In this study, 322 patients with acute pontine infarction were followed up for one year. The results showed that SUA/SCr at admission was independently related to the poor prognosis of AIPI at 1 year. In addition, age, baseline NIHSS and fasting blood glucose were closely related to poor prognosis. Therefore, the low level of SUA/SCr may be a potential predictor of poor long-term prognosis of AIPI, and SUA/SCr may have a neuroprotective effect in AIPI.
The results of previous studies on the incidence, severity, and prognostic correlation between SUA and AIS, especially those involving the prognosis of AIS, are highly controversial. Wu et al. found [15] that a low level of SUA is an independent predictor of adverse clinical outcomes after one year of cerebral infarction, and it is independently related to the occurrence of vascular events within one year of cerebral infarction. The results of Wang et al. Show [16] that a high SUA level is an important protective factor in patients with the large-artery atherosclerosis subtype and male AIS. Chamorro et al. [17] showed that SUA in AIS may reduce the infarct volume. These studies all support the idea that SUA is beneficial to a good prognosis of AIS. However, a prospective study showed that SUA is an indicator of a poor outcome in AIS [18]. In a prospective study involving Caucasian populations [19], Seet et al. assigned AIS patients into four groups according to SUA level and concluded that SUA had a U-shaped correlation with the clinical outcome after stroke. Compared with patients in the middle two groups, patients in the lowest SUA level group and the highest group had the worst clinical prognosis. The reason for these differences may be that SUA is greatly influenced by renal function.
High SUA is not only a risk factor for renal insufficiency [20] but also a complication of renal insufficiency. SUA levels are affected by renal excretion, and the relationship between them is complex, interdependent and interactive. Renal insufficiency is a risk factor for poor prognosis of AIS [21]. Therefore, renal insufficiency is the main interfering factor that causes the controversial role of SUA in the prognosis of AIS. In some studies, the interference of renal function status led to inconsistent SUA results and poor prognosis, such as a positive correlation, no correlation and U-shaped correlation. The research of Arévalo-Lorido and others supports this result. The results show that high SUA is beneficial to the good prognosis of stroke with or without chronic kidney disease, but the result is more important in patients without chronic kidney disease [6]. The existence of chronic kidney disease weakens the protective effect of high SUA. Based on this theory, a new uric acid marker, SUA/SCr, was found to reduce interference of renal function with SUA and possibly have more advantages than SUA alone in terms of disease pathogenesis, severity and prognosis judgment. Previous studies have confirmed the relationship between this new index and many diseases, including metabolic syndrome, NAFLD and cardiovascular diseases, and indicated that SUA/SCr has high clinical application value. Among 1277 participants, SUA/CR in middle-aged and elderly people was independently related to the risk of metabolic syndrome [22]. Studies in Korean, Chinese and American populations have confirmed that SUA/SCr is positively correlated with the incidence of NAFLD [9, 23, 24]. Wang et al. found that SUA/SCr increased the risk of cardiovascular disease and stroke [25].
Some studies have also confirmed that SUA/SCr is related to the prognosis of cerebral infarction. Sun et al. showed a positive correlation between SUA/SCr and the risk of recurrence in a study on the risk of recurrent stroke in young adults [11]. Another study showed that SUA/SCr is an independent predictor of good prognosis 3 months and 1 year after AIS, and its predictive ability is stronger than that of SUA and serum creatinine alone [10]. In our study, it was found that differences in both SUA and SUA/SCr were statistically significant in univariate analysis. Further multivariate analysis revealed that only SUA/SCr was related to poor prognosis, and Spearman correlation analysis further confirmed that SUA/SCr was negatively related to poor prognosis. Therefore, high SUA/SCr is an independent predictor of good neurological recovery at 1 year after AIPI.
Our findings further support the idea that in AIPI, SUA still plays a cerebral protective role in neurological recovery. This finding may be related to the antioxidant and anti-inflammatory effects of SUA, which is one of the products produced by purine metabolism; approximately 2/3 of the free radicals in the body can be scavenged by SUA [26], which is recognized as the largest natural antioxidant in the human body. A constructed animal model of middle cerebral artery occlusion showed [27] that UA stimulated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus under stress, increased Nrf2 protein expression, increased the expression of genes related to the original antioxidant response element (ARE), and inhibited lipid, protein, and DNA peroxidation in cortical cells; moreover, UA stimulated Nrf2 and upregulated the expression of heme oxygenase (HO)-1, which exerted antioxidant and anti-apoptotic protective effects, resulting in the reduction of cerebral infarct size, as well as a reduction in the extent of neurological deficits and brain edema. Another animal model experiment of ischemia‒reperfusion confirmed [28] that elevated uric acid concentration in the infarct zone not only reduces oxidative stress but also reduces MMP9/TIMP-1 ratio expression, attenuates disruption of the blood‒brain barrier, induces IL6 expression, regulates microglia activation, and inhibits inflammatory responses, ultimately leading to a reduction in the volume of cerebral infarction, edema, and neurological deficits. SUA therapy has also been shown in clinical studies to reduce the incidence of early ischemic worsening (EIW) in AIS patients treated with thrombolysis. [29]. Therefore, high levels of SUA/SCr attenuate neural tissue damage after stroke mainly through antioxidant and anti-inflammatory effects, reducing oxidative stress, the inflammatory response and blood‒brain barrier disruption of brain tissue, thus promoting a good clinical outcome.
In addition, our study found that patients with AIPI had higher NIHSS scores on admission and poorer clinical outcomes at 1 year. This is consistent with previous findings [4]. In AIPI, the distribution of the lesions was as high as approximately 60% in the paracentral area of the pontine pons [30], which is also the pathway of the corticospinal tract, possibly explaining why with higher NIHSS scores in AIPI, the corticospinal tracts are likely to be more heavily involved with a poorer long-term prognosis. Therefore, high NIHSS score may be a valid predictor of long-term poor outcome in AIPI.
Our study also showed that higher FBG levels were associated with poor long-term prognosis in AIPI. Recent studies have shown [31] that higher FBG is an independent risk factor for poor outcome in anterior circulation ischemic stroke. Bi et al. showed [32] that higher FBG increases the risk of early neurological deterioration in AIPI. The exact mechanism by which hyperglycemia is associated with poor long-term prognosis in AIPI is unclear; hyperglycemia may exacerbate brain tissue damage through a variety of pathways, such as abnormal cerebral energy metabolism, production of reactive oxygen species and oxidative stress, disruption of the blood‒brain barrier, increased cerebral edema, decreased endothelial vasodilatation, and inflammatory responses [33].
Finally, our study also found a significant positive correlation between age and poor long-term prognosis in AIPI. Mortality and disability rates were higher in older patients than in younger patients. Advanced age and coexisting infections, multiple organ insufficiency, and other diseases may explain this phenomenon.
There are some flaws in this study. First, this study is a single-center study with a small sample, which may lead to selection bias in the study population. Second, factors such as nutritional status and lifestyle were not included in the statistical analysis; their absence may have had a confounding effect on the study results. In addition, we only measured SUA levels within 24 hours of admission and did not dynamically monitor SUA levels to further analyze the correlation between SUA and stroke prognosis at each period. Finally, our study did not address the pathological mechanisms of SUA/SCr associated with AIPI prognosis, which need to be further analyzed in animal experiments. In the future, to address the above limitations, more comprehensive prospective, multicenter, and large-sample studies will be designed to further explore the correlation between SUA/SCr and AIPI prognosis.