Exogenous NADPH could mitigate pyroptosis-induced brain injury in fetal mice exposed to gestational intermittent hypoxia.

OBJECTIVE: Obstructive Sleep Apnea (OSA) during pregnancy is characterized by intermittent hypoxia (IH) during sleep and will lead to the rise of oxidative stress in the fetal body. Pyroptosis, a type of inflammatory and programmable cell death mediated by Gasdermin D (GSDMD), plays a substantial role in oxygen deprivation's contribution to neural system damage. Existing research shows that Nicotinamide Adenine Dinucleotide Phosphate (NADPH) plays a protective role in alleviating brain tissue pyroptosis. We speculate that exogenous NADPH may play a protective role in OSA during pregnancy. METHODS: A model of GIH group was established to simulate the pathophysiological mechanisms of OSA during pregnant and AIR group was established by giving the same frequency. Sham group was established by injecting NS and the NADPH group was established and given exogenous NADPH. We utilized the Morris Water Maze to assess cognitive function impairment, Luxol Fast Blue (LBF) staining to confirm myelin sheath formation, TUNEL staining to examine cell death in fetal mice brain tissue, and Western blotting to detect pertinent protein expressions. RESULTS: The GIH group offspring exhibited decreases in spatial learning and memory abilities, reduced numbers of oligodendrocytes and formed myelin, as well as increased expression of pyroptosis-related proteins. The NADPH group offspring showed restoration in spatial learning and memory abilities increased counts of oligodendrocytes and formed myelin sheaths, in addition to decreased expression of pyroptosis-related. CONCLUSIONS: This study demonstrates that early injection of exogenous NADPH can alleviate the damage to fetal brain development caused by gestational intermittent hypoxia (GIH).

The protective role of Nrf2 on cognitive impairment in chronic intermittent hypoxia and sleep fragmentation mice.

OBJECTIVE: Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) is a sleep respiratory disease associated with cognitive impairment, The nuclear factor erythroid 2 related factor 2 (Nrf2) plays a neuroprotective role. This study was designed to investigate the mechanism of Nrf2 protecting neural cells from endoplasmic reticulum stress (ERS), induced by chronic intermittent hypoxia (CIH) and sleep fragmentation (SF) which caused cognitive impairment in mice. METHODS: Establishment of CIH and SF mice to simulate OSAHS mouse model. An eight-arm maze behavior test measured the cognitive function of mice, and Nissl staining and TUNEL staining were used to detect pathological changes in hippocampal neurons. The expression of ERS and Nrf2 and its downstream related mRNAs and proteins were detected by qRT-PCR and Western blotting. RESULTS: CIH and SF lead to cognitive impairment in mice, and Sulforaphane (SFN, Nrf2 agonist) plays a protective role, while Nrf2-KO aggravates the cognitive impairment. CIH and SF reduced the number of Nissl bodies in neurons and induced apoptosis. The mRNA levels of BiP, CHOP, Nrf2, GCLC and Prdx1 in CIH, SF and CIH + SF groups were increased (p = 0.001), whereas the mRNA levels of BiP and CHOP in the CIH + SF + SFN group were decreased (p = 0.02) while those of Nrf2 and Prdx1 were increased (p = 0.005). The CIH + SF + Nrf2-KO group, the mRNA levels of CHOP were increased (p = 0.001) while Nrf2, GCLC and Prdx1 were decreased (p = 0.001). The protein levels of CHOP and active Caspase-12 in CIH, SF, CIH + SF and CIH + SF + Nrf2-KO groups were increased (p = 0.03), while those of Prdx1 and Nrf2 were increased (p = 0.03) in the CIH + SF + SFN group, while decreased (p = 0.02) in the Nrf2-KO group. CONCLUSIONS: Chronic intermittent hypoxia(CIH) and sleep fragmentation(SF) could aggravate the inflammatory response of nerve cells through endoplasmic reticulum stress, leading to apoptosis of nerve cells, and causing cognitive impairment in mice.Nrf2 alleviates cognitive impairment induced by chronic intermittent hypoxia and sleep fragmentation by modulating endoplasmic reticulum stress. Activation of Nrf2 protects cognitive impairment through the Nrf2-Prdx1 signaling pathway.

Neuroprotective Effects of Adenosine A1 Receptor Signaling on Cognitive Impairment Induced by Chronic Intermittent Hypoxia in Mice.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a breathing disorder associated with cognitive impairment. However, the mechanisms leading to cognitive deficits in OSAHS remain uncertain. In this study, a mouse model of chronic intermittent hypoxia (CIH) exposures were applied for simulating the deoxygenation-reoxygenation events occurring in OSAHS. The conventional adenosine A1 receptor gene (A1R) knockout mice and the A1R agonist CCPA- or antagonist DPCPX-administrated mice were utilized to determine the precise function of A1R signaling in the process of OSAHS-relevant cognitive impairment. We demonstrated that CIH induced morphological changes and apoptosis in hippocampal neurons. Further, CIH blunted hippocampal long-term potentiation (LTP) and resulted in learning/memory impairment. Disruption of adenosine A1R exacerbated morphological, cellular, and functional damage induced by CIH. In contrast, activation of adenosine A1R signaling reduced morphological changes and apoptosis of hippocampal neurons, promoted LTP, and enhanced learning and memory. A1Rs may up-regulate protein kinase C (PKC) and its subtype PKC-ζ through the activation of Gα(i) improve spatial learning and memory disorder induced by CIH in mice. Taken together, A1R signaling plays a neuroprotective role in CIH-induced cognitive dysfunction and pathological changes in the hippocampus.

Structural and Microvascular Changes in the Macular Are Associated With Severity of White Matter Lesions.

Purpose: This study aimed to characterize the microvascular and structural changes in the macular that occur in white matter hyperintensities (WMH) using optical coherence tomographic angiography. We also aimed to explore the association between macular microvascular and structural changes with focal markers of brain tissue on MRI in WMH using the Fazekas scale. Methods: This study enrolled healthy participants who were stroke- and dementia-free. MRI was used to image the cerebral white matter lesions, and Fazekas scale was used to evaluate the severity of the white matter lesions. Optical coherence tomography angiography (OCT-A) was used to image the radial peripapillary capillaries (RPCs), macular capillary plexuses [superficial capillary plexus (SCP) and deep capillary plexus (DCP)] and thickness around the optic nerve head, peripapillary retinal nerve fiber layer (pRNFL). Results: Seventy-four participants were enrolled and divided into two groups according to their Fazekas score (Fazekas scores ≤ 1 and ≥2). Participants with Fazekas score ≥2 showed significantly reduced RPC density (P = 0.02) and DCP density (P = 0.012) when compared with participants with Fazekas score ≤ 1. Participants with Fazekas score ≥2 showed reduced pRNFL (P = 0.004) when compared to participants with Fazekas score ≤ 1. Fazekas scores were significantly associated with the pRNFL thickness (Rho = -0.389, P = 0.001), RPC density (Rho = -0.248, P = 0.035), and DCP density (Rho = -0.283, P = 0.015), respectively. Conclusions: Microvascular impairment and neuro-axonal damage are associated with the disease cascade in WMH. We have shown that RPC and DCP densities are significantly affected, and these impairments are associated with the severity of the disease and cognitive function. OCT-A could be a useful tool in quantifying the retinal capillary densities in WMH.

Retinal sublayer defect is independently associated with the severity of hypertensive white matter hyperintensity.

PURPOSE: To investigate the association of specific retinal sublayer thicknesses on optical coherence tomography (OCT) imaging with brain magnetic resonance imaging (MRI) markers using the Fazekas scale in hypertensive white matter hyperintensity (WMH) subjects. METHODS: Eighty-eight participants (32 healthy controls and 56 hypertensive white matter hyperintensity subjects) underwent retinal imaging using the OCT and MRI. A custom-built algorithm was used to measure the thicknesses of the retinal nerve fiber layer (RNFL) and ganglion cell layer and inner plexiform layer (GCIP). Focal markers for white matter hyperintensities were assessed on MRI and graded using the Fazekas visual rating. RESULTS: Hypertensive WMH showed significantly reduced (p < .05) RNFL and GCIP layers when compared to healthy controls, respectively. A significant correlation was found between the RNFL (ρ = -.246, p < .001) and GCIP (ρ = -.338, p < .001) of the total participants and the Fazekas score, respectively. Statistical differences were still significant (p < .05) when correlations were adjusted for intereye correlation, age, hypertension, smoking, body mass index, and diabetes. Among the cases of hypertensive WMH, higher Fazekas scores were significantly associated (p < .05) with the thinning of both the RNFL and GCIP layers after adjustment of age and other risk factors. CONCLUSIONS: Retinal degeneration in the RNFL and GCIP was independently associated with focal lesions in the white matter of the brain and deteriorates with the severity of the lesions. We suggest that imaging and measurement of the retinal sublayers using the OCT may provide evidence on neurodegeneration in WMH.

Retinal Microvascular Impairment in the Early Stages of Parkinson's Disease.

Purpose: To detect the retinal microvascular impairment using optical coherence tomography angiography (OCT-A) in patients with Parkinson's disease (PD) and find a correlation between the microvascular impairment and the neuronal damage. Methods: This is a prospective, observational study including 49 eyes from 38 PD patients in their early stages and 34 eyes from 28 healthy controls with comparable age range. Macula microvasculature was evaluated with the spectral-domain optical coherence tomography (SD-OCT) angiography and intraretinal layer thickness evaluated with the SD-OCT. A custom algorithm was used for custom segmentation of retinal thickness and quantification of the superficial and deep microvascular density of the macula, respectively. Results: PD patients showed reduced microvascular density in most of the areas of the whole retina. In the superficial retinal capillary plexus, statistical difference (P < 0.01) was seen in the total annular zone (TAZ), superior, temporal, inferior, and nasal zones. In PD patients, there was a strong correlation between the average ganglion cell layer and inner plexiform (GCIP) thickness and the TAZ of the superficial microvascular density (r = 0.062, P = 0.032). Conclusion: We demonstrated that retinal microvascular density decreased in PD patients. The correlation between microvascular impairment in the superficial retinal capillary layer and GCIP thinning also revealed that the retinal microvascular abnormality may contribute to the neurodegeneration in PD patients. OCT-A with quantitative analysis offers a new path of study and will likely be useful in the future as an objective biomarker for detecting vessel impairment in early stages of PD.

Altered Macular Microvasculature in Neuromyelitis Optica Spectrum Disorders.

PURPOSE: To evaluate macular microvascular changes in neuromyelitis optica spectrum disorders (NMOSD) by using optical coherence tomography angiography (OCT-A) and investigate their correlations with neuroaxonal structural damage evaluated with spectral-domain OCT (SD-OCT). DESIGN: Cross-sectional study. METHODS: Twenty eyes of 20 patients with NMOSD and 21 eyes from 21 healthy controls were enrolled. OCT-A was used to obtain microvascular network images of the whole, superficial, and deep retinal capillary plexuses (WRCP, SRCP, and DRCP) in a 3-mm-diameter area around the macula. SD-OCT was used to obtain the intraretinal thickness. Custom automated algorithms quantified the thickness of the intraretinal layers as well as microvascular density of the retinal capillary layers. RESULTS: NMOSD patients showed significantly decreased microvascular density in both SRCP and DRCP (P < .05) compared to controls. The decreased microvascular density in SRCP and DRCP significantly correlated with the frequency of optic neuritis attack (P < .05). Both SRCP and DRCP microvascular density significantly correlated (P < .05) with retinal nerve fiber layer and ganglion cell layer with inner plexiform layer. SRCP microvascular density moderately correlated with visual acuity, while a stronger correlation was found between DRCP and visual acuity. CONCLUSIONS: Decreased microvascular density in NMOSD patients correlated with the worsening of their visual acuity. Correlation between microvascular impairment and neuroaxonal thinning revealed that retinal microvascular alteration may contribute to neuroaxonal loss in NMOSD patients. OCT-A with measurable analysis offers a new path of study and will likely be useful as an objective biomarker for detecting microvascular impairment in NMOSD.