Cerebrovascular and neuroprotective effects of adamantane derivative.

Ruben S Mirzoyan,Nina I Avdyunina,Tamara S Gan’Shina,Boris M Pyatin,Cristina B Alikhanyan,Nelly G Khostikyan,Vahe S Meliksetyan,Georgy I Kovalev,Narine R Mirzoyan,Anna M Kukhtarova,Denis V Maslennikov,Ivan A Zimin

doi:10.1155/2014/586501

Abstract

Objectives. The influence of 5-hydroxyadamantane-2-on was studied on the rats' brain blood flow and on morphological state of brain tissue under the condition of brain ischemia. The interaction of the substance with NMDA receptors was also studied. Methods. Study has been implemented using the methods of local blood flow registration by laser flowmeter, [3H]-MK-801binding, and morphological examination of the brain tissue. We used the models of global transient ischemia of the brain, occlusion of middle cerebral artery, and hypergravity ischemia of the brain. Results. Unlike memantine, antagonist of glutamatergic receptors, the 5-hydroxyadamantane-2-on does not block NMDA receptors but enhances the cerebral blood flow of rats with brain ischemia. This effect is eliminated by bicuculline. Under conditions of permanent occlusion of middle cerebral artery, 5-hydroxyadamantane-2-on has recovered compensatory regeneration in neural cells, axons, and glial cells, and the number of microcirculatory vessels was increased. 5-Hydroxyadamantane-2-on was increasing the survival rate of animals with hypergravity ischemia. Conclusions. 5-Hydroxyadamantane-2-on, an adamantane derivative, which is not NMDA receptors antagonist, demonstrates significant cerebrovascular and neuroprotective activity in conditions of brain ischemia. Presumably, the GABA-ergic system of brain vessels is involved in mechanisms of cerebrovascular and neuroprotective activity of 5-hydroxyadamantane-2-on.

Highlights

The brain ischemia is accompanied by a cascade of pathophysiological and biochemical processes caused by oxygen and energy deficiency as well as functional changes like failure of balance between excitatory and inhibitory processes in CNS, which leads to irreversible damage of the neural tissue
Earlier we showed that substances with GABA-ergic mechanism of action cause selective improvement of cerebral blood flow in conditions of ischemic damage of the brain [11,12,13,14,15]
Experiments of middle cerebral artery occlusion were conducted on 28 nonlinear male rats weighting 250–300 g, narcotized with chloral hydrate (400 mg/kg, i/p). 50 wakeful rats were involved in experiments with hypergravity ischemia and brains of 6 male Wistar rats (200– 250 g) were used in experiments of radioligand binding

Summary

Introduction

The brain ischemia is accompanied by a cascade of pathophysiological and biochemical processes caused by oxygen and energy deficiency as well as functional changes like failure of balance between excitatory and inhibitory processes in CNS, which leads to irreversible damage of the neural tissue. The decrease in the rate of aerobic glycolysis brings, to intracellular acidosis, decrease in work efficiency of the sodium-potassium pump, changes in ionic gradients, enhanced discharge of excitatory amino acid glutamate, high concentrations of which cause increased flow of calcium ions into the cell, and activation of enzyme systems. Under these conditions the process of oxidative phosphorylation fails and toxins and free radicals, including NO, are produced; lipid peroxidation is activated and oxidative stress develops.

Objectives

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Results

Conclusion