Identification of miRNAs That Mediate Protective Functions of Anti-Cancer Drugs During White Matter Ischemic Injury

Baltan, Selva; Sandau, Ursula S.; Brunet, Sylvain; Bastian, Chinthasagar; Tripathi, Ajai K.; Nguyen, Hung; Liu, Helen; Saugstad, Julie A.; Zarnegarnia, Yalda; Dutta, Ranjan

doi:10.1177/17590914211042220

Cited by 9 publications

(10 citation statements)

References 106 publications

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Section: Discussionmentioning

confidence: 65%

“…MiRNAs are promising candidates for biomarkers of injury and therapeutic interventions as they are readily detected in body fluids. We also show that CX-4945 regulates a group of murine-associated viral miRNAs (for example see Table 1 ) which may justify the use of CX-4945 in clinical trials for Covid19 patients ( Baltan et al, 2021 ) ( ClinicalTrials.gov Identifier: NCT04663737). Finally, our findings may have mechanistic and therapeutic implications for dementia, Alzheimer’s disease, multiple sclerosis, periventricular leukomalacia, and Parkinson’s disease that involve WM injury.…”

Section: Discussionmentioning

confidence: 82%

“…We propose that these miRNAs may be associated with the beneficial effects of CX-4945. In agreement, miR-501-3p is expressed in neurons which in optic nerve (pure WM tract without neuronal cell body) infers axonal expression ( Baltan et al, 2021 ). Because CK2 inhibition promotes axon function by preserving axonal mitochondria ( Bastian et al, 2019b ), we hypothesize that CK2 inhibition exerts white matter protection by regulating miR-501-3p.…”

Section: Introductionmentioning

confidence: 75%

“…Therefore, in our recent study, we characterized miRNA profiles in optic nerve following ischemia using the NanoString nCounter ® miRNA Expression Panel. Together with in situ hybridization, and in silico KEGG pathway analysis, we show that the most abundant miRNAs in the optic nerve are expressed in astrocytes, and oxygen-glucose deprivation (OGD) differentially regulates miRNA expression in the optic nerve ( Baltan et al, 2021 ).…”

Section: Introductionmentioning

confidence: 96%

“…Some miRNAs were reciprocally regulated by OGD or OGD and CX-4945 application. For instance, OGD and CX-4945 selectively modulated miR-1937a, miR-1937b, miR-1959, miR-200a, miR-501-3p, and miR-654-3p ( Table 1 ) ( Baltan et al, 2021 ). We propose that these miRNAs may be associated with the beneficial effects of CX-4945.…”

Section: Introductionmentioning

confidence: 99%

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Casein Kinase 2 Signaling in White Matter Stroke

Nguyen

Zhu

Baltan

2022

Front. Mol. Biosci.

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The growth of the aging population, together with improved stroke care, has resulted in an increase in stroke survivors and a rise in recurrent events. Axonal injury and white matter (WM) dysfunction are responsible for much of the disability observed after stroke. The mechanisms of WM injury are distinct compared to gray matter and change with age. Therefore, an ideal stroke therapeutic must restore neuronal and axonal function when applied before or after a stroke, and it must also protect across age groups. Casein kinase 2 (CK2), is expressed in the brain, including WM, and is regulated during the development and numerous disease conditions such as cancer and ischemia. CK2 activation in WM mediates ischemic injury by activating the Cdk5 and AKT/GSK3β signaling pathways. Consequently, CK2 inhibition using the small molecule inhibitor CX-4945 (Silmitasertib) correlates with preservation of oligodendrocytes, conservation of axon structure, and axonal mitochondria, leading to improved functional recovery. Remarkably, CK2 inhibition promotes WM function when applied after ischemic injury by specifically regulating the AKT/GSK3β pathways. The blockade of the active conformation of AKT confers post-ischemic protection to young and old WM by preserving mitochondria, implying AKT as a common therapeutic target across age groups. Using a NanoString nCounter miRNA expression profiling, comparative analyses of ischemic WM with or without CX-4945 treatment reveal that miRNAs are expressed at high levels in WM after ischemia, and CX-4945 differentially regulates some of these miRNAs. Therefore, we propose that miRNA regulation may be one of the protective actions of CX-4945 against WM ischemic injury. Silmitasertib is FDA approved and currently in use for cancer and Covid patients; therefore, it is plausible to repurpose CK2 inhibitors for stroke patients.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Casein Kinase 2 Signaling in White Matter Stroke

Nguyen

Zhu

Baltan

2022

Front. Mol. Biosci.

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Temporal expression profiles of microRNAs associated with acute phase of brain ischemia in gerbil hippocampus

Hamada,

Takata,

Iwama

et al. 2024

Heliyon

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Loss of microRNA-15a/16-1 function promotes neuropathological and functional recovery in experimental traumatic brain injury

Zhou,

Li,

Qiu

et al. 2024

JCI Insight

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The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir–treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.

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Identification of miRNAs That Mediate Protective Functions of Anti-Cancer Drugs During White Matter Ischemic Injury

Cited by 9 publications

References 106 publications

Casein Kinase 2 Signaling in White Matter Stroke

Casein Kinase 2 Signaling in White Matter Stroke

Temporal expression profiles of microRNAs associated with acute phase of brain ischemia in gerbil hippocampus

Loss of microRNA-15a/16-1 function promotes neuropathological and functional recovery in experimental traumatic brain injury

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