Inhibition of histone deacetylase 3 by MiR-494 alleviates neuronal loss and improves neurological recovery in experimental stroke

Abstract

HDAC3 is an essential negative regulator of neuronal plasticity and memory formation. Although a chemical inhibitor has been invented, little is known about its endogenous modulators. We explored whether miR-494 affects HDAC3-mediated neuronal injury following acute ischemic stroke. A substantial increase in plasma miR-494 was detected in AIS patients and was positively associated with the mRS at one year after symptom onset. The miR-494 levels were transiently increased in the infarcted brain tissue of mice. In contrast, miR-494 levels were reduced in neurons but increased in the medium after OGD. Intracerebroventricular injection of miR-494 agomir reduced neuronal apoptosis and infarct volume at the acute stage of MCAO, promoted axonal plasticity and long-term outcomes at the recovery stage, suppressed neuronal ataxin-3 and HDAC3 expression and increased acetyl-H3K9 levels in the ipsilateral hemisphere. In vitro studies confirmed that miR-494 posttranslationally inhibited HDAC3 in neurons and prevented OGD-induced neuronal axonal injury. The HDAC3 inhibitor increased acetyl-H3K9 levels and reversed miR-494 antagomir-aggravated acute cerebral ischemic injury, as well as brain atrophy and long-term functional recovery. These results suggest that miR-494 may serve as a predictive biomarker of functional outcomes in AIS patients and a potential therapeutic target for the treatment of ischemic stroke.

miRNA-Coordinated Schizophrenia Risk Network Cross-Talk With Cardiovascular Repair and Opposed Gliomagenesis

“…Importantly, in the case of the latter miRNA, protection against the development of the tumors comes at a cost of elevated susceptibility to neurotoxicity, after exposure to ischemia/ reperfusion for example. Notably, knockdown of hsa-miR-494-5p reverses the neurotoxic phenotype in multiple models (Song et al, 2017;Deng et al, 2019;Zhao et al, 2019a;Zhao et al, 2019b). Hsa-miR-494-5p-dependent antagonistic relationships between gliomagenesis and neurotoxicity are intriguing, as they support previously noted decrease in odds of the development of brain tumors in patients with schizophrenia (Grinshpoon et al, 2005;Levav et al, 2007;.…”

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

“…HDAC3 inhibition exerted protective effects against diabetic stroke via the enhancement of oxidative stress, inhibition of apoptosis, and improvement of autophagy, all of which might be mediated by the upregulation of Bmal1 [50]. Furthermore, miR-494 in MCAO mouse model produced neuroprotective effects by reducing the expression levels of HDAC3 in neurons [51].…”

“…HDAC3 inhibitors acted on several cell types in the CNS, including neurons, astrocytes, and microglia [52]. miR-193b-3p and its target HDAC3 may also be regulated by other mechanisms, including autophagy or apoptosis [49,51], possibly leading to neuroprotective effects. Further studies are required to account for the beneficial mechanisms of miR-193b-3p in vitro.…”

Intravenous antagomiR-494 lessens brain-infiltrating neutrophils by increasing HDAC2-mediated repression of multiple MMPs in experimental stroke

“…As discussed above, multiple MMPs could be regulated by the HDAC family, including HDAC1, HDAC2, HDAC3, and HDAC7. Our previous study suggested that HDAC3 was a direct target of miR-494 [34]. It is possible that miR-494 could regulate these MMPs by targeting HDAC3 or other members of the HDAC family.…”