through NMDA channels and a lower elevation of [Ca2+]i and [Na+]i. The reversibility of NMDA channel inhibition favors the normalization of brain functioning after termination of hemantane administration.

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Funding

The study was carried out according to the State tasks nos. 0520-2019-0029 and AAAA-A19-119012590191-3.

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    Authors and Affiliations

    1. Institute of General Pathology and Pathophysiology, Lomonosovskii pr. 2 str. 1, 119991, Moscow, Russia

      N. A. Voronina, O. Yu. Lisina, V. G. Kucheryanu & A. M. Surin

    2. National Medical Research Center of Children’s Health, Moscow, Russia

      I. A. Krasilnikova & A. M. Surin

    3. Zakusov Research Institute of Pharmacology, Moscow, Russia

      I. G. Kapitsa & T. A. Voronina

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    1. N. A. Voronina
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    2. O. Yu. Lisina
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    3. I. A. Krasilnikova
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    Correspondence to A. M. Surin.

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    Conflict of interests. The authors declare no conflicts of interest.

    Ethical approval. Experiments with animals were performed in accordance with the ethical principles and regulatory documents recommended by the European Convention for the Protection of Vertebrate Animals used for Experiments (Guide for the Care and Use of Laboratory Animals: Eighth Edition. 2010), as well as in accordance with the “Rules of Good Laboratory Practice” approved by order of the Ministry of Health of the Russian Federation No. 199n of April 1, 2016.

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    Voronina, N.A., Lisina, O.Y., Krasilnikova, I.A. et al. Influence of Hemantane on Changes in Ca2+ and Na+ Caused by Activation of NMDA Channels in Cultured Rat Brain Neurons. Neurochem. J. 15, 8–17 (2021). https://doi.org/10.1134/S1819712421010165

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