Transient Focal Cerebral Ischemia Leads to miRNA Alterations in Different Brain Regions, Blood Serum, Liver, and Spleen

Abstract

Ischemic stroke is characterized by an occlusion of a cerebral blood vessel resulting in neuronal cell death due to nutritional and oxygen deficiency. Additionally, post-ischemic cell death is augmented after reperfusion. These events are paralleled by dysregulated miRNA expression profiles in the peri-infarct area. Understanding the underlying molecular mechanism in the peri-infarct region is crucial for developing promising therapeutics. Utilizing a tMCAo (transient Middle Cerebral Artery occlusion) model in rats, we studied the expression levels of the miRNAs (miR) 223-3p, 155-5p, 3473, and 448-5p in the cortex, amygdala, thalamus, and hippocampus of both the ipsi- and contralateral hemispheres. Additionally, the levels in the blood serum, spleen, and liver and the expression of their target genes, namely, Nlrp3, Socs1, Socs3, and Vegfa, were assessed. We observed an increase in all miRNAs on the ipsilateral side of the cerebral cortex in a time-dependent manner and increased miRNAs levels (miR-223-3p, miR-3473, and miR-448-5p) in the contralateral hemisphere after 72 h. Besides the cerebral cortex, the amygdala presented increased expression levels, whereas the thalamus and hippocampus showed no alterations. Different levels of the investigated miRNAs were detected in blood serum, liver, and spleen. The gene targets were altered not only in the peri-infarct area of the cortex but selectively increased in the investigated non-affected brain regions along with the spleen and liver during the reperfusion time up to 72 h. Our results suggest a supra-regional influence of miRNAs following ischemic stroke, which should be studied to further identify whether miRNAs are transported or locally upregulated.

Intracranial self-stimulation reverses impaired spatial learning and regulates serum microRNA levels in a streptozotocin-induced rat model of Alzheimer disease

“…57 Here, serum levels of miR-181c were lower in streptozotocin-treated rats than in control rats, with no significant alteration observed when rats in the STZ+ICSS group were compared with control rats. Considering the studies that have shown associations between serum and tissue miRNA levels 58,59 and based on our previous findings showing upregulation of hippocampal miR-181c levels by MFB-ICSS in healthy rats, 9 we hypothesize that MFB-ICSS can reverse the memory and learning deficits in streptozotocintreated rats by modulating levels of hippocampal miR-181c. To examine this hypothesis, further research should aim to induce inhibition of miR-181c in the hippocampus of rats with AD-like pathology and analyze the effects of MFB-ICSS on behaviour and on the expression of its putative targets.…”

Are Ischemic Stroke and Alzheimer’s Disease Genetically Consecutive Pathologies?

“…For IS, miRNA profiles are provided in the blood of patients [114,115] and in brain tissues [116]. MiRNA profiles were also obtained for rats after tMCAO in the blood and in various tissues, including different areas of the brain [117]. Profiles are also available for oxygen glucose deprivation/re-oxygenation (ODG/R)-induced cell cultures, including astrocytes [118].…”

“…One model may show the compensation state of some pathological process, while another will show the decompensation state. As an example, even in one animal model we have significant spatial [117] and temporal [156] transcriptomic changes.…”

Molecular Signaling in Stroke

“…Early studies have focused on the role of non-coding RNAs by showing that targeting specific microRNAs could potentially be a new avenue for developing effective stroke therapies [ 6 , 7 ]. Voelz et al, 2022 [ 8 ], studied the changes in miRNA expression in various tissues after an episode of transient focal cerebral ischemia (TFCI). The authors analyzed the miRNA expression in different brain regions, blood serum, liver, and spleen of rats that underwent TFCI and compared it to a control group.…”