Upregulation of GLT-1 via PI3K/Akt Pathway Contributes to Neuroprotection Induced by Dexmedetomidine

Abstract

Perioperative ischemic stroke usually leads to neurological dysfunction caused by neuron death. During the ischemic condition, excitotoxity due to extracellular glutamate accumulation is a main mechanism of neuron damage. The clearance of glutamate mainly depends on glutamate transporter-1 (GLT-1) which is expressed in astrocytes. Dexmedetomidine, an α2 adrenergic receptor agonist, is proved to induce neuroprotection. This study was set out to investigate the glutamate-related mechanism involved in the neuroprotective effect of dexmedetomidine. Middle cerebral artery occlusion (MCAO) was used as a model of ischemic stroke in our study. We determined Neurological deficit scores (NDS) and Magnetic resonance imaging (MRI) at three points (2, 6, and 24 h) after middle cerebral artery occlusion (MCAO) to evaluate the neuroprotective effect of dexmedetomidine. Besides, we performed western blot (6 and 24 h after MACO) and immunofluorescent staining (24 h after MCAO) to observe the expression of GLT-1. The effect and mechanism of dexmedetomidine on GLT-1 in primary cultured astrocytes were investigated using western blot and RT-PCR. Our results showed that pretreatment with dexmedetomidine improved NDS and reduced infarct volume as well as upregulating GLT-1 expression. Furthermore, using Atipamezole and LY294002, we found that dexmedetomidine significantly increased GLT-1 levels in astrocytes via activating α2 adrenergic receptor and PI3K/AKT pathway both in vitro and in vivo study. Overall, our present study indicated that dexmedetomidine had neuroprotective effects on ischemia stroke and upregulation of GLT-1 levels by PI3K/AKT dependent pathway might be the potential mechanism.

WITHDRAWN: Combination of Paeoniflorin and Calycosin-7-glucoside Promotes Ischemic Stroke Recovery via the PI3K/AKT Signaling Pathway

“…The phosphatidylinositol 3-kinase (PI3K)/protein serine threonine kinase (AKT) pathway is an important signaling pathway in cells [11][12][13] . Activation of the signaling pathway can inhibit a variety of stimulationinduced apoptosis mechanisms and promote cell cycle progression, thereby promoting cell survival and proliferation while participating in angiogenesis 14 .…”

Dexmedetomidine Attenuates Glutamate-Induced Cytotoxicity by Inhibiting the Mitochondrial-Mediated Apoptotic Pathway

“…Cells were sub-cultured once every 3 days, and only those in the exponential growth phase were utilized in experiments. Cells were seeded in 6-well plates at a density of 5×10 5 /ml (2 ml per well) or in a 96-well plate at a density of 1×10 5 /ml (100 ul per well) and subsequently incubated for 24 h.…”

“…During cerebral ischemia, GLU is released in large quantities and accumulates in the synaptic cleft, followed by overwhelmed activation of GLU receptors, resulting in neuronal necrosis and apoptosis, which is called GLU excitotoxicity [5]. Excessive GLU can over-activate the NMDA receptors of neurons and cause oxidative stress and calcium overload [6,7].…”

MiR-206 is involved in neuroprotective effects of Dexmedetomidine in H2O2-induced SK-N-SH cells by targeting ANXA1

“…Thus, it is critically urgently to investigate the unearthing the underlying mechanism behind HIBD. Dexmedetomidine (DEX), a novel sedative-analgesic agent, is regarded as a highly specific and selective a2-adrenoceptor agonist which has sedative, analgesic, and anxiolytic properties, and it is commonly used in clinical practice as an anesthetic (Peng et al, 2019). In recent years, increasing studies indicated that DEX can provide neuroprotective effects against HIBD in multiple ways, such as inhibition of apoptosis, blocking the release of inflammatory cytokines and relieving oxidative stress, which also is able to improve the cognitive function under the condition of hypoxia-ischemia (Degos et al, 2013;Ren et al, 2016;Akpınar et al, 2016).…”