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. 2024 May 3;38(3):1162–1169. doi: 10.21873/invivo.13551

The Effect of Propofol on the Hippocampus in Chronic Cerebral Hypoxia in a Rat Model Through Klotho Regulation

HENGCHANG REN 1, MIN ZHU 1, HONGLI YU 1, YIQI WENG 1, WENLI YU 1
PMCID: PMC11059908  PMID: 38688607

Abstract

Background/Aim

Chronic cerebral hypoxia often leads to brain damage and inflammation. Propofol is suggested to have neuroprotective effects under anaesthesia.

Materials and Methods

This study used rat models with carotid artery coarctation or closure. Four groups of rats were compared: a control group, a propofol-treated group, a group with bilateral common carotid artery blockage (BCAO), and a BCAO group treated with propofol post-surgery.

Results

The Morris water maze test indicated cognitive impairment in BCAO rats, which also showed hippocampal structure changes, oxidative stress markers alteration, and reduced Klotho expression. Propofol treatment post-BCAO surgery improved these outcomes, suggesting its potential in mitigating chronic cerebral hypoxia effects.

Conclusion

Propofol may increase klotho levels and reduce apoptosis and inflammation linked to oxidative stress in cognitively impaired mice.

Keywords: Chronic cerebral hypoxia, oxidative stress, propofol, Klotho

Cognitive impairment and vascular dementia are frequently brought on by chronic cerebral hypoxia (CCH), which is also readily followed by inflammation and malfunction of the brain (1-3). The pathophysiological mechanism of dementia and cognitive decline brought on by CCH is unknown at this time. The usage and dose of anesthetics for individuals with CCH is not supported theoretically. Bilateral carotid artery occlusion (BCAO) can simulate chronic cerebral hypoxic injury caused by decreased cerebral blood flow in rats (4). Researchers often use this model to study the related pathological mechanism of chronic cerebral hypoxia (5).

A popular, quick and short-acting intravenous anaesthetic is propofol. Propofol reduces blood pressure and prevents inflammation in addition to causing hypnosis, drowsiness, and amnesia (6). Propofol’s anti-inflammatory and antioxidant activities have received a lot of attention in recent years in studies on its non-anaesthetic effects (7,8). Propofol has antioxidant capabilities, which have been demonstrated to reduce intracellular calcium overload (9,10), inhibit cell apoptosis (11,12), decrease neutrophil numbers (13,14) and endothelial cell adhesion (15), regulate the balance of inflammatory cytokines (16), and improve disorders of cellular energy metabolism (17). Propofol’s impact on brain damage and cognitive decline brought on by CCH in rats remains unknown at this time. In neuronal cell bodies, dendrites and axons, klotho, an anti-ageing protein, is present. It is most prevalent close to the nuclear membrane (18). Klotho knockout mice have early ageing, atherosclerosis, neuronal degeneration, osteoporosis, and aberrant movement patterns resembling Parkinson’s disease (18). Recent research has shown that neuronal Klotho can halt the progression of a number of neurodegenerative illnesses, including multiple sclerosis and Alzheimer’s disease (19). According to recent studies, its capacity to lessen oxidative stress may play a role in its neuroprotective mechanism (19,20). Therefore, increasing Klotho expression enhances neuronal functionality (21-23).

To our knowledge, a rat model of chronic cerebral hypoxia has not been used to assess the impact of propofol on klotho expression. Through this study, it has been hypothesised that propofol influences oxidative stress and processes that may be related to klotho expression. Therefore, in this experiment, histopathology, immunohistochemistry and oxidative stress assays were used to explore the neuroprotective effect of propofol and its influence on klotho, so as to provide a basis for further clarification of pharmacology and a theoretical basis for clinical drug use.

Materials and Methods

Experimental animals. In this investigation, 48 adult male albino rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. that weighed 200-250 g. Throughout the acclimatization and experimental phases, they were maintained in regulated temperature (23˚C), relative humidity, and light with a 12:12-hr light/dark cycle. They had unrestricted access to food and liquids.

Experimental design and treatments. A total of 48 rats were allocated into 4 groups at random, with 12 rats in each group: blank control group, propofol group, BCAO group, and BCAO+propofol group. BCAO rats were operated on at 200-250 g body weight at 8 weeks after birth. According to references (5,22,23), a 0.7% solution of pentobarbital sodium anaesthesia, with a dosage of 1 ml/mg, was administered to ligate the bilateral carotid arteries. This procedure includes making an incision in the skin, performing a blunt dissection of the nerves and the common carotid artery located beneath the thyroid gland, and permanently ligating the bilateral common carotid arteries using silk threads. Rats in both the control and propofol groups were subjected to the administration of pentobarbital, followed by the excision and stitching of the neck skin as part of a sham surgical procedure. 24 hrs after the surgical procedure, propofol (7.5 mg/kg/h) (24) was intravenously administered to the rats in the propofol group and the propofol+BCAO group for three consecutive days for one hour a day. An identical amount of intravenous normal saline was administered to the rats in the control and BCAO category.

The Tianjin First Central Hospital’s committee on animal experimentation established norms and guidelines were followed in all experiments. Natural Science Foundation of China (82072219) & Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-045A) both authorised this study.

Morris Water Maze (MWM) assay. MWM assessment was used to determine the rats’ cognitive function. Four weeks after receiving a propofol intravenous infusion, rats were put through a water maze test. The circumferential pool of the water labyrinth is 180 cm in diameter, 45 cm high, and 30 cm deep. A platform with a diameter of 12 cm is built at a height of 25 cm. With the aid of two vertical threads, the pool was divided into four equal quadrants. The rats were given 2 min to swim around in the pool on the first day of the experiment. Spatial training tests were performed on days 2 to 5, with a single session of 120 s and three times each day at set intervals in each of the four quadrants. During the whole experiment, the platform’s location remained constant. The rat was placed in the water, and the escape latency needed for it to locate and ascend onto the transparent platform was recorded using a computer. The platform was taken down on the sixth day, the space exploration experiment was carried away, and both the number of times the space passed the platform and the time it took to travel from the opposite quadrant to the intended area was noted. The changes in escape latency between the model and control groups were calculated.

Specimen collection. The rats were given intraperitoneal injections of xylazine (15 mg/kg) and ketamine (90 mg/kg) to provide anaesthesia and were then sacrificed. The brain was cut in two pieces, with one half being fixed in saline and the other being homogenised for quantitative examination of oxidative stress indicators (MDA, ROS, and SOD) and western blotting to explore the changes in Klotho, Caspase-3, Capsase-8, GFAP, S100β, TNFα RIP3, and RIP1 protein expression.

Evaluation of oxidative stress. In the brain tissue homogenate, the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and superoxide dismutase (SOD) were measured. The ROS kit (CA1410, Solarbo, PR China), the SOD kit (BC0175, Solarbo), and the MDA kit (BC0025, Solarbo) were used to determine the oxidative stress levels.

Western blotting. Western blotting experiments were performed to explore the changes of Klotho, caspase-3, Capsase-8, GFAP, S100β, TNFα RIP3 and RIP1 protein expression. Antibodies used in the experiment were: rabbit monoclonal to Klotho (1:1,000, ab181373, Abcam, Cambridge, MA, USA), rabbit monoclonal to Caspase-3 (1:1,000, ab184787, Abcam), Caspase-8 (1:500, ab25901, Abcam), rabbit monoclonal to GFAP (1:2,000, ab7260, Abcam), rabbit polyclonal to TNFα (1:1,000, ab183218, Abcam) rabbit monoclonal to RIP3 (1:2,000, ab305054, Abcam) and rabbit polyclonal to RIP1 (1:1,000, ab300617, Abcam,). All antibodies were incubated at 4˚C overnight. The secondary IgG H&L (HRP) (1:1,000, ab6721, Abcam) was incubated at 37˚C for 1h. The membrane was imaged using a Bio-Rad ChemiDoc imaging system (Bio-Rad, Shanghai, PR China) for gray value analysis.

Golgi staining. Golgi staining was carried out to observe the neurogenic change after injury and propofol by photographing dendritic spines for dendritic spine density calculation. The FD Rapid Golgi StainTM Kit (PK410) was used for Golgi staining. Fresh, unperfumed rat brain was rapidly washed in normal saline, before following the manufacturer’s instructions. Light microscopy was used to observe and photograph dendritic spines for dendritic spine density calculation.

Statistical analysis. Data analysis was done using SPSS, version 20.0 (IBM, Armonk, NY, USA). The data are presented as mean and standard deviation. A two-way ANOVA was performed to compare data from various groups, followed by Tukey’s post-hoc analysis. Statistical significance was set at p<0.05. GraphPad Prism 10.1.0 (GraphPad, San Diego, CA, USA) was used for all data visualization.

Results

Effect of propofol on working memory and impact on indicators of oxidative stress. In this investigation, the delay time of BCAO rats was significantly reduced in comparison to the control group. In contrast to the BCAO group, the injection of propofol into rats with BCAO significantly increased the duration of the latency time. There was no significant variation seen between the propofol category and the control group (Table I).

Table I. Water Morris maze test latency times for the various groups.

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*Significant (p<0.05) vs. the control category; #significant (p<0.05) vs. the propofol category; ^significant (p<0.05) vs. the BCAO category.

Hippocampal MDA and ROS levels increased in BCAO animals, but SOD levels significantly decreased. In comparison to the BCAO group, propofol treatment of BCAO rats considerably reduced MDA and ROS levels and significantly enhanced SOD levels. Excessive increases in ROS levels can trigger severe oxidative stress. SOD is a crucial antioxidant enzyme that clears cations by mimicking free radicals. Lipid peroxidation produces MDA. These are all indications of oxidative stress (25,26). The propofol and control categories did not vary in a way that was statistically significant (Figure 1A, B, and C).

Figure 1. Bar charts illustrating (A) the reactive oxygen species (ROS), (B) the superoxide dismutase (SOD), and (C), the malondialdehyde (MDA) levels, across the control, propofol, BCAO and BCAO & Propofol groups. *Significant vs. control (p<0.05); #significant vs. propofol (p<0.05); ^significant vs. BCAO (p<0.05).

Figure 1

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Effect of propofol on dendritic spines in the CA1 area of the hippocampus. Golgi staining was conducted to observe the neurogenic change after injury and propofol by photographing dendritic spines for dendritic spine density calculation. Dendritic spine density increased significantly in BCAO rats. Both the control and propofol categories of dendritic spines in the CA1 region had normal densities. When compared to BCAO animals, propofol administration significantly boosted the number of dendritic spines (Figure 2A and B).

Figure 2. (A) Golgi-Cox-stained pyramidal neurons in the CA1 region from every group. Scale bars, 20 mm, and 2 mm. (B) Histogram illustrating the density of dendritic spines from 12 neurons. *significant vs. control (p<0.05); #significant vs. propofol (p<0.05); Scale bars: 20 and 2 mm.

Figure 2

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Propofol’s impact on Klotho expression and apoptosis. In the propofol and control categories, klotho immune expression was seen in the rat hippocampus region. The propofol and control categories did not vary significantly. Comparing BCAO rats to the control category, a substantial drop in Klotho protein was observed. Comparing the BCAO category to the propofol-treated BCAO rats, the Klotho protein expression level increased significantly (Figure 3A and B).

Figure 3. (A) Western blot of Klotho protein expression in the hippocampal region from the control, propofol, BCAO and BCAO & Propofol groups. (B) The corresponding bar chart shows the klotho relative protein expression. (C) Western blots showing the expression of Caspase-3 and 8 in the hippocampal region from the 4 groups and (D) Corresponding bar charts show the Caspase-3 and 8 relative expression. (E) Western blots of GFAP, S100β and TNF-α in the hippocampal region from the 4 groups and (F) Corresponding bar charts show the GFAP, S100β and TNF-α relative expression. (G) Western blots of RIP1 and RIP3 in the hippocampal region from the 4 groups and (H) Corresponding bar charts show the RIP1 and RIP3 relative expressions. *Significant vs. control (p<0.05); #significant vs. propofol (p<0.05).

Figure 3

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Both caspase-3 and 8 are important apoptosis-related proteins, while RIP1 and 3 are downstream proteins of apoptosis, closely related to oxidative stress (27). The expression of caspase-3 and 8 in the propofol and control categories did not differ significantly. Caspase-3 and 8 levels were significantly higher in BCAO rats. When compared to the control category, the caspase-3 and 8 levels were significantly higher in the BCAO cohort. In comparison to the BCAO category, caspase-3 and 8 expression was significantly reduced in BCAO rats treated with propofol (Figure 3C and D). There was no discernible variation in the expression of RIP1 and 3 between the propofol and control categories. RIP1 and 3 levels in BCAO rats were reportedly higher than in the control category. In comparison to the BCAO category, the BCAO rats’ expression of caspase-3 and 8 was significantly reduced after propofol administration (Figure 3G and H). Compared to the BCAO category, propofol-treated BCAO animals had more clearly reduced necroptosis.

Effect of propofol on inflammation. GFAP is a marker of astrocytes associated with astrocyte activation and neuroinflammation, which secrete TNFα, a factor closely related to inflammation (28,29). Studies have shown that when hypoxia occurs, glial cells may be activated. S100β is a marker of resting astrocytes. GFAP, S100β, and TNFα expression in the control and propofol categories showed no significant transformation. BCAO rats showed increased levels of GFAP and TNFα and lower expression of S100β compared to the control and propofol group. When compared to the BCAO category, only the propofol administered to BCAO rats significantly reduced TNF-α expression (Figure 3E and F).

Discussion

BCAO rats exhibited clear cognitive dysfunction and impaired working memory, consistent with previous studies (30). Chronic cerebral hypoxia caused by carotid artery stenosis triggers increased oxidative stress in the brain and produces excess ROS (31,32). The cerebral microenvironment is altered by oxidative stress, which causes cerebellar shrinkage, apoptosis, increasing cellular damage, and myelin abnormalities (33).

At present, research has found histopathological changes in the hippocampus of BCAO rats. Pyramidal neurons’ dendritic ridge density and klotho expression in the CA1 region of the hippocampus decreased considerably when compared to the control category. Chronic hypoxia may be to blame for this through the induction of oxidative stress (34,35). In mouse and human kidney cell lines, Morii et al. (36) discovered that oxidative stress damage brought on by oxygen free radicals inhibited klotho expression in a dose-dependent manner. The aberrant working memory deficit seen in BCAO may be connected to these pathological alterations (37).

Klotho is an anti-ageing protein. According to several studies, increased Klotho expression guards against disorders that cause brain degeneration (38). Age-related disorders and ageing are slowed down by increasing endogenous Klotho expression or giving exogenous Klotho (39). It can therefore be viewed as a novel treatment to promote a healthy brain (40). Although the exact mechanism of Klotho neuronal protection is unknown, the following mechanism has been proposed: Klotho protein has antioxidant activity, possibly as a result of its function in triggering antioxidant enzymes (41). Klotho has also shown anti-apoptotic effects by enhancing erythropoietin expression (42,43), thereby preventing oxidative stress and apoptosis (44). In line with these, mice lacking Klotho have been reported to exhibit premature ageing, learning, and memory difficulties (38). This may partly explain the impairment of working memory in BCAO rats in this study, and the reduction of dendritic spines in the hippocampus.

Propofol is a commonly used intravenous anesthetic in clinical practice that can cross the blood-brain barrier to exert anesthesia (5). Studies have found that appropriate doses of propofol have antioxidant and anti-apoptotic effects (5). Recent studies have reported that certain doses of propofol have neuroprotective effects against degenerative neurological diseases such as Alzheimer’s disease and vascular dementia (45). In the present study, researchers found that, compared with the BCAO group, the dendritic spine density and the level of working memory impairment were significantly reduced in BCAO rats treated with a propofol continuous infusion. Some researchers reported similar symptom relief in a model of acute cerebral ischemia using a continuous infusion of propofol, attributed to the antioxidant and vasodilatory effects of propofol (46,47). Compared with the BCAO group, the use of propofol reduced the level of oxidative stress in the rat hippocampus, decreased epitope ROS, and increased MDA and SOD. This is in line with recent research showing that propofol increases antioxidant enzymes to provide antioxidant effects. In our study, continuous infusions of propofol reduced injury during the pathogenesis of chronic cerebral ischemia. Compared with the BCAO group, hippocampal vertebral neuron damage was reduced in rats receiving a continuous infusion of propofol postoperatively.

In our work, propofol increased the expression of klotho protein in rat hippocampal tissue compared to the BCAO group. Ergün et al. (48) reported that propofol had neuroprotective effects on global cerebral ischemia rats. Kuwahara et al. (49) demonstrated that in rats with chronic nitric oxide production inhibition, statins improved klotho expression and arteriosclerosis.

Propofol had beneficial effects on apoptosis and necroptosis in this work. The BCAO animals given propofol had considerably less Caspase-3 and 8 protein expression in their hippocampus as compared to the BCAO cohort. Some researchers have reported that propofol protects hippocampal cells from apoptosis by activating anti-apoptotic proteins and inhibiting pro-apoptotic proteins in an acute ischemia-reperfusion mouse model (50). In this study, it was shown that propofol also had effects on necroptosis. The RIP1 and 3 essential phosphatases and the Caspase-8 necroptosis marker were changed in BCAO with the propofol group. Propofol causes the production of bcl-2, which, in turn, has an anti-apoptotic impact. TNFα, an inflammatory marker, nevertheless, also showed a connection with the neuroprotective properties of propofol in our experiments (29). The decrease in apoptosis and necroptosis might be the cause of propofol’s influence on Klotho expression. Recombinant Klotho protein has been shown to prevent H2O2- and etoposide-induced apoptosis in human umbilical endothelial cells (51). Rats receiving a continuous infusion of propofol postoperatively had improved motor performance and working memory, with significantly lower latency in the water maze compared to BCAO. Overall, the findings concerning oxidative markers and histopathological features may provide valuable new insights into this phenomenon.

Conclusion

The study confirms propofol’s neuroprotective effects in rats after bilateral common carotid artery blockage, attributed to its antioxidant, anti-apoptotic properties, and promotion of Klotho expression, which is crucial for cellular homeostasis. Further research is needed to explore the underlying mechanisms.

Conflicts of Interest

The Authors declare no conflicts of interest.

Authors’ Contributions

This study was designed by Ren. Hengchang and Yu Wenli. Ren. Hengchang, Zhu Min, Yu Hongli and Weng Yiqi collected and analyzed the data. The manuscript was written by Ren Hengchang. The finished work was approved by all Authors.

Acknowledgements

This work was supported by the Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-045A) and Natural Science Foundation of China (No.82072219).

References

  • 1.Snyder B, Simone SM, Giovannetti T, Floyd TF. Cerebral hypoxia: its role in age-related chronic and acute cognitive dysfunction. Anesth Analg. 2021;132(6):1502–1513. doi: 10.1213/ANE.0000000000005525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Liu X, Ma Y, Ouyang R, Zeng Z, Zhan Z, Lu H, Cui Y, Dai Z, Luo L, He C, Li H, Zong D, Chen Y. The relationship between inflammation and neurocognitive dysfunction in obstructive sleep apnea syndrome. J Neuroinflammation. 2020;17(1):229. doi: 10.1186/s12974-020-01905-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Raz L, Knoefel J, Bhaskar K. The neuropathology and cerebrovascular mechanisms of dementia. J Cereb Blood Flow Metab. 2016;36(1):172–186. doi: 10.1038/jcbfm.2015.164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Wang J, Yang C, Wang H, Li D, Li T, Sun Y, Zhao M, Ma J, Hua W, Yang Z. A new rat model of chronic cerebral hypoperfusion resulting in early-stage vascular cognitive impairment. Front Aging Neurosci. 2020;12:86. doi: 10.3389/fnagi.2020.00086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Yang Y, Kimura-Ohba S, Thompson J, Rosenberg GA. Rodent models of vascular cognitive impairment. Transl Stroke Res. 2016;7(5):407–414. doi: 10.1007/s12975-016-0486-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Walsh CT. Propofol: Milk of amnesia. Cell. 2018;175(1):10–13. doi: 10.1016/j.cell.2018.08.031. [DOI] [PubMed] [Google Scholar]
  • 7.Vasileiou I, Xanthos T, Koudouna E, Perrea D, Klonaris C, Katsargyris A, Papadimitriou L. Propofol: A review of its non-anaesthetic effects. Eur J Pharmacol. 2009;605(1-3):1–8. doi: 10.1016/j.ejphar.2009.01.007. [DOI] [PubMed] [Google Scholar]
  • 8.Meiser A, Volk T, Wallenborn J, Guenther U, Becher T, Bracht H, Schwarzkopf K, Knafelj R, Faltlhauser A, Thal SC, Soukup J, Kellner P, Drüner M, Vogelsang H, Bellgardt M, Sackey P, Sedaconda study group Inhaled isoflurane via the anaesthetic conserving device versus propofol for sedation of invasively ventilated patients in intensive care units in Germany and Slovenia: an open-label, phase 3, randomised controlled, non-inferiority trial. Lancet Respir Med. 2021;9(11):1231–1240. doi: 10.1016/S2213-2600(21)00323-4. [DOI] [PubMed] [Google Scholar]
  • 9.Lucchinetti E, Wang L, Ko KW, Troxler H, Hersberger M, Zhang L, Omar MA, Lopaschuk GD, Clanachan AS, Zaugg M. Enhanced glucose uptake via GLUT4 fuels recovery from calcium overload after ischaemia–reperfusion injury in sevoflurane- but not propofol-treated hearts. Br J Anaesth. 2011;106(6):792–800. doi: 10.1093/bja/aer065. [DOI] [PubMed] [Google Scholar]
  • 10.Bickler PE, Warren DE, Clark JP, Gabatto P, Gregersen M, Brosnan H. Anesthetic protection of neurons injured by hypothermia and rewarming: roles of intracellular Ca2+ and excitotoxicity. Anesthesiology. 2012;117(2):280–292. doi: 10.1097/ALN.0b013e318260a7b9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Lv X, Zhou X, Yan J, Jiang J, Jiang H. Propofol inhibits LPS-induced apoptosis in lung epithelial cell line, BEAS-2B. Biomed Pharmacother. 2017;87:180–187. doi: 10.1016/j.biopha.2016.12.074. [DOI] [PubMed] [Google Scholar]
  • 12.Sun L, Ma W, Gao W, Xing Y, Chen L, Xia Z, Zhang Z, Dai Z. Propofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome. Cell Death Dis. 2019;10(8):542. doi: 10.1038/s41419-019-1761-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Mayor D. Handbook of experimental pharmacology. New Series Vol. 33. Catecholamines. J Anat 114(Pt. 1973;2):284–285. [Google Scholar]
  • 14.Chen CY, Tsai YF, Huang WJ, Chang SH, Hwang TL. Propofol inhibits endogenous formyl peptide-induced neutrophil activation and alleviates lung injury. Free Radic Biol Med. 2018;129:372–382. doi: 10.1016/j.freeradbiomed.2018.09.048. [DOI] [PubMed] [Google Scholar]
  • 15.Ji H, Qiu R, Gao X, Zhang R, Li X, Hei Z, Yuan D. Propofol attenuates monocyte-endothelial adhesion via modulating connexin43 expression in monocytes. Life Sci. 2019;232:116624. doi: 10.1016/j.lfs.2019.116624. [DOI] [PubMed] [Google Scholar]
  • 16.Yang P, Yang N, Zhang X, Xu X. The significance and mechanism of propofol on treatment of ischemia reperfusion induced lung injury in rats. Cell Biochem Biophys. 2014;70(3):1527–1532. doi: 10.1007/s12013-014-0088-0. [DOI] [PubMed] [Google Scholar]
  • 17.Li J, Wu G, Song W, Liu Y, Han Z, Shen Z, Li Y. Prophylactic melatonin treatment ameliorated propofol-induced cognitive dysfunction in aged rats. Neurotox Res. 2021;39(2):227–239. doi: 10.1007/s12640-020-00307-9. [DOI] [PubMed] [Google Scholar]
  • 18.Buchanan S, Combet E, Stenvinkel P, Shiels PG. Klotho, aging, and the failing kidney. Front Endocrinol (Lausanne) 2020;11:560. doi: 10.3389/fendo.2020.00560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Neyra JA, Hu MC, Moe OW. Klotho in clinical nephrology: Diagnostic and therapeutic implications. Clin J Am Soc Nephrol. 2020;16(1):162–176. doi: 10.2215/CJN.02840320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Torbus-Paluszczak M, Bartman W, Adamczyk-Sowa M. Klotho protein in neurodegenerative disorders. Neurol Sci. 2018;39(10):1677–1682. doi: 10.1007/s10072-018-3496-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Xu Y, Sun Z. Molecular basis of Klotho: from gene to function in aging. Endocr Rev. 2015;36(2):174–193. doi: 10.1210/er.2013-1079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Li T, Mo X, Jiang Z, He W, Lu W, Zhang H, Zhang J, Zeng L, Yang B, Xiao H, Hu Z. Study of αB-crystallin expression in Gerbil BCAO model of transient global cerebral ischemia. Oxid Med Cell Longev. 2012;2012:945071. doi: 10.1155/2012/945071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Ren Q, Zhang XF, Yang JY. Erythropoietin reduces white matter damage in two-day-old rats exposed to hypoxic/ischemia injury. Neurol Res. 2016;38(11):1020–1026. doi: 10.1080/01616412.2016.1242451. [DOI] [PubMed] [Google Scholar]
  • 24.Jevtović-Todorović V, Kirby CO, Olney JW. Isoflurane and propofol block neurotoxicity caused by MK-801 in the rat posterior cingulate/retrosplenial cortex. J Cereb Blood Flow Metab. 1997;17(2):168–174. doi: 10.1097/00004647-199702000-00006. [DOI] [PubMed] [Google Scholar]
  • 25.Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med. 2002;33(3):337–349. doi: 10.1016/s0891-5849(02)00905-x. [DOI] [PubMed] [Google Scholar]
  • 26.Li R, Jia Z, Trush MA. Defining ROS in biology and medicine. React Oxyg Species (Apex) 2016;1(1):9–21. doi: 10.20455/ros.2016.803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Nagata S. Apoptosis and clearance of apoptotic cells. Annu Rev Immunol. 2018;36(1):489–517. doi: 10.1146/annurev-immunol-042617-053010. [DOI] [PubMed] [Google Scholar]
  • 28.Danielson M, Wiklund A, Granath F, Blennow K, Mkrtchian S, Nellgård B, Oras J, Jonsson Fagerlund M, Granström A, Schening A, Rasmussen LS, Erlandsson Harris H, Zetterberg H, Ricksten SE, Eriksson LI. Neuroinflammatory markers associate with cognitive decline after major surgery: Findings of an explorative study. Ann Neurol. 2020;87(3):370–382. doi: 10.1002/ana.25678. [DOI] [PubMed] [Google Scholar]
  • 29.Dahlke C, Saberi D, Ott B, Brand-Saberi B, Schmitt-John T, Theiss C. Inflammation and neuronal death in the motor cortex of the wobbler mouse, an ALS animal model. J Neuroinflammation. 2015;12:215. doi: 10.1186/s12974-015-0435-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Yang Y, Kimura-Ohba S, Thompson J, Rosenberg GA. Rodent models of vascular cognitive impairment. Transl Stroke Res. 2016;7(5):407–414. doi: 10.1007/s12975-016-0486-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Peers C, Pearson HA, Boyle JP. Hypoxia and Alzheimer’s disease. Essays Biochem. 2007;43:153–164. doi: 10.1042/BSE0430153. [DOI] [PubMed] [Google Scholar]
  • 32.Zhao YS, Tan M, Song JX, An JR, Yang XY, Li WY, Guo YJ, Ji ES. Involvement of hepcidin in cognitive damage induced by chronic intermittent hypoxia in mice. Oxid Med Cell Longev. 2021;2021:8520967. doi: 10.1155/2021/8520967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Roberts RA, Laskin DL, Smith CV, Robertson FM, Allen EM, Doorn JA, Slikker W. Nitrative and oxidative stress in toxicology and disease. Toxicol Sci. 2009;112(1):4–16. doi: 10.1093/toxsci/kfp179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Netzer N, Gatterer H, Faulhaber M, Burtscher M, Pramsohler S, Pesta D. Hypoxia, oxidative stress and fat. Biomolecules. 2015;5(2):1143–1150. doi: 10.3390/biom5021143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Wu X, Gong L, Xie L, Gu W, Wang X, Liu Z, Li S. NLRP3 deficiency protects against intermittent hypoxia-induced neuroinflammation and mitochondrial ROS by promoting the PINK1-parkin pathway of mitophagy in a murine model of sleep apnea. Front Immunol. 2021;12:628168. doi: 10.3389/fimmu.2021.628168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Morii K, Yamasaki S, Doi S, Irifuku T, Sasaki K, Doi T, Nakashima A, Arihiro K, Masaki T. microRNA-200c regulates KLOTHO expression in human kidney cells under oxidative stress. PLoS One. 2019;14(6):e0218468. doi: 10.1371/journal.pone.0218468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Urabe A, Doi S, Nakashima A, Ike T, Morii K, Sasaki K, Doi T, Arihiro K, Masaki T. Klotho deficiency intensifies hypoxia-induced expression of IFN-α/β through upregulation of RIG-I in kidneys. PLoS One. 2021;16(10):e0258856. doi: 10.1371/journal.pone.0258856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Abraham CR, Mullen PC, Tucker-Zhou T, Chen CD, Zeldich E. Klotho is a neuroprotective and cognition-enhancing protein. Vitam Horm. 2016;101:215–238. doi: 10.1016/bs.vh.2016.02.004. [DOI] [PubMed] [Google Scholar]
  • 39.Kuro-O M. Klotho and calciprotein particles as therapeutic targets against accelerated ageing. Clin Sci (Lond) 2021;135(15):1915–1927. doi: 10.1042/CS20201453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Vo HT, Laszczyk AM, King GD. Klotho, the key to healthy brain aging. Brain Plast. 2018;3(2):183–194. doi: 10.3233/BPL-170057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Boksha IS, Prokhorova TA, Savushkina OK, Tereshkina EB. Klotho protein: Its role in aging and central nervous system pathology. Biochemistry (Mosc) 2017;82(9):990–1005. doi: 10.1134/S0006297917090024. [DOI] [PubMed] [Google Scholar]
  • 42.Maltese G, Fountoulakis N, Siow RC, Gnudi L, Karalliedde J. Perturbations of the anti-ageing hormone Klotho in patients with type 1 diabetes and microalbuminuria. Diabetologia. 2017;60(5):911–914. doi: 10.1007/s00125-017-4219-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Maltese G, Psefteli PM, Rizzo B, Srivastava S, Gnudi L, Mann GE, Siow RC. The anti-ageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells. J Cell Mol Med. 2017;21(3):621–627. doi: 10.1111/jcmm.12996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Cheng MF, Chen LJ, Niu HS, Yang TT, Lin KC, Cheng JT. Signals mediating Klotho-induced neuroprotection in hippocampal neuronal cells. Acta Neurobiol Exp (Wars) 2015;75(1):60–71. doi: 10.55782/ane-2015-2016. [DOI] [PubMed] [Google Scholar]
  • 45.Fan W, Zhu X, Wu L, Wu Z, Li D, Huang F, He H. Propofol: an anesthetic possessing neuroprotective effects. Eur Rev Med Pharmacol Sci. 2015;19(8):1520–1529. [PubMed] [Google Scholar]
  • 46.Xu F, Ma R, Zhang G, Wang S, Yin J, Wang E, Xiong E, Zhang Q, Li Y. Estrogen and propofol combination therapy inhibits endoplasmic reticulum stress and remarkably attenuates cerebral ischemia-reperfusion injury and OGD injury in hippocampus. Biomed Pharmacother. 2018;108:1596–1606. doi: 10.1016/j.biopha.2018.09.167. [DOI] [PubMed] [Google Scholar]
  • 47.Hausburg MA, Banton KL, Roman PE, Salgado F, Baek P, Waxman MJ, Tanner A 2nd, Yoder J, Bar-Or D. Effects of propofol on ischemia-reperfusion and traumatic brain injury. J Crit Care. 2020;56:281–287. doi: 10.1016/j.jcrc.2019.12.021. [DOI] [PubMed] [Google Scholar]
  • 48.Ergün R, Akdemir G, Şen S, Taşçı A, Ergüngör F. Neuroprotective effects of propofol following global cerebral ischemia in rats. Neurosurg Rev. 2002;25(1-2):95–98. doi: 10.1007/s101430100171. [DOI] [PubMed] [Google Scholar]
  • 49.Narumiya H, Sasaki S, Kuwahara N, Irie H, Kusaba T, Kameyama H, Tamagaki K, Hatta T, Takeda K, Matsubara H. HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. Cardiovasc Res. 2004;64(2):331–336. doi: 10.1016/j.cardiores.2004.07.011. [DOI] [PubMed] [Google Scholar]
  • 50.Chen L, Xue Z, Jiang H. Effect of propofol on pathologic time-course and apoptosis after cerebral ischemia–reperfusion injury. Acta Anaesthesiol Scand. 2008;52(3):413–419. doi: 10.1111/j.1399-6576.2007.01560.x. [DOI] [PubMed] [Google Scholar]
  • 51.Romero A, San Hipólito-Luengo Á, Villalobos LA, Vallejo S, Valencia I, Michalska P, Pajuelo-Lozano N, Sánchez-Pérez I, León R, Bartha JL, Sanz MJ, Erusalimsky JD, Sánchez-Ferrer CF, Romacho T, Peiró C. The angiotensin-(1-7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation. Aging Cell. 2019;18(3):e12913. doi: 10.1111/acel.12913. [DOI] [PMC free article] [PubMed] [Google Scholar]

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