Effects of mTOR on neurological deficits after transient global ischemia

Abstract

Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase and activation of its signal pathway plays an important role in regulating protein growth and synthesis as well as cell proliferation and survival. In the present study, we examined the contribution of mTOR and its downstream products to brain injuries and neurological deficiencies after cardiac arrest (CA) induced-transient global ischemia. CA was induced by asphyxia followed by cardiopulmonary resuscitation (CPR) in rats. Our results showed that expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1) and p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in CA rats compared to their controls. Blocking mTOR using rapamycin attenuated upregulation of pro-inflammatory cytokines (namely IL-1β, IL-6 and TNF-α), and Caspase-3, indicating cell apoptosis and also promoting the levels of vascular endothelial growth factor (VEGF) and its subtype receptor VEGFR-2 in the hippocampus. Moreover, the effects of rapamycin were linked to improvement of neurological deficits and increased brain water content observed in CA rats. In conclusion, activation of mTOR signal is engaged in pathophysiological process during CA-induced transient global ischemia and blocking mTOR pathway plays a beneficial role in regulating injured neuronal tissues and neurological deficits via PIC, apoptotic Caspase-3 and VEGF mechanisms. Targeting one or more of these specific mTOR pathways and its downstream signaling molecules may present new opportunities for neural dysfunction and vulnerability related to transient global ischemia.

Inhibition of VEGFR‐2 by SU5416 increases neonatally glutamate‐induced neuronal damage in the cerebral motor cortex and hippocampus

“…Apoptosis involves the activation of cell death receptors belonging to the TNF family, which promotes the sequential activation of caspase-8 and caspase-3 and subsequent cell death. [36] Neonatal MSG treatment has been reported to increase cerebral concentrations of TNF-α and other proinflammatory cytokines, such as IL-1 and IL-6, [33,37] whose signaling might be involved in the neuronal apoptosis observed in the present study. In addition, another cell death process related to glutamate excitotoxicity, which is referred to as necroptosis or programmed necrotic cell death, is a delayed and organized process, and the trigger mechanism involves TNF-α signaling through the activation of its receptor TNFR1, [35,38] which might also participate in the degenerative processes described here, but the involvement of this pathway remains to be determined.…”

2D:4D Ratio differs in ischemic stroke: A single center experience

“…Also, sex hormones lead to microglia and astrocyte activation [ 17 , 18 ], which are major contributing cells in neuroinflammation in response to various insults [ 19 , 20 , 21 ]. The inflammatory status would exacerbate the atherosclerosis in vascular arteries [ 22 ]. Some researchers have confirmed the link between 2D:4D ratio and arterial atherosclerosis through biopsy [ 23 ].…”

Single-cell transcriptomics reveal hyperacute cytokine and immune checkpoint axis in patients with poor neurological outcomes after cardiac arrest

“…Experimental IRI models have highlighted the infiltration of innate immune cells to end-organs, and suggest a hypothesis that the cell subpopulations in our study represent immune cells in transit to end-organs. In animal models of CA, monocytes expand in circulation and accumulate in the brain in areas of neuronal injury (Giuliano et al, 2021; Jiang et al, 2020; Uray et al, 2021; Xing and Lu, 2017; Zhang et al, 2018). In experimental single-organ IRI, activated monocytes and NK cells migrated to sites of injury early in myocardial IRI (Bajpai et al, 2019), stroke (Chu et al, 2015; Planas, 2018; Zhang et al, 2014), and renal IRI (Zhang et al, 2020, 2008).…”