Sodium/Hydrogen Exchanger 1 Participates in Early Brain Injury after Subarachnoid Hemorrhage both in vivo and in vitro via Promoting Neuronal Apoptosis

Abstract

Sodium/hydrogen exchanger 1 (NHE1) plays an essential role in maintaining intracellular pH (pHi) homeostasis in the central nervous system (CNS) under physiological conditions, and it is also associated with neuronal death and intracellular Na+ and Ca2+ overload induced by cerebral ischemia. However, its roles and underlying mechanisms in early brain injury (EBI) induced by subarachnoid hemorrhage (SAH) have not been fully explored. In this research, a SAH model in adult male rat was established through injecting autologous arterial blood into prechiasmatic cistern. Meanwhile, primary cultured cortical neurons of rat treated with 5 μM oxygen hemoglobin (OxyHb) for 24 h were applied to mimic SAH in vitro. We find that the protein levels of NHE1 are significantly increased in brain tissues of rats after SAH. Downregulation of NHE1 by HOE642 (a specific chemical inhibitor of NHE1) and genetic-knockdown can effectively alleviate behavioral and cognitive dysfunction, brain edema, blood-brain barrier (BBB) injury, inflammatory reactions, oxidative stress, neurondegeneration, and neuronal apoptosis, all of which are involved in EBI following SAH. However, upregulation of NHE1 by genetic-overexpression can produce opposite effects. Additionally, inhibiting NHE1 significantly attenuates OxyHb-induced neuronal apoptosis in vitro and reduces interaction of NHE1 and CHP1 both in vivo and in vitro. Collectively, we can conclude that NHE1 participates in EBI induced by SAH through mediating inflammation, oxidative stress, behavioral and cognitive dysfunction, BBB injury, brain edema, and promoting neuronal degeneration and apoptosis.

Functional NHE1 expression is critical to blood brain barrier integrity and sumatriptan blood to brain uptake

“…Recently, NHE1 inhibition was reported as a viable strategy to alleviate BBB injury induced by stroke and subarachnoid hemorrhage in animal models [26][27][28][29]45]. We asked if functional expression of NHE1 is critical to maintaining paracellular integrity of the BBB using an in vitro model.…”

Attenuating vascular stenosis-induced astrogliosis preserves white matter integrity and cognitive function

“…after ischemia induction, significantly reduced neuronal loss, gliosis, and oxidative damage in the hippocampus [ 62 ]. Lastly, in a rat spontaneous subarachnoid hemorrhage model, intravenous injection of HOE642 (15 mg/kg) at 20 min before induction of subarachnoid hemorrhage decreased inflammatory reactions, oxidative stress, and neuronal loss [ 63 ]. In all these prior studies, NHE1 inhibitors were administered in the acute post-injury phase, which lasted no longer than one week.…”

Neuroprotective effect of Na+/H+ exchangers isoform‐1 inactivation against 6‐hydroxydopamine‐induced mitochondrial dysfunction and neuronal apoptosis in Parkinson's disease models

“…To investigate the role of NHE1 inactivation in PD rats induced by 6‐OHDA, different doses of the NHE1 inhibitor HOE642 (5 or 25 mg/kg, dissolved in DMSO and then diluted in .9% saline; 159,138‐80‐4, Sigma‐Aldrich) were selected following a previous study with some modifications (Song et al, 2019) and injected intraperitoneally into rats daily for three consecutive weeks. The 6‐OHDA group and control group received equal volume of .9% saline alone.…”