Aldo-Keto Reductase 1C15 Characterization and Protection in Ischemic Brain Injury.
Tuo YangQianqian LiGeorge FadoulNour AlraqmanyMilos IkonomovicFeng ZhangPublished in: Antioxidants (Basel, Switzerland) (2023)
Aldo-keto reductase (AKR) 1C15, a member of the AKR superfamily, was recently identified and cloned, and reported to alleviate oxidative stress in endothelial cells in rodent lungs. However, its expression and role in the brain and ischemic brain diseases have not been investigated. AKR1C15 expression was detected with real-time PCR. Mouse ischemic stroke and ischemic preconditioning (IPC) were established with middle cerebral artery occlusion (MCAO) for 1 h or 12 min, respectively. Recombinant AKR1C15 was administered intraperitoneally, and stroke outcome was evaluated with neurobehavioral tests and infarct volumes. Rat primary brain cell cultures were subjected to oxygen-glucose deprivation (OGD) to mimic ischemic injury. Cell survival or in vitro blood-brain barrier (BBB) permeability was measured, and nitric oxide (NO) release was detected. Immunostaining and Western blotting were used to evaluate oxidative-stress-related protein expression. AKR1C15 administration decreased the infarct volume and neurological deficits 2d post-stroke, and its early (1-h) administration after IPC abolished the protection of IPC against stroke. In rat primary brain cell cultures, AKR1C15 was most abundantly expressed in brain microvascular endothelial cells (BMVECs) and microglia. Its expression decreased upon OGD in most cell types except for BMVECs and microglia. In primary neuronal cultures, AKR1C15 treatment prevented OGD-induced cell death accompanied by decreased levels of 4-hydroxynonenal, 8-hydroxy-2'-deoxyguanosine, and heme oxygenase-1. In BMVEC cultures, AKR1C15 treatment protected against OGD-induced cell death and in vitro BBB leakage. In primary microglial cultures, AKR1C15 reduced the release of NO upon proinflammatory stimulation. Our results provide a characterization of the novel antioxidant AKR1C15 and demonstrate its protective role against ischemic injury, both in vivo and in vitro. AKR1C15 may be a promising agent for ischemic stroke treatment.
Keyphrases
- cerebral ischemia
- blood brain barrier
- brain injury
- subarachnoid hemorrhage
- oxidative stress
- cell death
- endothelial cells
- ischemia reperfusion injury
- poor prognosis
- nitric oxide
- diabetic rats
- resting state
- white matter
- single cell
- middle cerebral artery
- atrial fibrillation
- metabolic syndrome
- acute myocardial infarction
- inflammatory response
- cell therapy
- multiple sclerosis
- bone marrow
- induced apoptosis
- blood pressure
- mass spectrometry
- stem cells
- cell proliferation
- left ventricular
- transcription factor
- neuropathic pain
- spinal cord
- south africa
- traumatic brain injury
- adipose tissue
- pi k akt
- long non coding rna
- drug induced
- coronary artery disease
- heat shock