Dexmedetomidine Alleviates Hypoxia‐Induced Synaptic Loss and Cognitive Impairment via Inhibition of Microglial NOX2 Activation in the Hippocampus of Neonatal Rats

Abstract

Background. Perinatal hypoxia is a universal cause of death and neurological deficits in neonates worldwide. Activation of microglial NADPH oxidase 2 (NOX2) leads to oxidative stress and neuroinflammation, which may contribute to hypoxic damage in the developing brain. Dexmedetomidine has been reported to exert potent neuroprotection in several neurological diseases, but the mechanism remains unclear. We investigated whether dexmedetomidine acts through microglial NOX2 to reduce neonatal hypoxic brain damage. Methods. The potential role of microglial NOX2 in dexmedetomidine-mediated alleviation of hypoxic damage was evaluated in cultured BV2 microglia and neonatal rats subjected to hypoxia. In vivo, neonatal rats received dexmedetomidine (25 μg/kg, i.p.) 30 min before or immediately after hypoxia (5% O2, 2 h). Apocynin-mediated NOX inhibition and lentivirus-mediated NOX2 overexpression were applied to further assess the involvement of microglial NOX2 activation. Results. Pre- or posttreatment with dexmedetomidine alleviated hypoxia-induced cognitive impairment, restored damaged synapses, and increased postsynaptic density-95 and synaptophysin protein expression following neonatal hypoxia. Importantly, dexmedetomidine treatment suppressed hypoxia-induced microglial NOX2 activation and subsequent oxidative stress and the neuroinflammatory response, as reflected by reduced 4-hydroxynonenal and ROS accumulation, and decreased nuclear NF-κB p65 and proinflammatory cytokine levels in cultured BV2 microglia and the developing hippocampus. In addition, treating primary hippocampal neurons with conditioned medium (CM) from hypoxia-activated BV2 microglia resulted in neuronal damage, which was alleviated by CM from dexmedetomidine-treated microglia. Moreover, the neuroprotective effect of dexmedetomidine was reversed in NOX2-overexpressing BV2 microglia and diminished in apocynin-pretreated neonatal rats. Conclusion. Dexmedetomidine targets microglial NOX2 to reduce oxidative stress and neuroinflammation and subsequently protects against hippocampal synaptic loss following neonatal hypoxia.

Dexmedetomidine alleviates early brain injury following traumatic brain injury by inhibiting autophagy and neuroinflammation through the ROS/Nrf2 signaling pathway

“…Chen et al ( 45 ) aimed to further clarify the mechanisms and report that DEX protects against MTX-induced cognitive impairment by inhibiting neuronal toxicity and inflammation. In hypoxia-activated BV2 microglia and neonatal rats subjected to hypoxia, DEX decreases hippocampal synaptic loss and neuronal damage and the potential mechanisms may be that DEX prevents hypoxia-induced microglial NOX2 activation and then inhibits oxidative stress and the neuroinflammatory response ( 46 ). Mei et al ( 47 ) also report that DEX alleviates BBB disruption, learning and memory impairments, systemic inflammation and neuroinflammation in a cecal ligation and puncture (CLP)-induced septic model.…”

Propofol via Antioxidant Property Attenuated Hypoxia-Mediated Mitochondrial Dynamic Imbalance and Malfunction in Primary Rat Hippocampal Neurons

“…First, it is known that intracellular ROS was produced through multiple enzymes mainly composed of, but not limited to, NADPH oxidase, nitric oxidase, amine oxidase, oxalate oxidase, and peroxidases. Although it was reported that hypoxia may increase ROS production in microglia by inducing NADPH oxidase 2 [ 56 ], and it was shown that hypoxia induced ROS generation via NADPH oxidase 4 in mouse hippocampus [ 57 ], highly implying the role of NADPH oxidase, we did not investigate the exact pathway responsible for ROS production in the current study. Second, intracellular oxidative status depends on the balance between the generation and removal of ROS, which may involve superoxide dismutases, catalase, and glutathione peroxidase.…”

mTOR‐mediated autophagy in the hippocampus is involved in perioperative neurocognitive disorders in diabetic rats

“…The Morris water maze (MWM) test was performed to test the cognitive function of diabetic and nondiabetic rats on days 3, 7, and 14 after surgery as previously described. 33 The maze (150 cm in diameter and 50 cm in depth) was divided into four quadrants, and a platform (12 cm in diameter) was submerged 1 cm below the water line in one quadrant of the pool. In the MWM test, a video camera connected to the computer running the tracking software (Panlab) was placed above the center of the maze to record and analyze the rats' movements.…”