The protective mechanism of protein kinase R to inhibit neuronal ferroptosis in cerebral injury from subarachnoid hemorrhage

Abstract

To investigate the role and mechanism of protein kinase R (PKR) in subarachnoid hemorrhage (SAH)-mediated ferroptosis.Methods: A rat SAH model was constructed and treated with PKR inhibitor C16 to observe SAH and neurological impairment in rats and to detect malonaldehyde (MDA), iron ions content, ferritin heavy polypeptide 1 (FTH1) and glutathione peroxidase 4 (GPX4), and other related ferroptosis indicators in brain tissue. RNA sequencing analysis was used to investigate the mechanism of PKR, affecting the ferroptosis network of SAH.Results: SAH caused severe fundic hemorrhage, neurological impairment, MDA and iron ion accumulation, and significant decrease in GPX4 and FTH1 levels in rats.C16 treatment significantly improved the above signs caused by SAH. By RNA-seq analysis, brain tissue of SAH-treated rats with SAH and C16 differentially expressed mRNA target genes enriched in stress response and organic developmental signaling pathways. Conclusion:Inhibition of PKR may improve cerebral injury after SAH by inhibiting ferroptosis, and RNA sequencing staged its mechanism of action may be related to the stress response.

Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes

“…The depletion of GSH [ 335 , 344 , 345 ] and the reduction of GPX4 [ 335 , 345 , 346 , 347 , 348 ] induced ferroptosis after SAH, leading to EBI‐SAH. The overexpression of GPX4 ameliorates ferroptosis‐mediated EBI‐SAH, evidenced by reduced LPO and cell death in both in vitro and in vivo experimental SAH models, and decreased brain edema and neurological deficits after SAH.…”

“…Astragaloside IV, [ 335 ] PKR inhibitor C16, [ 347 ] netrin‐1, [ 398 ] quercetin, [ 399 ] taurine, [ 400 ] puerarin, [ 345 ] an inhibitor of inducible nitrite oxide synthase L‐NIL, [ 401 ] resveratrol and selisistat, [ 348 ] cepharanthine, [ 344 ] baicalin, [ 334 ] Fer‐1, [ 333 , 402 ] and Lip‐1 [ 346 ] alleviate early brain injury after SAH through inhibiting ferroptosis ( Table 6 ).…”

“…Inhibiting ACSL4 alleviated EBI-SAH, evidenced by decreased inflammation, blood-brain barrier (BBB) impairment, oxidative stress, brain edema, and behavioral and cognitive deficits, and increased the number of surviving neurons, indicating that ACSL4 exacerbated SAH-induced EBI by mediating ferroptosis. [343] The Role of Inhibition of GSH/GPX4 Axis in SAH: The depletion of GSH [335,344,345] and the reduction of GPX4 [335,[345][346][347][348] induced ferroptosis after SAH, leading to EBI-SAH. The overexpression of GPX4 ameliorates ferroptosis-mediated EBI-SAH, evidenced by reduced LPO and cell death in both in vitro and in vivo experimental SAH models, and decreased brain edema and neurological deficits after SAH.…”