Paper Summaries

Pădurariu, M., Ciobîcă, A., Hriţcu, L., Stoica, B., Bild, W., & Ştefănescu, C. (2010). Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer’s disease. Neuroscience Letters, 469(1), 6–10. https://doi.org/10.1016/j.neulet.2009.11.033

Summary: The purpose of this study was to determine the relationship between mild cognitive impairment (MCI) and the progression to Alzheimer's Disease (AD).  Blood samples were taken of the controls, people with MCI and people with AD.  The levels of antioxidant and prooxidant levels were measured. Oxidative damage was found in both MCI and AD patients compared to the controls.  There was a similar decrease of the main enzymatic antioxidant defenses (SOD and GPX) and increased production of lipid peroxidation marker (MDA) in the serum of the MCI and AD patients, compared to age-matched control group. There was a positive correlation of increased lipid peroxidation and decreased antioxidant defense.

Devore, E. E., Grodstein, F., Van Rooij, F. J., Hofman, A., Stampfer, M. J., Witteman, J. C. M., & Breteler, M. M. (2010). Dietary antioxidants and long-term risk of dementia. Archives of Neurology, 67(7). https://doi.org/10.1001/archneurol.2010.144

Summary: The purpose of this study was to examine the effect diet has on developing Dementia. 7983 people diagnosed with AD, who were 55 years or older, from a district in the Netherlands were surveyed on their nutritional intake, specifically antioxidants like Vitamin E, Vitamin C, Beta Carotene, and Flavonoids. A total of 5395 participants, 55 years and older, who were free of dementia and provided dietary information at study baseline. There was a follow-up after 6 years, dementia developed in 465 participants, of whom 365 were diagnosed as having AD. An increased intake of Vitamin E was associated with a lower risk of developing both AD and Dementia. However the other three antioxidants has no effect on the development or progression of AD. This is consistent with past results that have found that vitamin E has been shown to attenuate toxic effects of Beta-amyloid and improve cognitive performance in rodents.

Lira, Amanda Bastos, and Célio Fernando De Sousa Rodrigues. “Evaluation of oxidative stress markers in obstructive sleep apnea syndrome and additional antioxidant therapy: A review article.” Sleep and Breathing, vol. 20, no. 4, 2016, pp. 1155–1160, https://doi.org/10.1007/s11325-016-1367-3.

Summary: Obstructive sleep apnea syndrome (OSAS) causes a change in the oxidative balance, specifically differences in thioredoxin, malondialdehyde, superoxide dismutase, and iron. The hypoxia and reoxygenation cycles that accompany sleep apnea cause a change in oxidative balance, leading to an increase in free radicals. Thioredoxin levels increased in correlation to the severity of the disease, implying that more severe cases of sleep apnea have increased oxidative stress. This is especially true in more obese patients. However these levels increased in patients that were receiving CPAP (Continuous positive airway pressure) treatment. Other factors studied were SOD levels (antioxidant levels) and products of lipid peroxidation. A significant decrease in SOD occurred in patients with the disease, especially those of mild to moderate severity, when purchased to control (p < 0.05 for all groups), while there was a significant increase in TBARS levels, mainly malondialdehyde, with increasing severity of OSAS. The more severe is the OSAS, the greater the loss of antioxidant capacity of the patient, mainly through a significant lowering of the antioxidant power of reduced iron (FRAP) in OSAS patients than in control. 

Christou, Konstantinos, et al. “Nasal continuous positive airway pressure treatment reduces systemic oxidative stress in patients with severe obstructive sleep apnea syndrome.” Sleep Medicine, vol. 10, no. 1, 2009, pp. 87–94, https://doi.org/10.1016/j.sleep.2007.10.011.

Summary: 46 patients with OSA and 46 controls (those w/o OSA or mild OSA) were assessed were given CPAP treatment and their oxidative stress levels were evaluated via blood samples both the night of treatment (10 pm) and the morning following treatment (7 am). Patients with severe OSA presented higher levels of oxidative stress than patients with mild OSA in the evening and morning. Patients with severe OSA presented a significant reduction the levels of oxidative stress the morning after the CPAP treatment, and this progress was maintained 2 months on treatment. 

Goussakov, Ivan, et al. “Immediate and delayed decrease of long term potentiation and memory deficits after neonatal intermittent hypoxia.” International Journal of Developmental Neuroscience, vol. 74, no. 1, 2019, pp. 27–37, https://doi.org/10.1016/j.ijdevneu.2019.03.001.

Summary: The effect of multiple episodes of severe oxygen desaturation accompanied by bradycardia on late synaptic plasticity and long-term cognitive deficits. 6 mouse pups were exposed to intermittent hypoxia (IH) consisting of alternating cycles of 5% oxygen for 2.5 min and room air for 5–10 min. Long-term potentiation in hippocampal slices were tested (as the hippocampus is involved in learning and memory). Long-term potentiation shows synaptic strength as we know, the more a neuron fires, the more a synapse is used, and the stronger it is. Results showed LTP was decreased in IH group relative to controls at both time points. There were deficits in spatial memory on the Morris water maze and context fear conditioning test in mice exposed to IH compared to the controls. Hypomyelination was observed in multiple gray and white matter areas on in vivo MRI.

Xu, W, et al. “Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea.” Neuroscience, vol. 126, no. 2, 2004, pp. 313–323, https://doi.org/10.1016/j.neuroscience.2004.03.055.

Summary: Chronic intermittent hypoxia (CIH), as occurs in obstructive sleep apnea (SA), is associated with substantial cortico-hippocampal damage leading to impairments of neurocognitive, respiratory and cardiovascular functions. Previous studies in a rat model have shown that CIH increases brain cortical neuronal cell death. Researchers put mice into a chamber and oscillated the oxygen levels to mimic people with OSA and assessed both oxidative damage markers and cell death. There was an increased expression of oxidative stress response markers, c-Fos, c-Jun, and NF-B in the mouse brain cortex. There were increased protein oxidation levels, lipid peroxidation, and nucleic acid oxidation in mouse brain cortex. Furthermore, exposure of mice to CIH induced caspase-3 activation and increased some cortical neuronal cell apoptosis. However, the experiment was repeated with transgenic mice overexpressing Cu, Zn-superoxide dismutase and it was found that there was a lower level of steady-state ROS production and reduced neuronal apoptosis in the brain cortex compared to controls. 

Shen YX, Xu SY, Wei W, Sun XX, Yang J, Liu LH, Dong C. Melatonin reduces memory changes and neural oxidative damage in mice treated with D-galactose. J. Pineal Res. 2002; 32:173–178.

Summary: The purpose is to investigate the role of melatonin in D-galactose-induced amnesic mice and assess cognitive function using the avoidance/escape and water maze tests. In mice treated with D-galactose there are increased levels of Thiobarbituric acid (a byproduct of lipid peroxidation) and decreased levels of antioxidant defenses such as SOD1 and gluthionine peroxidase. In addition, there were severe memory and learning deficits seen. Therefore D-galactose is involved in accelerating the brain aging process by elevating free radical generation and reducing antioxidative enzyme activities in vivo. Amnesic mice treated with melatonin did not exhibit changes in free radical and antioxidant levels, but cognitive results seemed to be improved. 

Row, Barry W., et al. “Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat.” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 11, 2003, pp. 1548–1553, https://doi.org/10.1164/rccm.200209-1050oc.

Summary: Intermittent hypoxia caused by sleep apnea is associated with behavioral impairments and increased apoptosis in the hippocampus specifically the CA1 region. Researchers induced 60 Sprague–Dawley rats with intermittent hypoxia (thus inducing oxidative stress) by changing the oxygen concentration while they slept- g. O2 concentration was continuously measured by an O2 analyzer and was changed by a computerized system controlling gas outlets, as described previously such as to generate a cyclical pattern of 10 and 21% O2 every 90 seconds (IH). There were split into three groups, the controls who were given room air, a group that underwent intermittent hypoxia but were administered with an antioxidant (t PNU-101033E), and a group that underwent IH with no treatment. It was found that IH rats significant impairments of spatial learning in the water maze compared to the controls but they were improved in rats treated with PNU-101033E. 

Yamauchi, Motoo, et al. “Oxidative stress in obstructive sleep apnea.” Chest, vol. 127, no. 5, 2005, pp. 1674–1679, https://doi.org/10.1378/chest.127.5.1674.

Summary: The purpose of this study was to compare the severity of obstructive sleep apnea to oxidative stress. They used 128 participants, who were referred by a hospital to the sleep laboratory. Of the 128 participants, 113 were male and 15 were female. Oxidative stress was measured using the level of 8-hydroxy-2′-deoxyguanosine (8-OHdG) via a urine sample. The results found that 70 subjects had nonsevere OSA (an apnea-hypopnea index [AHI] < 30), and 58 subjects had severe OSA (AHI ≥ 30). Urinary 8-OHdG excretion was significantly higher in the severe OSA group, showing that people with more severe obstructive sleep apnea will exhibit more oxidative stress. 

Massaad, Cynthia A., et al. “Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer’s disease.” Proceedings of the National Academy of Sciences, vol. 106, no. 32, 2009, pp. 13576–13581, https://doi.org/10.1073/pnas.0902714106.

Summary: Researchers measured the SOD-2 levels in Tg2576 mice, SOD-2 overexpression mice and the wild type. Tg2576 mice exhibited higher levels of hippocampal superoxide compared with WT littermate. In Tg2576 mice, there is a further increase in superoxide that was also reduced with SOD-2 overexpression. Then mice were subjected to behavioral testing to evaluate the effects of the transgenes on locomotor activity, motor coordination, and balance. Tg2576 mice have severe associative learning and memory impairments at 8 and 12 months of age, as their freezing behavior was significantly decreased compared with WT littermates. SOD-2 could prevent spatial memory impairments exhibited by the Tg2576 mice (22). Eight- and 12-month-old Tg2576 mice exhibited a severe deficit in spatial memory during the probe test in the Morris water maze. Also, overexpression of SOD-2 in the Tg2576 mice caused a significant reduction in plaque deposition in those 12 months old (Fig. 3), suggesting that mitochondrial superoxide plays a role in A plaque formation. 

Chen, Y.-J., et al. “Protective effects of glucosamine on oxidative-stress and ischemia/reperfusion-induced retinal injury.” Investigative Ophthalmology &amp; Visual Science, vol. 56, no. 3, 2015, pp. 1506–1516, https://doi.org/10.1167/iovs.14-15726.

Summary: The purpose is to investigate the protective effects of glucosamine (GlcN) on oxidative stress in rat models of ischemia-reperfusion (I/R) injury. ROS-induced oxidative stress plays an important role in the pathophysiological mechanism of glaucoma. Glucosamine (GlcN), a naturally occurring amino monosaccharide, exerts a certain degree of immunosuppressive effects and is used as an alternative therapeutic regimen for rheumatoid arthritis and osteoarthritis. Eight-week-old male Sprague-Dawley (SD) rats were used and underwent a surgical procedure for induction of acute glaucoma-induced ischemia-reperfusion injury. The rats were split into 5 groups: the control group (no treatment of any kind), the GlcN group, the SD rats received intraperitoneal injection of 1000 mg/kg (Sigma-Aldrich Corp.), the I/R group, the SD rats were subjected to acute glaucoma-induced I/R injury and intraperitoneal injection of normal saline rather than GlcN, GlcN + I/R group, the SD rats were treated with a single-dose intraperitoneal injection of 1000 mg/kg GlcN and (5) I/R + GlcN group, the SD rats were intraperitoneally injected over a 7-day period with 1000 mg/kg GlcN. GlcN There were increased levels of O-GlcNAc in a dose-dependent manner in the retinal ganglion cells. The GlcN resulted in increased cell survival and reduced apoptosis in the RGCs under oxidative stress conditions and significantly protected against I/R-induced retinal thinning and suppressed the I/R-induced reductions in a- and b-wave amplitudes of the ERG. 

Lee, Yunkyoung, et al. “Hypoxia-induced neuroinflammation and learning–memory impairments in adult zebrafish are suppressed by glucosamine.” Molecular Neurobiology, vol. 55, no. 11, 2018, pp. 8738–8753, https://doi.org/10.1007/s12035-018-1017-9.

Summary: This study investigated changes in neuroinflammation and cognitive function in adult zebrafish exposed to acute hypoxia and protective effects of glucosamine (GlcN) against hypoxia-induced brain damage.  The survival rate of the zebrafish improved following glucosamine treatment. Hypoxia-induced upregulation of neuroglobin, NOS2α, glial fibrillary acidic protein, and S100β in zebrafish was suppressed by GlcN. GlcN decreased the number of bromodeoxyuridine (BrdU)-positive cells in the telencephalon region, but not in cerebellum regions and improved d learning and memory ability previously impaired by hypoxia. Acetylcholine levels were reduced by hypoxia and restored by GlcN. 

Lloyd, Eric E., et al. “Pathological effects of obstructive apneas during the sleep cycle in an animal model of cerebral small vessel disease.” Hypertension, vol. 66, no. 4, 2015, pp. 913–917, https://doi.org/10.1161/hypertensionaha.115.05764.

Summary: Rats between the ages of 8-17 weeks had intratracheal balloons implanted that could be remotely inflated to occlude the trachea as a model for Obstructive Sleep Apnea. All of the rats had the balloons implanted, but only half of them had the balloon inflated for 8 hours while they slept, the other half were the controls. Rats were subjected to repeated apneas (60 apneas per hour for 8 hours during the sleep cycle, with each apnea lasting 10 s) lasting for about 2 weeks. It was found that rats with OSA and older rats tended to have higher systolic blood pressure, higher acceleration of the breakdown of the blood-brain barrier, and a higher activation of microglia. Additionally, it was observed that SHRSP rats exposed to OSA had cognitive deficits that were not observed in sham rats at either age. As CSVD progresses in both humans and rats, white matter tracks can be seen to be disturbed, and myelin basic protein, a major constituent of white matter, can be significantly decreased. However damage to deep brain structures, including disorganization or disarray of white matter tracts, white matter loss, microinfarcts, microbleeds, or astrogliosis, in any SHRSP rats, regardless of age or treatment were seen. 

Chen, Jin, et al. “The protective role of SOD1 overexpression in central mediation of bradycardia following chronic intermittent hypoxia in mice.” American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, vol. 320, no. 3, 2021, https://doi.org/10.1152/ajpregu.00147.2020.

Summary: Wild-type C57BL/6J and the transgenic human Cu/Zn superoxide dismutase mice were used in the experiment. we tested whether human Cu/Zn Superoxide Dismutase (SOD1) overexpression in transgenic mice offers protection against CIH-induced deficit of the baroreflex arc. Mice were either exposed to room air (approximately 21% O2) or Chronic Intermittent Hypoxia (CIH). Mean arterial pressure and heart rate were measured. CIH impaired baroreflex sensitivity but increased maximum baroreceptor gain and bradycardic response to vagal efferent stimulation. Additionally, CIH reduced the bradycardic response to ADN stimulation, indicating a diminished central regulation of bradycardia. Interestingly, SOD1 overexpression prevented CIH-induced attenuation of HR responses to ADN stimulation and preserved HR responses to vagal efferent stimulation in transgenic mice. 

Champod, Anne Sophie, et al. “Effects of acute intermittent hypoxia on working memory in Young healthy adults.” American Journal of Respiratory and Critical Care Medicine, vol. 187, no. 10, 2013, pp. 1148–1150, https://doi.org/10.1164/rccm.201209-1742le.

Summary: They examined the effect of selective exposure to acute IH can directly result in decreased performance on working memory tasks, using healthy adults to eliminate the confound of typical comorbidities. 17 Young males participated in two experiments. Participants were separated into the hypoxia and the controls (normoxia). In study 1, the main effect of the condition was significant, that is, spatial n-back RTs were significantly slower in the experimental IH condition compared with the sham IH (normoxia) condition, however, there was no effect of IH was seen on RTs for verbal n-back tasks. This study demonstrated that short-term exposure to IH per se (i.e., without the confounding influence of sleep fragmentation and medical comorbidities) can negatively impact performance on spatial working memory tasks, even in healthy young adults. 

Ntalapascha, Melpomeni, et al. “Oxidative stress in patients with obstructive sleep apnea syndrome.” Sleep and Breathing, vol. 17, no. 2, 2012, pp. 549–555, https://doi.org/10.1007/s11325-012-0718-y.

Summary: 18 people with OSA were used in the study and 13 controls. Inclusion criteria for OSAS patients were: snoring and apnea–hypopnea index, no previous treatment for OSAS, non-smoking status, and a medical history of being free of comorbidities known to increase oxidative stress. Blood samples were collected for evaluation of oxidative stress biomarkers [protein carbonyls, reduced (GSH) and oxidized (GSSG) glutathione, 8-isoprostane, thiobarbituric acid-reactive substances (TBARS), catalase activity, Cu–Zn superoxide dysmutase (SOD), total antioxidant capacity (TAC) in both before going to sleep and the morning after. The GSH/ GSSG ratio and GSH was significantly different between OSAS and controls specifically at night. Plasma protein carbonyls, erythrocyte catalase activity, 8- isoprostane, SOD, TBARS, and TAC plasma values were not different between OSAS and controls at any time. This is conflicting with previous studies claiming that OSA exacerbates oxidative stress, but that was not the case here. 

Cechetti, Fernanda, et al. “Forced treadmill exercise prevents oxidative stress and memory deficits following chronic cerebral hypoperfusion in the rat.” Neurobiology of Learning and Memory, vol. 97, no. 1, 2012, pp. 90–96, https://doi.org/10.1016/j.nlm.2011.09.008.

Summary: A study was conducted with rats to see if continual exercise impacted both reference and working memory in rats with cerebral hypoperfusion. Both hypoperfusion and oxidative stress have been known to contribute to the development and progression of neurodegenerative diseases such as Alzheimer's Disease and Dementia both of which have an effect on learning and memory. This study was done in rats, in which both carotid arteries were separated from the vagus nerve and occluded with a 5-0 silk suture to induce hypoperfusion. There were three exercise groups (preop, postop and pre+post op) as well as one group that did not exercise (left on a treadmill for 5 mins w/o running stimulus). Rats that exercised, ran for 20 mins, 3 times a week, the speeds progressively each week (for a total of 12 weeks). Three months post-op, rats were tested on memory both reference and working. For reference memory, rats were placed in a pool, facing the wall, and had to find the platform. Then the platform was removed and they had to find the spot where the platform should have been. For working memory, the same technique was used, however the platform remained in the pool but moved for each trial. It was found that forced treadmill running protects from spatial learning and memory deficits in 2VO rats when applied to either post- and pre + - post ischemia. Lipid peroxidation was significantly increased after chronic cerebral hypoperfusion Exercise did not alter the levels of basal free radicals in the hippocampus but increased the levels of antioxidants such as thiols and TBARS. On the other hand, there are also studies where swimming and treadmill training did not affect brain antioxidant defenses. It is proposed that exercise, through its continuous free radical-generating effect, induces the adaptation of the cellular antioxidant system.