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Tavricheskii Vernadskii University, Simferopol', Crimean Autonomic Republic,. Ukraine. Effects of Some Benzimidazole Derivatives on Electrical. Activity in ...
Neurophysiology, Vol. 34, Nos. 2/3, 2002

Effects of Some Benzimidazole Derivatives on Electrical Activity in Molluscan Neurons T. V. Gamma,1 I. I. Korenyuk,1 M. Yu. Baevsky,1 M. Yu. Ravaeva,1 and V. B. Pavlenko1 Neirofiziologiya/Neurophysiology, Vol. 34, Nos. 2/3, pp. 147-149, March-June, 2002. We studied the effects of applications of bemitil, 2-ethylbenzimidazole hydrochloride, and 2-methyl benzimidazole hydrochloride in 10–5 and 10–4 M concentrations on identified molluscan neurons. It was found that the agents exert clear neurotropic effects, which, as we assume, are determined by their influence on different types of ion channels.

Keywords: action potential, neuron, mollusc, benzimidazole derivatives, bemitil.

INTRODUCTION Some benzimidazole derivatives demonstrate effective psychostimulating, anticonvulsive, and antidepressive properties [1, 2]. A well-known drug, bemitil, has actoprotecting properties. According to the increase in the capacity for work and rehabilitation rate provided by the drug, it was assumed that the action of bemitil is based on its interaction with the gene apparatus, due to some similarities of the molecular structure of benzimidazole derivatives with that of nucleic acid bases, adenine and guanine. Despite the fact that the pharmacological properties of bemitil itself and other synthesized benzimidazole derivatives have been extensively studied, its effect on the neuronal membrane and the mechanism of its action remain unclear in many aspects. Thus, the aim of our study was to investigate the effects of the benzimidazole derivatives bemitil (compound 1), 2-ethylbenzimidazole hydrochloride (2), and 2-methyl benzimidazole hydrochloride (3) on the parameters of the electrical activity of molluscan neurons. METHODS Experiments were conducted on identified neurons of Helix albescens Rassm. with the use of the earlier 1

Tavricheskii Vernadskii University, Simferopol’, Crimean Autonomic Republic, Ukraine.

described technique [3, 4]. Measurements of the temporal and amplitude parameters of the potentials (critical level of depolarization, CLD; ascending and descending phases of the action potentials AP, and afterhyperpolarization) were provided using a computer program. First, we measured the initial electrical characteristics typical of the background functional state of the neurons (8-10 control AP); then we repeated the measurements 0.5, 1, and 5 min from the moment of application of the substance, and did the same after the beginning of washing-off. RESULTS AND DISCUSSION The effects of application of benzimidazole derivatives in 10 –4 and 10 –5 M concentrations were studied in 24 RPa1, 18 RPa2, and 16 RPa7 neurons. All types of investigated neurons responded to a threshold concentration equal to 10 –5 M. Below this concentration, only insignificant modulations of the electrical characteristics of the neuronal membrane were detected. Clear application effects of agents 1, 2, and 3 were displayed when their concentration reached 10 –4 M. They were manifested in significant changes in the CLD, AP amplitude, duration of the ascending and descending phases of AP, and the amplitude of afterhyperpolarization (Fig. 1). In all the investigated neurons, the amplitudes of the transsynaptically evoked spikes

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Effects of Benzimidazole Derivatives on Molluscan Neurons decreased by 2-3 mV within the 1st min of application of the above-mentioned derivatives (A). Together with CLD changes, the amplitude of afterhyperpolarization decreased, but its duration increased. At the 5th min of exposure to agents 1 and 3, the CLD values returned to the initial values. During washing-off, the CLD values increased by 1.5-3.0 mV compared with the initial ones (A). It should be noted that the CLD usually did not return precisely to the initial values. During washingoff, the CLD increased and became 1.5-3.0 mV higher than the initial values (A). It should be noted that the CLD did not return to the initial values even 20 min

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after washing-off of compound 2. Based on the results, we can assume that compounds 1 and 3 interact with molecular components of the cell membranes through relatively weak connections. This is why their action in the used concentrations is easily abolished. At the same time, compound 2 creates much more stable connections. During application of compounds 1 and 2, the background AP amplitude decreased by 5-10 mV (B). Slowing-down of both membrane depolarization and repolarization within the AP development was observed (C, D). It should be noted that an increase in the AP

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Fig. 1. Effects of benzimidazole derivatives 1, 2, and 3 in a 10–4 M concentration on the membrane CLD (A), amplitude of AP (B), duration of ascending (C) and descending phases (D) of AP, and amplitude of afterhyperpolarization (E) in RPa1, RPa2, and RPa7 neurons. Stages of the experiment: 1) background; 2) 0.5 min; 3) 1 min; 4) 5 min from the beginning of application of the drug, and 5, 6, 7) from the beginning of washing-off, respectivelly.

132 duration resulted mostly due to prolongation of the repolarization phase (it was protracted up to 5-8 msec). As both AP phases were prolonged, we can conclude that the above agents influence Na + , K +, and other currents responsible for the formation of these components of AP [8]. Compound 3 exerted no significant influence on the AP duration. During application of compounds 1 and 3, from the 1st min of influence a decrease in the amplitude of afterhyperpolarization by 3-5 mV (E) was observed. Yet, in 5 min of the influence of compound 1 the amplitude of this potential increased by 5-10 mV compared with that within the background, and the effect of this compound was displayed in a decrease in the amplitude of afterhyperpolarization by 4-6 mV (E). Since afterhyperpolarization is mostly due to the K+ and Cl conductivities of the membrane and activity of the membrane pumps [9], we can assume that the tested substances exert a specific influence on these processes. Compound 2 exerted no significant influence on the after-AP phenomena in the examined cells. Based on the fact that benzimidazole derivatives in a concentration of 10–4 M are capable of changing the CLD parameters, processes of AP depolarization and repolarization, as well as afterhyperpolarization, we believe that these compounds influence membrane receptors of different types, which results in modulation of the activity of the respective ion channels. In the future, we intend to

T. V. Gamma et al. study ion currents under the influence of benzimidazole derivatives. REFERENCES 1. 2. 3. 4. 5.

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