scholarly journals Maternal Exposure to Sevoflurane Disrupts Oligodendrocyte Myelination of the Postnatal Hippocampus and Induces Cognitive and Motor Impairments in Offspring

2021 ◽  
Author(s):  
Ze Fan ◽  
Lirong Liang ◽  
Ruixue Ma ◽  
Rougang Xie ◽  
Youyi Zhao ◽  
...  
Keyword(s):  
Motor Coordination ◽  
Maternal Exposure ◽  
Morris Water Maze Test ◽  
The Novel ◽  
Motor Impairments ◽  
Object Recognition Test ◽  
Maze Test ◽  
Transmission Electron ◽  
Proliferation And Differentiation ◽  
Oligodendrocyte Precursor

Abstract Maternal exposure to sevoflurane can impose significant neurocognitive risks on the developing brain of infants. Several studies have indicated that oligodendrocytes may be involved in sevoflurane-induced neurotoxicity, but the concrete effects of sevoflurane on the development and myelination of oligodendrocytes remain unclear. In this study, we assessed fetal myelination and neural behavior after maternal exposure to sevoflurane. Pregnant C57BL/6J mice (gestational day 15.5) were exposed to sevoflurane (2.5%) for 6 h. The cognitive function and motor coordination of offspring (8 weeks of age) were determined via the novel object recognition test, the Morris water maze test and the accelerating rotarod test. Proliferation and differentiation of cultured oligodendrocyte precursor cells (OPCs) were detected via immunocytochemistry. Expression and ultrastructure of myelin in the fetal hippocampus were analyzed using immunohistochemistry and transmission electron microscopy (TEM). Myelin-associated genes and proteins were tested via qRT-PCR, immunofluorescence and western blotting. The functionality of myelin was evaluated by electrophysiology. The results showed that maternal exposure to sevoflurane induced cognitive and motor impairments in infants, accompanied by inhibitions of OPC proliferation and differentiation, and damages of myelin structure. Myelin-associated genes and proteins (including MBP, Olig1, PDNFRα, Sox10, etc.) were downregulated. The conduction velocity of axons also declined. These results suggested that maternal exposure to sevoflurane could induce detrimental effects on cognitive and motor functions in offspring, which might be associated with disrupted myelination of oligodendrocytes in the hippocampus.

scholarly journals Effects of Pueraria candollei var mirifica (Airy Shaw and Suvat.) Niyomdham on Ovariectomy-Induced Cognitive Impairment and Oxidative Stress in the Mouse Brain

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3442
Author(s):  
Yaowared Chulikhit ◽  
Wichitsak Sukhano ◽  
Supawadee Daodee ◽  
Waraporn Putalun ◽  
Rakvajee Wongpradit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
Morris Water Maze Test ◽  
Object Recognition Test ◽  
Pueraria Mirifica ◽  
Beneficial Effects ◽  
Maze Test ◽  
Y Maze ◽  
Tnf Α ◽  
17Β Estradiol

The effects of the phytoestrogen-enriched plant Pueraria mirifica (PM) extract on ovari-ectomy (OVX)-induced cognitive impairment and hippocampal oxidative stress in mice were investigated. Daily treatment with PM and 17β-estradiol (E2) significantly elevated cognitive behavior as evaluated by using the Y maze test, the novel object recognition test (NORT), and the Morris water maze test (MWM), attenuated atrophic changes in the uterus and decreased serum 17β-estradiol levels. The treatments significantly ameliorated ovariectomy-induced oxidative stress in the hippocampus and serum by a decrease in malondialdehyde (MDA), an enhancement of superoxide dismutase, and catalase activity, including significantly down-regulated expression of IL-1β, IL-6 and TNF-α proinflammatory cytokines, while up-regulating expression of PI3K. The present results suggest that PM extract suppresses oxidative brain damage and dysfunctions in the hippocampal antioxidant system, including the neuroinflammatory system in OVX animals, thereby preventing OVX-induced cognitive impairment. The present results indicate that PM exerts beneficial effects on cognitive deficits for which menopause/ovariectomy have been implicated as risk factors.

scholarly journals Biological Evaluation of Newly Synthesized Biaryl Guanidine Derivatives to Arrest β-Secretase Enzymatic Activity Involved in Alzheimer’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Sayyad Ali ◽  
Muhammad Hassham Hassan Bin Asad ◽  
Fahad Khan ◽  
Ghulam Murtaza ◽  
Albert A. Rizvanov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Evaluation ◽  
Morris Water Maze Test ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Object Recognition Test ◽  
Promising Target

Proteases BACE1 (β-secretases) enzymes have been recognized as a promising target associated with Alzheimer’s disease (AD). This study was carried out on the principles of molecular docking, chemical synthesis, and enzymatic inhibition of BACE1 enzymes via biaryl guanidine-based ligands. Based on virtual screening, thirteen different compounds were synthesized and subsequently evaluated via in vitro and in vivo studies. Among them, 1,3-bis(5,6-difluoropyridin-3-yl)guanidine (compound (9)) was found the most potent (IC50=97±0.91 nM) and active to arrest (99%) β-secretase enzymes (FRET assay). Furthermore, it was found to improve the novel object recognition test and Morris water maze test significantly (p<0.05). Improved pharmacokinetic parameters, viz., Log Po/w (1.76), Log S (-2.73), and better penetration to the brain (BBB permeation) with zero Lipinski violation, made it possible to hit the BACE1 as a potential therapeutic source for AD.

scholarly journals Neonatal Anesthesia by Ketamine in Rats Interferes with Proliferation and Differentiation of Hippocampal Neural Stem Cells and Neurocognitive Function in Adulthood via Inhibition of Notch1 Signalling Pathway

2021 ◽  
Author(s):  
He Huang ◽  
Chao Zhao ◽  
Qian Hu ◽  
Qiang Liu ◽  
Yi-Man Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Water Maze ◽  
Notch Signalling ◽  
Signalling Pathway ◽  
Morris Water Maze Test ◽  
Notch Signalling Pathway ◽  
Maze Test ◽  
Proliferation And Differentiation ◽  
Old Rats ◽  
Related Proteins

Abstract Objective: The proliferation and differentiation of developing neural stem cells (NSCs) have been particularly interesting targets to study ketamine-induced neurotoxicity. Our previous findings have shown that neonatal ketamine exposure inhibits the proliferation of NSCs in the hippocampal dentate gyrus (DG) and promotes neuronal differentiation. However, the potential mechanisms are poorly understood. Notch signalling pathway plays an important role in the regulation of neurogenesis. The objective of this study was to investigate whether Notch signalling pathway was involved in neurogenesis impairment and long-term neurocognitive dysfunction caused by neonatal ketamine exposure. Methods: Postnatal day 7 (PND-7) male Sprague-Dawley (SD) rats were intraperitoneally injected with normal saline (NS) or 40 mg/kg ketamine for four consecutive times (40 mg/kg×4) at an interval of 1 h. Notch ligand Jagged1 (0.5 mg/kg) was micro-injected into the hippocampal DG with the stereotactic apparatus at 1 h before NS or ketamine administration. Lentivirus over-expressing Notch1 intracellular domain (LV-NICD1) was micro-injected into the hippocampal DG 4 days before NS or ketamine administration. Western blot was used to detect the changes of Notch1 signalling pathway related proteins in the hippocampal DG at 24 h after administration. The S-phase marker 5-bromodeoxyuridine (BrdU) was administered immediately after the treatment, then the proliferation and differentiation of NSCs in hippocampal DG were detected by using double-immunofluorescence staining at 24 h after treatment. Moreover, the changes of hippocampus-dependent spatial memory in the adult rats were tested by Morris water maze test in 2-month-old rats. Results: Ketamine anesthesia in neonatal rats decreased the expression levels of Jagged1, Notch1, Notch1 intracellular domain (NICD1) and hairy enhancer of split 1 (Hes1), and inhibited the proliferation and astrocytic differentiation of NSCs and promoted neuronal differentiation. Neonatal ketamine exposure induced the deficit in hippocampus-dependent spatial reference memory tasks in 2-month-old rats. The micro-injection of Jagged1 or LV-NICD1 reversed the inhibitory effect of ketamine on the expression of Notch1 related proteins in the hippocampal DG, and attenuated the ketamine-induced interference of NSCs proliferation and differentiation. In addition, Morris water maze test suggested that the administration of Jagged1 or LV-NICD1 could improve cognitive function in 2-month-old rats after neonatal ketamine exposure. Conclusions: These results suggest that neonatal exposure to ketamine in rats interferes with the proliferation and differentiation of hippocampal NSCs and impairs neurocognitive function in adulthood via inhibition of Notch1 signalling pathway. These findings contribute to further understanding of the neonatal neurotoxicity induced by ketamine and its underlying mechanisms.

scholarly journals Transplanted Human Oligodendrocyte Progenitor Cells Restore Neurobehavioral Deficits in a Rat Model of Preterm White Matter Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaohua Wang ◽  
Jing Zang ◽  
Yinxiang Yang ◽  
Siliang Lu ◽  
Qian Guan ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
White Matter ◽  
Rat Model ◽  
Water Maze ◽  
White Matter Injury ◽  
Morris Water Maze Test ◽  
Oligodendrocyte Progenitor Cells ◽  
Maze Test ◽  
Transmission Electron

Background: Preterm white matter injury (PWMI) is a common brain injury and a leading cause of life-long neurological deficits in premature infants; however, no effective treatment is available yet. This study aimed to investigate the fate and effectiveness of transplanted human oligodendrocyte progenitor cells (hOPCs) in a rat model of PWMI.Methods: Hypoxia-ischemia was induced in rats at postnatal day 3, and hOPCs (6 × 105 cells/5 μL) were intracerebroventricularly transplanted at postnatal day 7. Neurobehavior was assessed 12 weeks post-transplant using the CatWalk test and Morris water maze test. Histological analyses, as well as immunohistochemical and transmission electron microscopy, were performed after transcardial perfusion.Results: Transplanted hOPCs survived for 13 weeks in PWMI brains. They were widely distributed in the injured white matter, and migrated along the corpus callosum to the contralateral hemisphere. Notably, 82.77 ± 3.27% of transplanted cells differentiated into mature oligodendrocytes, which produced myelin around the axons. Transplantation of hOPCs increased the fluorescence intensity of myelin basic protein and the thickness of myelin sheaths as observed in immunostaining and transmission electron microscopy, while it reduced white matter atrophy at the level of gross morphology. With regard to neurobehavior, the CatWalk test revealed improved locomotor function and inter-paw coordination after transplantation, and the cognitive functions of hOPC-transplanted rats were restored as revealed by the Morris water maze test.Conclusions: Myelin restoration through the transplantation of hOPCs led to neurobehavioral improvements in PWMI rats, suggesting that transplanting hOPCs may provide an effective and promising therapeutic strategy in children with PWMI.

Activation of the α2A adrenoceptor in microglia promotes LPS-induced TNF-α production and cognitive impairment in mice

2020 ◽  
Author(s):  
Ming Fang ◽  
Wen-Liang Song ◽  
Xiao-Meng Dai ◽  
Rui-Jie Wang ◽  
Hui Xu ◽  
...  
Keyword(s):  
Western Blotting ◽  
Gene Knockout ◽  
Neurological Dysfunction ◽  
Morris Water Maze Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Motor Impairments ◽  
Knock Out ◽  
Pkc Inhibitor ◽  
Elevated Plus Maze Test ◽  
Maze Test

Abstract Background: a2A adrenoceptor receptor (a2A-AR) plays an important role in inflammatory response in Kupffer cells in sepsis. Blockage of a2A-AR inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor a (TNF-a) production and protects the target organ functions in sepsis animal models; however, its expression and function in microglia have remained obscure. This study aimed to determine whether a2A-AR was expressed in microglia and whether its activation would exacerbate microglial inflammation and sepsis-related neurological dysfunction. Methods: Western blotting and immunofluorescence were used to detect a2A-AR expression in BV-2 microglia. Enzyme-linked immunosorbent assay (ELISA) was used to assess the TNF-a production in the supernatant after LPS induced BV-2 cells were pretreated with a2A-AR agonist BHT933, and/or a2A-AR antagonist BRL44408, and also in the supernatants derived from BV-2 cells treated with BHT933 and/or PKC inhibitor. Signaling pathways including JNK，P38，ERK，IκBa, CREB and PCK were detected by western blotting. a2A-AR gene knock-out (KO) and wild type (WT) mice were prepared by intraperitoneal injection of LPS. Lectin /TNF-a labeled microglia and synaptophysin/NeuN expression in the hippocampus were localized by immunofluorescence. Morris water maze test, Rotating-stick test, Elevated plus maze test and Open-field test were conducted over 4 weeks.Results: a2A-AR was constitutively expressed in BV-2 microglia, which was enhanced by LPS. Pretreatment with BHT933 promoted LPS-induced IκB and JNK phosphorylation, and TNF-a secretion in BV-2 microglia which were abrogated by BRL44408. Activation of a2A-AR by BHT933 also increased PKC phosphorylation in LPS-treated BV-2 microglia. PKC inhibitor significantly reversed the promoting effects of BHT933 on IκB and JNK phosphorylation as well as TNF-a secretion in LPS-treated BV-2 microglia. Furthermore, LPS treatment significantly increased hippocampal microglia activation and TNF-a expression, decreased hippocampal synaptophysin expression, and impaired cognitive and motor functions in WT mice, all of which were markedly reversed by a2A-AR gene knockout. Conclusion: a2A-AR activation promotes LPS-induced IκB and JNK phosphorylation as well as TNF-a production in microglia through the PKC signaling pathway. Knockout of a2A-AR gene significantly improves LPS-induced cognitive and motor impairments in mice, indicating that a2A-AR is a potential therapeutic target for sepsis-associated encephalopathy.

scholarly journals Genetic Inactivation of Two-Pore Channel 1 Impairs Spatial Learning and Memory

2020 ◽  
Vol 50 (6) ◽  
pp. 401-410
Author(s):  
Robert Theodor Mallmann ◽  
Norbert Klugbauer
Keyword(s):  
Learning And Memory ◽  
Spatial Learning ◽  
Motor Performance ◽  
Motor Coordination ◽  
Morris Water Maze Test ◽  
Pore Channel ◽  
Spatial Learning And Memory ◽  
Genetic Inactivation ◽  
Maze Test ◽  
Higher Order Functions

Abstract Two-pore channels (TPCs) constitute a small family of cation channels that are localized in membranes of endosomal and lysosomal compartments. Although their roles for vesicular fusion and endolysosomal trafficking have been investigated, our knowledge on their expression pattern and higher order functions in the murine brain is still limited. Western blot analysis indicated a broad expression of TPC1 in the neocortex, cerebellum and hippocampus. In order to investigate the consequences of the genetic inactivation of TPC1, we performed a set of behavioural studies with TPC1−/− mice. TPC1−/− mice were analysed for an altered motor coordination and grip-strength, exploratory drive and anxiety as well as learning and memory. TPC1−/− mice did not show any differences in their exploratory drive or in their anxiety levels. There were also no differences in spontaneous activity or motor performance. However, the Morris water maze test uncovered a deficit in spatial learning and memory in TPC1−/− mice.

scholarly journals Secondary hypoxic ischemia alters neurobehavioral outcomes, neuroinflammation, and oxidative stress in mice exposed to controlled cortical impact

2021 ◽  
Vol 8 (3) ◽  
pp. 216-228
Author(s):  
Se-Kwang Oh ◽  
Hyun-Jeong Park ◽  
Gyeong-Gyu Yu ◽  
Seong-Hae Jeong ◽  
Suk-Woo Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Novel Object Recognition ◽  
The Novel ◽  
Barnes Maze ◽  
Object Recognition Test ◽  
Novel Object ◽  
Maze Test ◽  
Hypoxic Ischemia ◽  
Novel Object Recognition Test ◽  
And Oxidative Stress

Objective Hypoxic ischemia (HI) is a secondary insult that can cause fatal neurologic outcomes after traumatic brain injury (TBI), ranging from mild cognitive deficits to persistent vegetative states. We here aimed to unravel the underlying pathological mechanisms of HI injury in a TBI mouse model.Methods Neurobehavior, neuroinflammation, and oxidative stress were assessed in a mouse model of controlled cortical impact (CCI) injury followed by HI. Mice underwent CCI alone, CCI followed by HI, HI alone, or sham operation. HI was induced by one-vessel carotid ligation with 1 hour of 8% oxygen in nitrogen. Learning and memory were assessed using the novel object recognition test, contextual and cued fear conditioning, and Barnes maze test. Brain cytokine production and oxidative stress-related components were measured.Results Compared to TBI-only animals, TBI followed by HI mice exhibited significantly poorer survival and health scores, spatial learning and memory in the Barnes maze test, discrimination memory in the novel object recognition test, and fear memory following contextual and cued fear conditioning. Malondialdehyde levels were significantly lower, whereas glutathione peroxidase activity was significantly higher in TBI followed by HI mice compared to TBI-only and sham counterparts, respectively. Interleukin-6 levels were significantly higher in TBI followed by HI mice compared to both TBI-only and sham animals.Conclusion Post-traumatic HI aggravated deficits in spatial, fear, and discrimination memory in an experimental TBI mouse model. Our results suggest that increased neuroinflammation and oxidative stress contribute to HI-induced neurobehavioral impairments after TBI.

Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

2019 ◽  
Vol 16 (8) ◽  
pp. 710-722 ◽  
Author(s):  
Xiao-Ying Sun ◽  
Quan-Xiu Dong ◽  
Jie Zhu ◽  
Xun Sun ◽  
Li-Fan Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Synaptic Proteins ◽  
Morris Water Maze Test ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Maze Test ◽  
N2a Cells ◽  
Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

scholarly journals Protective effects and mechanisms of high-dose vitamin C on sepsis-associated cognitive impairment in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ning Zhang ◽  
Wei Zhao ◽  
Zhen-Jie Hu ◽  
Sheng-Mei Ge ◽  
Yan Huo ◽  
...  
Keyword(s):  
Vitamin C ◽  
Escape Latency ◽  
Morris Water Maze Test ◽  
Protective Mechanism ◽  
High Dose ◽  
Maze Test ◽  
Tnf Α ◽  
Histopathologic Changes ◽  
High Dose Vitamin ◽  
Necrosis Factor

AbstractSepsis survivors present long-term cognitive deficits. The present study was to investigate the effect of early administration of high-dose vitamin C on cognitive function in septic rats and explore its possible cerebral protective mechanism. Rat sepsis models were established by cecal ligation and puncture (CLP). Ten days after surgery, the Morris water maze test was performed to evaluate the behavior and cognitive function. Histopathologic changes in the hippocampus were evaluated by nissl staining. The inflammatory cytokines, activities of antioxidant enzymes (superoxide dismutase or SOD) and oxidative products (malondialdehyde or MDA) in the serum and hippocampus were tested 24 h after surgery. The activity of matrix metalloproteinase-9 (MMP-9) and expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) in the hippocampus were measured 24 h after surgery. Compared with the sham group in the Morris water maze test, the escape latency of sepsis rats was significantly (P = 0.001) prolonged in the navigation test, whereas the frequency to cross the platform and the time spent in the target quadrant were significantly (P = 0.003) reduced. High-dose vitamin C significantly decreased the escape latency (P = 0.01), but increased the time spent in the target quadrant (P = 0.04) and the frequency to cross the platform (P = 0.19). In the CLP+ saline group, the pyramidal neurons were reduced and distributed sparsely and disorderly, the levels of inflammatory cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the serum and hippocampus were significantly increased (P = 0.000), the blood brain barrier (BBB) permeability in the hippocampus was significantly (P = 0.000) increased, the activities of SOD in the serum and hippocampus were significantly (P = 0.000 and P = 0.03, respectively) diminished while the levels of MDA in the serum and hippocampus were significantly (P = 0.007) increased. High-dose vitamin C mitigated hippocampus histopathologic changes, reduced systemic inflammation and neuroinflammation, attenuated BBB disruption, inhibited oxidative stress in brain tissue, and up-regulated the expression of nuclear and total Nrf2 and HO-1. High-dose vitamin C significantly (P < 0.05) decreased the levels of tumor necrosis factor- (TNF)-α, interleukin-6 (IL-6), MDA in the serum and hippocampus, and the activity of MMP-9 in the hippocampus, but significantly (P < 0.05) increased the levels of SOD, the anti-inflammatory cytokine (IL-10) in the serum and hippocampus, and nuclear and total Nrf2, and HO-1 in the hippocampus. In conclusion, high-dose vitamin C can improve cognition impairment in septic rats, and the possible protective mechanism may be related to inhibition of inflammatory factors, alleviation of oxidative stress, and activation of the Nrf2/HO-1 pathway.

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