Effect of Mexidol and Nitroxymexidol on Phosphodiesterase Activity, Some Oxidation Processes, and Hypoxia Resistance

Abstract

The effect of mexidol (M) and nitroxymexidol (NM) on the activity of phosphodiesterase of cyclic guanosine monophosphate (PDEcGMP), regulation of lipid peroxidation (LPO), and antiradical and antihypoxic activity was investigated under normoxia and normobaric hypercapnic hypoxia conditions. Reversible and noncompetitive inhibition of the hydrolytic function of PDEcGMP by M and NM was revealed. The K i value for M was 1´10 -4 M; for NM, 1´10 -5 M, i.e., NM was 10 times more active than M. It was shown that the lifetime of experimental animals in a closed space increased by 36% under the action of M as compared with that of the control group while it increased by 53% for NM. The ventricular contraction time increased by 137% for NM. The atrial contraction time increased from 31 min in the control to 52 and 57 min for M and NM, respectively.Syntheses of new highly effective and non-toxic drugs capable of generating NO during biotransformation have recently been developed at the IPCP, RAS [1, 2].Mexidol (M) is widely used in medical practice as a lipid peroxidation (LPO) inhibitor [3,4].A new non-toxic mexidol derivative, nitroxymexidol (NM), was synthesized at the IPCP, RAS [5].The goal of the present work was to study the roles of M and NM in the regulation of LPO, antiradical protection, modulation of cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) activity, and antihypoxic activity with normoxia and hypercapnic normobaric hypoxia. EXPERIMENTAL PARTWe used cGMP nucleotidase (as cobra venom), histidine, and Tris-HCl (Sigma) without additional purification. Trichloroacetic acid and ammonium molybdate (Reakhim, Russia) were purified before use. Mexidol (M) was synthesized as before [6]. Nitroxymexidol (NM) was synthesized by the literature method [5] with its nitro group bonded to succinic acid. It was 98% pure according to GC.PDE of cGMP (PDEcGMP) was isolated from the brain cortex of male Wistar rats [7]. Brain tissue was homogenized in a Potter homogenizer in ten times the weight of cold Tris-HCl buffer (0.2 M) at pH 7.5. The homogenate was centrifuged for 1 h at 40,000 g in a K-32M centrifuge. The supernatant containing the enzyme was frozen in liquid nitrogen. 4170091-150X/14/4807-0417