Effects of pyrimidine nucleotides on local cerebral blood flow under conditions of impaired circulation

Background: The search for new agents to correct cerebrovascular disorders remains an important task in neuroscience, given the prevalence and increasing incidence of ischemic brain injury and its consequences. In this regard, endogenous biologically active compounds, especially neurochemical components of brain tissue, are of particular interest. Based on these findings, the importance of nucleotides in regulating brain activity has been confirmed. Pyrimidine nucleotides such as cytidine and uridine are essential endogenous compounds that play an important role in nucleic acid synthesis (DNA/RNA), cellular energy transfer, and neuronal membrane phospholipid synthesis, while also acting as signaling molecules. It has been shown that the levels of these compounds decline under ischemic conditions. Cytidine, in the form of cytidine triphosphate (CTP), and uridine, which is first converted to uridine triphosphate (UTP) and then to CTP, contribute to the biosynthesis of phosphatidylcholine and phosphatidylethanolamine in the brain via the Kennedy pathway. Due to their key role in this pathway, the therapeutic potential of cytidine and uridine has been evaluated in neurological disorders such as acute or chronic brain injury and cognitive impairment. Scientific evidence indicates that dietary pyrimidine nucleotides, particularly uridine and its derivatives, exert neuroprotective and neuroregenerative effects, making them promising bioactive compounds for neurofunctional foods and nutraceutical interventions. The combination of uridine and cytidine has been shown to support peripheral nerve regeneration, suggesting a possible role in the regulation of cerebral blood flow. Therefore, the effects of endogenous pyrimidine nucleotides, cytidine and uridine, as well as their combination, were investigated .on cerebral circulation. Objective: To investigate the effects of cytidine-5-monophosphate (CMP), uridine diphosphate (UDP)-choline, and their combination on impaired cerebral circulation caused by brain ischemia. Results: The conducted experiments showed that intraperitoneal injection of CMP at a dose of 10mg/kg after RCCA occlusion did not produce any significant changes in cerebral blood flow compared with the ischemic level. Under conditions of impaired cerebral circulation, UDP-choline administration at a dose of 10mg/kg following RCCA occlusion resulted in an improvement in cerebral blood flow. The result showed that, 60 minutes after occlusion, local cerebral blood flow exceeded the value recorded after occlusion by 35,37 % (p<0.05). Intraperitoneal injection of the investigated nucleotides combination at a doses 1,6 mg/kg CMP and 1mg/kg uridine phosphate salts, as well as 5 mg/kg CMP and 3mg/kg uridine phosphate salts in rats subjected to RCCA occlusion resulted in stimulation of local cerebral blood flow by approximately 32.65% and 62%, respectively after 60 minutes (compared to RCCA occlusion value, p<0.05). The tested combinations of uridine and cytidine at the same doses were not accompanied by any significant changes in arterial pressure or heart rate. Conclusion: The present study demonstrates the potential of the pyrimidine nucleotides cytidine and uridine as effective agents for improving cerebral blood flow under ischemic conditions. Our results indicate that the uridine nucleotide plays an important role in this. The combination of cytidine and uridine also demonstrated cerebrovascular efficacy. Notably, these effects of pyrimidines were not accompanied by any significant changes in arterial pressure or heart rate. These results support the potential use of a combination of uridine and cytidine phosphates as agents for improving cerebral blood flow. The dose-dependent improvement observed with the combined nucleotide treatment suggests that uridine-containing formulations may provide greater cerebrovascular benefit than CMP administered alone. Because these effects occurred without detectable systemic hemodynamic changes, the findings support further investigation of pyrimidine combinations as targeted nutritional or pharmacological strategies for ischemia-related cerebral circulatory impairment. Keywords: pyrimidine nucleotide, uridine, cytidine, brain blood flow, cerebral ischemia