Some aspects of neuroprotective action of a new derivative of 3-methylxanthine (compound C-3) under conditions of acute disorder of cerebral circulation (ADCC) modeling by ischemic stroke type

Abstract

The purpose of the research was to study the antioxidant and neuroprotective properties of 8-benzilaminotheophyllinil-7-acetic acid (Compound C-3), as well as peculiarities of its action and advantages over the reference drugs. The work was performed on 80 white nonlinear rats of both sexes weighing 160-170 g. Bilateral ligation of the common carotid arteries was performed under thiopental (40 mg/kg) anesthesia. The investigated compound С-3 in a dose of 100 mg/kg and reference drugs in doses recommended by earlier studies (thiotriazolin 50 mg/kg, mexidol 200 mg/kg and 100 mg/kg citicoline) were administered endogastrically with a metal feeding tube for 4 days. Acute disorder of cerebral circulation (ADCC) modeling have led to disturbance in the system NO (increase in NOS activity and NO hyperproduction), deprivation in the activity of antioxidant enzymes (SOD, catalase and glutathione peroxidase) in the brain of experimental animals, and as a result, the activation of oxidative and nitrosative stress: increase in level of carbonylated proteinsaldehyde phenylhydrazone (APH) and ketone phenylhydrazone (KPH), markers of free radicals activation, and nitrotyrosine. 64 I.F. Belenichev et al. The introduction of 8-benzilaminotheophyllinil-7-acetic acid (Compound 3) in a dose of 100 mg/kg endogastrically for 4 days to rats with bilateral carotid artery occlusion resulted in inhibition of oxidative nitrosative stress: reduction in nitrotyrosine level by 51.1% (p<0.05), APH-59%, KPH-63%, nitrite anion-44.1%. The introduction of compound 3 (C-3) to the rats with ADCC led to increase in activity of antioxidant enzymes in the brain of animals on the 4th day of the experiment: SOD by 95.6%, catalase-78.4%, and glutathione peroxidase (GPx) by 82.3%. Antioxidant and neuroprotective action of C-3 exceeded piracetam and citicoline on its influence on the parameters of the antioxidant system and markers of oxidative and nitrosative stress as well as was superior or comparable to similar effects of thiotriazolin. Mechanism of antioxidant and neuroprotective action of C-3 is connected with the peculiarities of its chemical structure, and hydrazide of 8-benzilaminotheophyllinil-7-acetic acid play the role of "spin trap" interacting with NO.

Nitric Oxide in the Mechanisms of Cell Death and Cytoprotection

“…Administration of C-3 to animals with intracerebral hemorrhage (ICH) resulted in a significant decrease in the expression of neuronal nitric oxide synthase (nNOS) mRNA in the CA1 zone of the hippocampus by 95.3% compared to control values, along with an increase in nNOS mRNA expression relative to sham-operated animals. Moreover, the expression of inducible nitric oxide synthase (iNOS) mRNA decreased % following C-3 administration relative to the control and was at levels comparable to those of sham-operated animals [282][283][284]. Furthermore, the course administration of compound C-3 to animals with ICH led to a significant decrease in the activity of NOS, nitrites, and nitrotyrosine in brain mitochondria on the 4th day of the experiment, respectively.…”

Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection

“…The administration of C-3 to animals with intracerebral hemorrhage (ICH) resulted in a significant decrease in the expression of neuronal nitric oxide synthase (nNOS) mRNA in the CA1 zone of the hippocampus by 95.3% compared with the control values, along with an increase in nNOS mRNA expression relative to sham-operated animals. Moreover, the expression of inducible nitric oxide synthase (iNOS) mRNA decreased % following C-3 administration relative to the control and was at levels comparable to those of sham-operated animals [280][281][282]. Furthermore, the course administration of compound C-3 to animals with ICH led to a significant decrease in the activity of NOS, nitrites, and nitrotyrosine in brain mitochondria on the 4th day of the experiment, respectively.…”