Alpha-Ketoglutarate Alleviates Neuronal Apoptosis Induced by Central Insulin Resistance through Inhibiting S6K1 Phosphorylation after Subarachnoid Hemorrhage

Abstract

Neuronal apoptosis after subarachnoid hemorrhage (SAH) is believed to play an important role in early brain injury after SAH. The energy metabolism of neuron is closely related to its survival. The transient hyperglycemia caused by insulin resistance (IR) after SAH seriously affects the prognosis of patients. However, the specific mechanisms of IR after SAH are still not clear. Studies have shown that α-KG takes part in the regulation of IR and cell apoptosis. In this study, we aim to investigate whether α-KG can reduce IR after SAH, improve the disorder of neuronal glucose metabolism, alleviate neuronal apoptosis, and ultimately play a neuroprotective role in SAH-induced EBI. We first measured α-KG levels in the cerebrospinal fluid (CSF) of patients with SAH. Then, we established a SAH model through hemoglobin (Hb) stimulation with HT22 cells for further mechanism research. Furthermore, an in vivo SAH model in mice was established by endovascular perforation. Our results showed that α-KG levels in CSF significantly increased in SAH patients and could be used as a potential prognostic biomarker. In in vitro model of SAH, we found that α-KG not only inhibited IR-induced reduction of glucose uptake in neurons after SAH but also alleviated SAH-induced neuronal apoptosis. Mechanistically, we found that α-KG inhibits neuronal IR by inhibiting S6K1 activation after SAH. Moreover, neuronal apoptosis significantly increased when glucose uptake was reduced. Furthermore, our results demonstrated that α-KG could also alleviate neuronal apoptosis in vivo SAH model. In conclusion, our study suggests that α-KG alleviates apoptosis by inhibiting IR induced by S6K1 activation after SAH.

Association Between Insulin Resistance Markers and Poor Prognosis in Patients With Acute Ischemic Stroke After Intravenous Thrombolysis

“…The interaction of IR and oxidative stress may contribute to influence AIS development. Finally, previous studies have shown that IR could inhibit glucose translocator 4 membrane translocation, leading to neuronal apoptosis due to insufficient glucose uptake 21 …”

“…Finally, previous studies have shown that IR could inhibit glucose translocator 4 membrane translocation, leading to neuronal apoptosis due to insufficient glucose uptake. 21 In a survey of the general population based on the Northeast China Rural Cardiovascular Health Study and the National Stroke Screening and Intervention Program in Liaoning, Du et al 11 found a linear association between TyG-BMI levels and ischemic stroke risk. As the level of TyG-BMI increased, the risk of ischemic stroke significantly increased (P < 0.05).…”

Insulin resistance in ischemic stroke: Mechanisms and therapeutic approaches

“…Furthermore, our team found that IR inhibits GLUT4 membrane translocation, leading to the apoptosis of neurons due to insufficient glucose uptake. Inhibiting neuronal IR attenuates neuronal apoptosis ( 100 ). All of this suggests that IR could cause neuronal death.…”

“…This conflicting outcome indicates that statins for insulin resistance still require additional experimental confirmation. Apart from this, several medicines (e.g., α-ketoglutarate, astaxanthin) can reduce IR and increase neuronal survival by decreasing aberrant serine phosphorylation of IRS1 directly via inhibiting mTOR/S6K1 ( 100 , 128 ). In summary, there is substantial evidence that insulin sensitizers can boost brain insulin sensitivity, successfully treat ischemic stroke, and improve neurological function.…”

Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage

“…Neuronal death is considered a major cause of EBI ( Macdonald and Schweizer, 2017 ). Hence, a reduction in the number of neuronal deaths could improve nerve dysfunction and eventually improve the prognosis of patients ( Dong et al, 2016 ; Ding et al, 2022 ). Thus, further study on the mechanism of EBI and neuronal death is vitally important.…”