Sphingolipidomics Investigation of the Temporal Dynamics after Ischemic Brain Injury

Abstract

Sphingolipids (SPLs) have been proposed as potential therapeutic targets for strokes, but no reports have ever profiled the changes of the entire range of SPLs after a stroke. This study applied sphingolipidomic methods to investigate the temporal and individual changes in the sphingolipidome including the effect of atorvastatin after ischemic brain injury. We conducted sphingolipidomic profiling of mouse brain tissue by liquid chromatography–electrospray ionization tandem mass spectrometry at 3 h and 24 h after 1 h of middle cerebral artery occlusion (MCAO), and SPL levels were compared with those of the Sham control group. At 3 h post-MCAO, ceramides (Cers) exhibited an increase in levels of long-chain Cers but a decrease in very-long-chain Cers. Moreover, sphingosine, the precursor of sphingosine-1-phosphate (S1P), decreased and S1P increased at 3 h after MCAO. In contrast to 3 h, both long-chain and very-long-chain Cers showed an increased trend at 24 h post-MCAO. Most important, the administration of atorvastatin improved the neurological function of the mice and significantly reversed the SPL changes resulting from the ischemic injury. Furthermore, we used plasma samples from nonstroke control and stroke patients at time points of 72 h after a stroke, and found a similar trend of Cers as in the MCAO model. This study successfully elucidated the overall effect of ischemic injury on SPL metabolism with and without atorvastatin treatment. The network of SPL components that change upon ischemic damage may provide novel therapeutic targets for ischemic stroke.

Ceramide Dynamics and Prognostic Value in Acute and Subacute Ischemic Stroke: Preliminary Findings in a Clinical Cohort

“…Our finding of increased circulating plasma levels of longchain ceramides, in our case specifically C18:0-ceramide, is in keeping with previously published preclinical and clinical studies [12,14]. Murine studies showed that plasma levels of long-chain ceramides even though rising in the first hours of AIS reached their peaks at least 24 h after ischemic insult [12] with similar findings in the ischemic tissue [11,29,30]. Our study is the first report to date which now recapitulates these animal findings in humans.…”

“…Contrary to the rising long-chain ceramide levels, we observed decreasing over time levels of very-long-chain ceramides which is also consistent with reported results [12,13]. Production of long-chain and very-long-chain ceramides is regulated by different ceramide synthases [35]; in contrast to long-chain ceramides, very-long-chain ceramides have been linked to cell proliferation and potentially neuroprotective effects during anoxia [35,36].…”

“…Elevated levels of specific ceramides and SPLs have been also associated with small vessel ischemic disease and white matter hyperintensity [9,10]. Several preclinical and clinical studies reported changes in plasma and/or cerebral levels of ceramides in acute stroke [11][12][13], with a recent case-control study proposing cut-off levels of specific ceramides as supplemental predictors of risk and severity of ischemic stroke [14]. Ceramides are evidently important players in the pathogenesis of acute cerebral ischemia; however, little is known about SPL and ceramide dynamics between acute and subacute stroke phases, which is crucial for applicability of proposed predictors as well as association between plasma ceramide levels and long-term neurological outcomes.…”

A Sphingosine 1-Phosphate Gradient Is Linked to the Cerebral Recruitment of T Helper and Regulatory T Helper Cells during Acute Ischemic Stroke

“…In that respect, various T H cell populations and T REG cells in the ischemic hemisphere have been found to amass on the first day after MCAO [ 53 , 54 , 55 ]. Moreover, it can be argued that neurons are an important source of S1P [ 56 ], suggesting that as cerebral blood flow (CBF) decreases and neuronal damage worsens, the release of S1P into the ischemic core could contribute to the maintained high S1P levels [ 40 , 57 ]. This, in turn, would establish a new S1P gradient allowing various immune cell populations to invade the peri-infarct cortex.…”

Plasma lipidomic analysis of sphingolipids in patients with large artery atherosclerosis cerebrovascular disease and cerebral small vessel disease

“…We noticed that there were several ceramides in common in the LAA cerebrovascular disease and age-related CSVD when they were compared with control, probably due to enrollment of patients with acute stroke. Studies have found several ceramides were increased after stroke [36,37]. However, there were no statistically significant differences in the proportion of patients with acute stroke between the LAA cerebrovascular disease and age-related CSVD groups.…”