Abstract
The limited accessibility to the brain has turned the cerebrospinal fluid (CSF) into a valuable source that may contribute to the complete understanding of the stroke pathophysiology. Here we have described the CSF proteome in the hyper-acute phase of cerebral ischemia by performing an aptamer-based proteomic assay (SOMAscan) in CSF samples collected before and 30 min after male Wistar rats had undergone a 90 min Middle Cerebral Artery Occlusion (MCAO) or sham-surgery. Proteomic results indicated that cerebral ischemia acutely increased the CSF levels of 716 proteins, mostly overrepresented in leukocyte chemotaxis and neuronal death processes. Seven promising candidates were further evaluated in rat plasma and brain (CKB, CaMK2A, CaMK2B, CaMK2D, PDXP, AREG, CMPK). The 3 CaMK2 family-members and CMPK early decreased in the infarcted brain area and, together with AREG, co-localized with neurons. Conversely, CKB levels remained consistent after the insult and specifically matched with astrocytes. Further exploration of these candidates in human plasma revealed the potential of CKB and CMPK to diagnose stroke, while CaMK2B and CMPK resulted feasible biomarkers of functional stroke outcome. Our findings provided insights into the CSF proteome following cerebral ischemia and identified new outstanding proteins that might be further considered as potential biomarkers of stroke.
Highlights
Stroke is one of the most frequent causes of mortality worldwide and is still considered the leading cause of permanent adult disability in developed countries[1]
The activation and accumulation of leukocytes, and several inflammatory processes related to the infiltration of immune cells into the brain, including immune cells movement and leukocytes chemotaxis, were largely represented in the cerebrospinal fluid (CSF) from Middle Cerebral Artery Occlusion (MCAO) animals
Particular interest was directed towards the specific biological processes encompassed in the category of neurological disease, since molecular mechanisms of cell death of brain cells, of cortical neurons, were the foremost annotations reported in the CSF at this early time-point after ischemia (Fig. 2A)
Summary
Stroke is one of the most frequent causes of mortality worldwide and is still considered the leading cause of permanent adult disability in developed countries[1]. CSF evaluation in the field of ischemic stroke might provide additional insights about the pathogenic alterations underlying cerebral ischemia, and may contribute to the complete interpretation of stroke pathology and the identification of potential therapeutic targets for its pharmacological modulation[9]. In this context, the use of pre-clinical models has proven to be notably relevant to examine those biological fluids that are difficult to obtain from human, as for the case of CSF
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