Cell death inhibitors protect against brain damage caused by cardiac ischemia/reperfusion injury

Abstract

Cognitive impairment has been reported in patients with myocardial infarction despite a successful reperfusion therapy. Several modes of cell death are involved in brain damage during cardiac ischemia/reperfusion (I/R) injury. Although apoptosis, necroptosis, and ferroptosis inhibitors provided neuroprotection against cerebral I/R injury, the effects of these cell death inhibitors on the brain following cardiac I/R injury have never been investigated. We hypothesized that apoptosis, necroptosis, and ferroptosis inhibitors attenuate brain damage following cardiac I/R injury. One-hundred and twenty-six male rats were used: 6 rats were assigned to sham operation and 120 rats were subjected to 30-min regional cardiac ischemia and 120-min reperfusion. Rats in cardiac I/R group were pretreated with either vehicle (n = 12) or one of cell death inhibitors. Rats treated with apoptosis, necroptosis, or ferroptosis inhibitor were subdivided into three different doses including low (L), medium (M), and high (H) doses (n = 12/group). Z-VAD, necrostatin-1 (Nec-1), and ferrostatin-1 (Fer-1) were used as apoptosis, necroptosis, and ferroptosis inhibitor, respectively. Rats were sacrificed at the end of reperfusion, and the brain was used to analyze dendritic spine density, Alzheimer’s disease (AD)-related proteins, blood–brain barrier (BBB) tight junction proteins, mitochondrial function, inflammation, and cell death. Our data showed that cardiac I/R led to brain damage and only apoptosis occurred in the hippocampus after cardiac I/R injury. In the cardiac I/R group, treatment with M-Z-VAD and all doses of Nec-1 decreased hippocampal apoptosis and amyloid beta aggregation, thereby reducing dendritic spine loss. M- and H-Fer-1 also reduced dendritic spine loss by suppressing ACSL4, TNF-α, amyloid beta, and tau hyperphosphorylation. Moreover, Bax/Bcl-2 was decreased in all treatment regimen except L-Z-VAD. Additionally, M-Z-VAD and M-Fer-1 partially attenuated mitochondrial dysfunction. Only L-Nec-1 preserved BBB proteins. In conclusion, cell death inhibitors prevented hippocampal dendritic spine loss caused by cardiac I/R injury through different mechanisms.

Ameliorative effects of epigallocatechin-3-gallate nanoparticles on 2,4-dinitrochlorobenzene induced atopic dermatitis: A potential mechanism of inflammation-related necroptosis

“…More recently, more focus has been given to TNF-α mediated necroptosis, an alternative mode of regulated cell death, which contributed to neurodegenerative disease, cancer, and myocardial ischemia-reperfusion injury, as well as psoriasis ( 46 – 48 ). In the present study, necroptotic proteins mainly expressed and located in the epidermis, which is consistent with the expression of inflammatory cytokines.…”

Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis

“…A previous study suggested that amyloid-β deposition and hippocampal dendritic spine loss could be improved by ferrostatin-1 (a well-known inhibitor of ferroptosis), thereby alleviating brain damage caused by cardiac I/R injury. 35 Mitochondrial ferritin could reduce lipid peroxidation and stabilize GSH to inhibit ferroptosis, thus attenuating brain injury and neurological deficits in rats with cerebral I/R. 36 Previous studies suggested that the inhibition of ferroptosis may exert effects against cerebral I/R injury.…”

Molecular mechanisms of ferroptosis and relevance to inflammation

“…The content of serum TNF-α in tissues was significantly increased when ferroptosis occurs. Studies have shown that ferroptosis inhibitors can inhibit TNF-α [ 51 ]. TNF-α has complex pathophysiological functions: it participates in the formation of vasodilation and edema, as well as the adhesion between leukocytes and epithelial cells via the expression of adhesion molecules, regulates blood coagulation, and indirectly induces fever [ 52 ].…”