The Administration of the New Pyrimidine Derivative-4-{2-[2-(3,4-Dimethoxyphenyl)-Vinyl]-6-Ethyl-4-Oxo-5-Phenyl-4H-Pyrimidine-1-Il}Benzsulfamide Restores the Activity of Brain Cells in Experimental Chronic Traumatic Encephalopathy by Maintaining Mitochondrial Function.

Dmitry I Pozdnyakov,Andey V Voronkov,Tat’Yana G Kovaleva,Kirill A Miroshnichenko

doi:10.3390/medicina55070386

Abstract

Background and objectives: To evaluate the effect of a new pyrimidine derivative on the change of mitochondrial function in experimental chronic traumatic encephalopathy. Materials and methods: The study was performed on male mice of the BALB/c line (acute toxicity was assessed) and male rats of the Wistar line, which were modeled chronic traumatic encephalopathy by the method of free fall of the load (weight 150 g from a 50 cm height). The injury to rats was reproduced once a day for 7 days. Further, cognitive functions, changes in sensorimotor deficiency, cerebral blood flow, neuron-specific enolase(NSE), S100β, glial fibrillary acidic protein (GFAP) (in blood serum) and β-amyloid, adenosine triphosphate (ATP) (in brain tissue supernatant) were evaluated. Mitochondrial respiration was also measured. Choline alfoscerate (100 mg/kg) was used as a reference drug. Results: The study found that the use of a new pyrimidine derivative contributed to the preservation of the mitochondrial respirometric function and cognitive functions in rats. In addition, against the administration of test-object marked increase in the concentration of ATP, the velocity of cerebral blood flow was 4.2 times (p < 0.05) and 35.6% (p < 0.05), respectively, as well as reduced concentration and GFAP, NSE, S100β, β-amyloid and sensorimotor deficit at 2.7 (p < 0.05) times; 2 times (p < 0.05); 2.4 times (p < 0.05); of 30.4% (p < 0.05 and 46.5% (p < 0.05), respectively. The LD50 (per os) for the test-object was 4973.56 ± 573.72 mg/kg. Conclusion: Based on the obtained data, high therapeutic efficacy and low systemic toxicity of the application are assumed 4-{2-[2-(3,4-dimethoxyphenyl)-vinyl]-6-ethyl-4-oxo-5-phenyl-4H-pyrimidine-1-Il}benzsulfamide in chronic traumatic encephalopathy.

Highlights

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs as a result of repetitive episodes of mild or moderately severe traumatic brain injury, the clinical manifestations of which are cognitive, sensorimotor and neurological deficits
The first reports on the development of CTE are dated to the first half of the 20th century when this pathology was diagnosed in professional boxers and was called “dementia pugilistica” [1]
In a study conducted by Kondo et al 2015, it was shown that the use of specific antibodies to tau-protein reduced progressive tau-pathology after a traumatic brain injury [19]

Summary

Introduction

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs as a result of repetitive episodes of mild or moderately severe traumatic brain injury, the clinical manifestations of which are cognitive, sensorimotor and neurological deficits. The pathogenetic basis of CTE is the destruction of neurons as a result of repeated exposure to traumatic factors and the accumulation of β-amyloid in the brain tissue [4]. In this case, as noted by McKee et al., 2013, the deposition of β-amyloid plaques in the brain leads to generalized vasculopathy, resulting in increased ischemic-hypoxic processes in the brain tissues [5]. To evaluate the effect of a new pyrimidine derivative on the change of mitochondrial function in experimental chronic traumatic encephalopathy. Results: The study found that the use of a new pyrimidine derivative contributed to the preservation of the mitochondrial respirometric function and cognitive functions in rats

Methods

Results

Discussion

Conclusion