Integrating Bioinformatics To Identify Potential Cytokines ALPL /TNAP In Children With Spastic Cerebral Palsy

Abstract

Background: Several published studies have shown the significance of neuroinflammation in the pathophysiological development of cerebral palsy (CP). However, the underlying molecular mechanisms by which neuroinflammation is associated with brain injury in CP remain poorly understood. Spastic CP is the most common form of CP, comprising 80% of all cases. Therefore, identifying patterns of inflammatory and related biomarkers would serve to understand the etiology of spastic CP.Methods: Related clinical parameters were assessed in 18 children with spastic CP and 20 age-matched healthy individuals. Blood samples of children with spastic CP and controls were analyzed with integrated transcriptomics and proteomics profiling to detect common differentially expressed mRNAs and proteins. Hypoxic ischemic encephalopathy was induced in postnatal day 7 rat pups. Behavioral testing was performed postinjury, and then, the differentially expressed markers and inflammatory cytokines were verified in the peripheral blood and cerebral cortex of the CP model rats by ELISA and Western blot. Independent sample t-tests, one-way analysis of variance and the Pearson correlation were used for statistical analysis.Results: Through proteomic and transcriptome analysis, we identified common differentially expressed genes. Among them, ALPL, encoding tissue nonspecific alkaline phosphatase (TNAP), was downregulated in spastic CP. In addition, compared with those of the corresponding controls, significantly lower mRNA and protein levels of TNAP were found in children with CP and the CP model rats. In contrast, compared with the control rats, the model rats demonstrated a significant increase in osteopontin and proinflammatory biomarkers, such as interleukin (IL)-6, IL-17, and C-reactive protein (CRP), in both the plasma and cerebral cortex, while serum 25 hydroxyvitamin D and anti-inflammatory cytokines such as IL-10 were significantly decreased. Additionally, the level of serum TNAP was correlated with the content of serum CRP and IL-10 in model rats.Conclusion: These results suggest that TNAP, the gene expression product of ALPL, is closely related to the pathogenesis and development of spastic CP, particularly in the upregulation of proinflammatory cytokines and the downregulation of anti-inflammatory cytokines, which contribute to the occurrence of inflammation in the progression of spastic CP.