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

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.

Recent Preclinical Insights Into the Treatment of Chronic Traumatic Encephalopathy

“…In order to avoid losing candidate therapies in translation, CTE research must not only address fundamental differences between human patients and animal models but also ensure the development of robust preclinical CTE models that may continue to build on pathomechanistic insights and candidate treatments. Currently, some preclinical models of CTE fail to demonstrate tau pathology (Pozdnyakov et al, 2019) or attain it without TBI (Morin et al, 2018). A variety of reliable models may be useful to encapsulate the heterogeneous nature of TBIs.…”

“…Across laboratories, several variations in the force, frequency, and total number of impacts in such models of CTE exist. In general, most employ a week-long exposure of daily impacts (for a total of 7 exposures, Kondo et al, 2015;Pozdnyakov et al, 2019). A number of procedures have been developed to induce TBI via compressive, focal, or rotational FIGURE 2 | Two main approaches utilized preclinically to apply standardized and precise trauma to rodents include the stereotaxic approach (left) where a head-restrained rodent receives a vertically oriented impact of a specific velocity, force, and dwell time.…”

“…The severity of CTE is dependent on both magnitude and frequency of rmTBI. Many CTE models (Kondo et al, 2015;Pozdnyakov et al, 2019;Rubenstein et al, 2019) induce 5-10 concussive TBIs over a period of a week. While practical in a laboratory setting, this methodology may not be translationally accurate as most reported cases of human CTE occur in individuals with years of participation in a contact sport and include individuals who have only received sub-concussive impacts (Sundman et al, 2015).…”

“…Across laboratories, several variations in the force, frequency, and total number of impacts in such models of CTE exist. In general, most employ a week-long exposure of daily impacts (for a total of 7 exposures, Kondo et al, 2015 ; Pozdnyakov et al, 2019 ). A number of procedures have been developed to induce TBI via compressive, focal, or rotational forces.…”

“…Intraperitoneal administration of one such pyrimidine derivative abbreviated "OCH" (4-{2-[2-(3,4-dimethoxyphenyl)-vinyl]-6-ethyl-4-oxo-5-phenyl-4H-pyrimidine-1-Il}benzsulfamide) during a rmTBI rat model provided significant preservation of mitochondrial respiration and glycolytic activity. Additionally, OCH-treated rats displayed a reduction in CTE-associated markers GFAP, NSE, S100 beta, and beta-amyloid, together with improvements in sensorimotor control assessed through a beam-walking task (Pozdnyakov et al, 2019). Another promising strategy to control neuroinflammation following rmTBI may be through modulation of arachidonic acid metabolism.…”