Role of Oxidative Stress in the Neurocognitive Dysfunction of Obstructive Sleep Apnea Syndrome

Table 2

The role of OS in the neurocognitive deficits of OSA animal model.

Reference	E group	C group	Detecting parameter	Morris water maze testing	Outcome
Wang et al., 2010 [100]	Male Wistar mice + IH	Male Wistar mice + RA; male Wistar mice + CH	Apoptotic neuronal cell, HIF-1α protein, and RNA	NA	HIF-1α distributing with neuron apoptosis consistently in brain cortex and hippocampus of E group
Xu et al., 2004 [101]	Transgenic mice overexpressing; SOD + IH; C578L/6J mice + IH	Transgenic mice overexpressing; SOD + RA; C578L/6J mice + RA	ROS production, c-Fos, c-Jun, NF-κβ, caspase-3, carbonyl protein, MDA, 8-hydroxyguanosine, and neuronal cell apoptosis	Spatial task acquisition↓, working spatial memory↓	All the parameters increased in brain cortex upon CIH-C578L/6J mice; transgenic mice showing lower level compared with NCM
Row et al., 2003 [102]	V-IH; PNU-IH	V-RA; PNU-RA	MDA, isoprostane, and oxo8dG/oxo8G	The longest latencies and path lengths to locate the hidden platform in V-IH	The highest MDA, isoprostane, and oxo8DG/oxo8G in the cortex and hippocampal CA1 region of V-IH. PNU-101033E decreased OS level and improved neurocognitive deficits
Shan et al., 2007 [103]	() Transgenic mice overexpressing; SOD + IH; C578L/6J mice + IH; () Cortical neurons + CIH	() Mice + RA; () Cortical neurons + RA	ROS production in cortical neurons, MDA, and protein oxidation	Reduced spatial learning deficits in the mice exposure to CIH	Elevated ROS production in cortical neuronal cortex and apoptotic neuronal cell. Transgenic mice showing reduced cortical neuron apoptosis and ROS production
Nair et al., 2011 [104]	gp91phox−/Y mice + IH; C578L/6J mice + IH	gp91phox−/Y mice +RA; C578L/6J mice + RA	NADPH oxidase expression and activity, MDA, and 8-OHDG	Spatial learning and memory deficits showing in IH-C57BL6/J mice, not in gp91phox−/Y mice exposed to IH	All the parameters were significantly increased in IH-C57BL6/J mice in the cortex and hippocampus. Nox activities were attenuated in gp91phox−/Y mice
Zhan et al., 2005 [105]	gp91phox−/− mice + IH; C578L/6J mice + IH	Mice + sham LTIH (normal Sp02)	NADPH oxidase gene and protein responses; p67phox, TNF-α, iNOS, COX-2 gene; protein carbonyl; F2 isoprostanes	NA	All the parameters showing increase in wide-type mice exposed to LTIH in wake-active region of the brain; transgenic absence and inhibiting NADPH oxidase activity showing declined OS damage
Yang et al., 2012 [106]	CIH + NS group; CIH + NAC group	Sham CIH + NS group; sham CIH + NAC group	Expression of Trx mRNA and protein, cells apoptosis in the hippocampus CA1 region	Impaired spatial learning and memory in CIH-rats	CIH rats showing decreased Trx mRNA and protein levels and elevated apoptotic cells in the hippocampus
Chou et al., 2013 [28]	CHOP null adult male mice + LTIH; wild-type adult male mice + LTIH	CHOP null + sham LTIH; wild-type adult male mice + sham LTIH	Nox2, CC-3, MAP-2, ChAT, and ERO1L in motor nuclei, CHOP; protein oxidation; neuronal apoptosis	NA	Relative to wild-type mice, CHOP mice prevent oxidative stress (superoxide production/carbonyl proteins), neuronal apoptosis, and upregulation of Nox and HIF-1α in brain regions of cortex, hippocampus, and brainstem motoneurons
Kheirandish et al., 2005 [87, 107]	ApoE mice, wild-type littermates in IH	ApoE mice, wild-type littermates in RA	Prostaglandin E2 and MDA in hippocampal region	Longer times (latency) and distances (pathlength) to locate the hidden platform in IH mice	The highest PGE2 and MDA concentrations presenting in hippocampal brain tissues of ApoE mice exposed to IH
Row et al., 2004 [108]	PAFR–/– mice, wild-type littermates in IH	PAFR–/– mice, wild-type littermates in RA	NOS activity, PGE2, COX-2, proteasomal activity, and CC-3	PAFR–/–mice in CIH displaying normal spatial; learning compared with wild-type littermates	All the parameters showing increase in prefrontal cortex and the hippocampus CA1 region of wide-type mice exposed to IH. PAFR mice showing attenuated OS
Dayyat et al., 2012 [109]	() V-IH; EPO-IH; () Primary neuronal cell cultures	(1) V-SH; EPO-SH; (2) V-RA; EPO-RA	NADPH oxidase, MDA, 8-OHDG, and EPO	EPO-IH mice showing normal learning. V-IH mice displaying spatial learning deficits	V-IH mice, but not EPO-treated IH-exposed mice, showing elevated levels of NADPH oxidase expression, MDA, and 8-OHDG in cortical and hippocampal lysates
Nair et al., 2013 [110]	V-IH; JI-34-IH	V-RA; JI-34-RA	MDA, 8-OHDG, HIF-1α DNA, EPO, and IGF-1 expression	JI-34 attenuated spatial learning performance deficits in mice exposed to IH	V-IH mice showing increased MDA and 8-OHDG in hippocampus and cortex; JI-34 reduced OS and increased HIF-1α DNA binding and expression of IGF-1 and EPO
Li et al., 2011 [111]	V-IH; GH-IH	() V-RA; GH-RA; () CH	EPO, VEGF, HO-1, and GLUT-1 mRNA expression	GH attenuated IH-induced neurocognitive deficits	GH increased mRNA expression of IGF-1, EPO, and VEGF in the hippocampus
Yuan et al., 2015 [112]	V-IH; telmisartan-IH	V-RA; telmisartan-RA	MDA, NOS activity, NO content, and apoptotic cells in hippocampus; plasma CRP and IL-6	NA	Increased iNOS, NO content, MDA, and inflammatory reaction showing in the hippocampus of IH mice. Telmisartan attenuated above response and apoptosis in hippocampus
Goldbart et al., 2006 [113]	HF/RC + IH; LF/CC + IH	HF/RC + RA; LF/CC + RA	CREB phosphorylation in the CA1 region of the hippocampus	The worst place-training reference memory task deficits occurring in HF/RC + IH mice	Abundant reduced CREB phosphorylation showing in CA1 of IH mice
Li et al., 2003 [114]	V-IH; NS398-IH	() V-RA; NS398-RA; () V-CH	COX-1 gene, COX-2 genes and protein expression and activity, and PGE2 concentration in cortical regions of rat brain	Deficits in the acquisition and retention of a spatial task showing in IH mice. NS-398 treatment attenuated IH-induced neurobehavioral deficits	Increased COX-2 protein and gene expression, PGE2 levels, and neuronal apoptosis in cortex
Burckhardt et al., 2008 [115]	V-IH; GTP-IH;	V-RA; GTP-RA	MDA, PGE2, p47phox mRNA, GFAP, RAGE, and the ratio of RAGE/β-actin in the cortical and hippocampal regions of rat model	GTPs are capable of attenuating; IH-induced spatial learning deficits	All parameters showed increases in the brain cortex and hippocampus of IH-exposed rats. GTPs attenuated IH-induced oxidative stress and inflammatory reaction damage in the rat brain
B. A. Abdel-Wahab and M. M. Abdel-Wahab, 2016 [116]	V-IH; resveratrol-IH	V-RA; resveratrol-RA	TBARS, GSH, glutamate, GSH-Px activity, 8-OHdG, total protein, and p47phox mRNA in the hippocampus	Resveratrol protects animals from IH-induced spatial memory deficits	Resveratrol prevented IH-induced increases of glutamate, TBARS, and 8-OHdG levels and p47Phox expression in the hippocampus of IH rats and decreases of hippocampal GSH levels and GSH-Px activity

8-OHDG: 8-hydroxydeoxyguanosine; MDA: malondialdehyde; PGE2: prostaglandin E2; NOS: nitric oxide synthase; MAP-2: microtubule associate protein-2; ChAT: choline acetyltransferase; CC-3: cleaved caspase-3; Nox: NADPH oxidase; ERO1L: endoplasmic reticulum oxidoreductin-1-like; COX-2: cyclooxygenase-2; VEGF: vascular endothelial growth factor; HO-1: heme oxygenase-1; CREB: cyclic AMP response element binding protein; PNU: PNU-101033E; oxo8DG/oxo8G: 8-hydroxy-2′-deoxyguanosine/8-hydroxyguanosine; COX: cyclooxygenase; Trx: thioredoxin; ApoE: apolipoprotein E; GFAP: glial fibrillary acidic protein; RAGE: receptor for advanced glycation end products; TBARS: thiobarbituric acid reactive substances; GSH: glutathione; GSH-Px: glutathione peroxidase; GTPs: green tea catechin polyphenols.
E group: experiment group; C group: control group; CIH + NS group: CIH + normal saline; (CIH + NAC) group: N-acetylcysteine-treated CIH; sham CIH + NS: a sham CIH group; CIH + NAC group: sham NAC-treated sham CIH; EPO-IH: exogenously erythropoietin treated IH; HF/RC + IH: high fat/refined carbohydrate diet + IH; LF/CC + IH: low fat/complex carbohydrate diet + IH.
V-IH: vehicle + IH; ApoE: ApoE-deficient mice; PAFR–/–: PAFR-deficient mice.
IH: intermittent hypoxia; RA: room air; CH: continued hypoxia; LTIH: long-term intermittent hypoxia; sham LTIH.
NA: not administrated.