Protective effects of peroxiredoxin-1 at the injured blood–brain barrier

Polyphenolic antioxidants, including dietary plant lignans, modulate the gut–brain axis, which involves transformation of these polyphenolic compounds into physiologically active and neuroprotector compounds (called human lignans) through gut bacterial metabolism. These gut bacterial metabolites exert their neuroprotective effects in various neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and also have protective effects against other diseases, such as cardiovascular diseases, cancer, and diabetes. For example, enterolactone and enterodiol, the therapeutically relevant polyphenols, are formed as the secondary gut bacterial metabolites of lignans, the non-flavonoid polyphenolic compounds found in plant-based foods. These compounds are also acetylcholinesterase inhibitors, and thereby have potential applications as therapeutics in AD and other neurological diseases. Polyphenols are also advanced glycation end product (AGE) inhibitors (antiglycating agents), and thereby exert neuroprotective effects in cases of AD. Thus, gut bacterial metabolism of lignans and other dietary polyphenolic compounds results in the formation of neuroprotective polyphenols—some of which have enhanced blood–brain barrier permeability. It is hypothesized that gut bacterial metabolism-derived polyphenols, when combined with the nanoparticle-based blood–brain barrier (BBB)-targeted drug delivery, may prove to be effective therapeutics for various neurological disorders, including traumatic brain injury (TBI), AD, and PD. This mini-review addresses the role of polyphenolic compounds in the gut–brain axis, focusing on AD.

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The role of LINC 00094/miR‐224‐5p (miR‐497‐5p)/Endophilin‐1 axis in Memantine mediated protective effects on blood‐brain barrier in AD microenvironment

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.14214 ◽

2019 ◽

Vol 23 (5) ◽

pp. 3280-3292 ◽

Cited By ~ 10

Author(s):

Lu Zhu ◽

Meiqing Lin ◽

Jun Ma ◽

Wenjing Liu ◽

Lili Gao ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Protective Effects ◽

Blood Brain

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Polyphenol Microbial Metabolites Exhibit Gut and Blood–Brain Barrier Permeability and Protect Murine Microglia against LPS-Induced Inflammation

Metabolites ◽

10.3390/metabo9040078 ◽

2019 ◽

Vol 9 (4) ◽

pp. 78 ◽

Cited By ~ 13

Author(s):

Shelby L. Johnson ◽

Riley D. Kirk ◽

Nicholas A. DaSilva ◽

Hang Ma ◽

Navindra P. Seeram ◽

...

Keyword(s):

Blood Brain Barrier ◽

Systemic Circulation ◽

Brain Barrier ◽

Protective Effects ◽

Microbial Metabolites ◽

Dietary Polyphenols ◽

Beneficial Effects ◽

Blood Brain ◽

Traditional Mediterranean Diet

Increasing evidence supports the beneficial effects of polyphenol-rich diets, including the traditional Mediterranean diet, for the management of cardiovascular disease, obesity and neurodegenerative diseases. However, a common concern when discussing the protective effects of polyphenol-rich diets against diseases is whether these compounds are present in systemic circulation in their intact/parent forms in order to exert their beneficial effects in vivo. Here, we explore two common classes of dietary polyphenols, namely isoflavones and lignans, and their gut microbial-derived metabolites for gut and blood–brain barrier predicted permeability, as well as protection against neuroinflammatory stimuli in murine BV-2 microglia. Polyphenol microbial metabolites (PMMs) generally showed greater permeability through artificial gut and blood–brain barriers compared to their parent compounds. The parent polyphenols and their corresponding PMMs were evaluated for protective effects against lipopolysaccharide-induced inflammation in BV-2 microglia. The lignan-derived PMMs, equol and enterolactone, exhibited protective effects against nitric oxide production, as well as against pro-inflammatory cytokines (IL-6 and TNF-α) in BV-2 microglia. Therefore, PMMs may contribute, in large part, to the beneficial effects attributed to polyphenol-rich diets, further supporting the important role of gut microbiota in human health and disease prevention.

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Protective Effects of Ifenprodil on Ischemic Injury Size, Blood-Brain Barrier Breakdown, and Edema Formation in Focal Cerebral Ischemia

Neurosurgery ◽

10.1097/00006123-199702000-00026 ◽

1997 ◽

Vol 40 (2) ◽

pp. 364-371 ◽

Cited By ~ 26

Author(s):

Mustafa K. Ba??kaya ◽

A. Muralikrishna Rao ◽

David Donaldson ◽

M. Renuka Prasad ◽

Robert J. Dempsey

Keyword(s):

Cerebral Ischemia ◽

Blood Brain Barrier ◽

Focal Cerebral Ischemia ◽

Ischemic Injury ◽

Brain Barrier ◽

Protective Effects ◽

Edema Formation ◽

Blood Brain ◽

Barrier Breakdown ◽

Blood Brain Barrier Breakdown

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Protective effects of monomethyl fumarate at the inflamed blood–brain barrier

Microvascular Research ◽

10.1016/j.mvr.2015.12.003 ◽

2016 ◽

Vol 105 ◽

pp. 61-69 ◽

Cited By ~ 12

Author(s):

Jamie L. Lim ◽

Susanne M.A. van der Pol ◽

Flaminia Di Dio ◽

Bert van het Hof ◽

Gijs Kooij ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Protective Effects ◽

Blood Brain ◽

Monomethyl Fumarate

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Protection Against Blood-brain Barrier Permeability as a Possible Mechanism for Protective Effects of Thymoquinone Against Sickness Behaviors Induced by Lipopolysaccharide in Rats

Jundishapur Journal of Natural Pharmaceutical Products ◽

10.5812/jjnpp.67765 ◽

2021 ◽

Vol 16 (2) ◽

Author(s):

Rahimeh Bargi ◽

Mahmoud Hosseini ◽

Fereshteh Asgharzadeh ◽

Majid Khazaei ◽

Mohammad Naser Shafei ◽

...

Keyword(s):

Blood Brain Barrier ◽

Active Role ◽

Brain Barrier ◽

Control Group ◽

Protective Effects ◽

Blood Brain ◽

Immobility Time ◽

Sickness Behaviors ◽

Bbb Permeability ◽

The Brain

Background: Blood-brain barrier (BBB), as well-known protection for the brain, plays an active role in normal homeostasis. It might be changed by a range of inflammatory mediators to have a role in sickness behaviors. Objectives: Regarding the anti-inflammatory effects of thymoquinone (TQ), its protection against BBB permeability, as a possible mechanism for protective effects against sickness behaviors elicited by lipopolysaccharide (LPS), was evaluated in rats. Methods: The animals were grouped as follows and treated (n = 10 in each): (1) control (saline); (2) LPS 1 mg/kg, was injected two hours before behavioral tests for two weeks; (3-5) 2, 5, and 10 mg/kg TQ, respectively was injected 30 min before LPS injection. Open-field (OF), elevated plus-maze (EPM) and Forced Swimming test (FST) were done. Finally, the animals were anesthetized to evaluate for BBB permeability using Evans blue (EB) dye method. Results: Compared with control, LPS decreased the peripheral distance and crossing and also total crossing and distance in OF, (P < 0.01 - P < 0.001). The central crossing and distance and central time in all three treatment groups were more than LPS (P < 0.05 - P < 0.001). LPS also reduced the entries and the time spent in the open arm while increased the time spent in the closed arm in EPM (P < 0.05 - P < 0.001). The effects of LPS were reversed by TQ (P < 0.05 - P < 0.001). In FST, the immobility time and active time were increased and decreased by LPS compared with control (P < 0.001), respectively. In all three TQ-treated groups, the active and climbing times were more while the immobility time was fewer than the LPS (P < 0.05 - P < 0.001). The animals of the LPS group showed more EB dye content in their brain tissue than the control group (P < 0.05 - P < 0.001). TQ significantly reduced EB dye content of the brain tissues (P < 0.05 - P < 0.001). Conclusions: According to this study, protection against BBB permeability as a possible mechanism for the protective effects of TQ against sickness behaviors induced by LPS might be suggested.

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Protective effects of tirilazad mesylate and metabolite U-89678 against blood-brain barrier damage after subarachnoid hemorrhage and lipid peroxidative neuronal injury

Journal of Neurosurgery ◽

10.3171/jns.1996.84.2.0229 ◽

1996 ◽

Vol 84 (2) ◽

pp. 229-233 ◽

Cited By ~ 54

Author(s):

Sarah L. Smith ◽

Heidi M. Scherch ◽

Edward D. Hall

Keyword(s):

Subarachnoid Hemorrhage ◽

Blood Brain Barrier ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Brain Barrier ◽

Phase Iii ◽

Blue Dye ◽

Ferrous Ammonium Sulfate ◽

Protective Effects ◽

Blood Brain ◽

Tirilazad Mesylate

✓ The 21-aminosteroid lipid-peroxidation inhibitor, tirilazad mesylate (U-74006F), recently was shown in a large multinational Phase III clinical trial to decrease mortality and improve neurological recovery in patients 3 months after onset of aneurysmal subarachnoid hemorrhage (SAH). A major tirilazad metabolite in animals and man, U-89678 is formed when the 4–5 double bond in the A-ring is reduced and has been postulated to contribute significantly to tirilazad's neuroprotective effects. In the first experiment of the present study, the authors compared the effects of tirilazad and U-89678 on acute blood-brain barrier (BBB) damage in rats subjected to SAH via injection of 300 µl of autologous nonheparinized blood under the dura of the left cortex. The rats were treated by intravenous administration of either 0.3 or 1.0 mg/kg of tirilazad or U-89678 10 minutes before and 2 hours after SAH, and BBB damage was quantified according to the extravasation of the protein-bound Evans' blue dye into the injured cortex 3 hours post-SAH. The results revealed that 0.3 and 1.0 mg/kg tirilazad significantly reduced SAH-induced BBB damage 35.2% (p < 0.05) and 60.6% (p < 0.0001), respectively, in comparison to treatment with vehicle. The 0.3- and 1.0-mg/kg doses of U-89678 also decreased injury by 39.1% (p < 0.05) and 21.3% (not significant), respectively. In the second experiment, the investigators assessed the relative abilities of tirilazad and U-89678 to protect cultured neurons from iron-induced lipid peroxidative injury. Fetal mouse spinal cord cells were pretreated with 3, 10, or 30 µM tirilazad or U-89678 for 1 hour and then exposed to 200 µM ferrous ammonium sulfate (FAS) for 40 minutes. Cell viability was measured in terms of the uptake of [3H]α-(methyl)-aminoisobutyric acid 45 minutes after the FAS treatment. Both compounds enhanced neuronal survival in a concentration-dependent fashion. Although the two were equally efficacious, U-89678 was slightly more potent than its parent. On the basis of these findings, the authors conclude that the tirilazad metabolite, U-89678, possesses vaso- and neuroprotective properties that are essentially equivalent to the parent 21-aminosteroid. Hence, U-89678 probably contributes to the protective effects of tirilazad in SAH and other insults to the central nervous system.

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Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4

Cerebrovascular Diseases ◽

10.1159/000460261 ◽

2017 ◽

Vol 44 (1-2) ◽

pp. 10-25 ◽

Cited By ~ 23

Author(s):

Heling Chu ◽

Xiaobo Yang ◽

Chuyi Huang ◽

Zidan Gao ◽

Yuping Tang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Blood Brain Barrier ◽

Infarct Volume ◽

Neurological Function ◽

Aquaporin 4 ◽

Brain Barrier ◽

Cell Swelling ◽

Protective Effects ◽

Aqp4 Expression ◽

Blood Brain

Background: Apelin-13 has been found to have protective effects on many neurological diseases, including cerebral ischemia. However, whether Apelin-13 acts on blood-brain barrier (BBB) disruption following cerebral ischemia is largely unknown. Aquaporin-4 (AQP4) has a close link with BBB due to the high concentration in astrocyte foot processes and regulation of astrocytes function. Here, we aimed to test Apelin-13′s effects on ischemic BBB injury and examine whether the effects were dependent on AQP4. Methods: We detected the expression of AQP4 induced by Apelin-13 injection at 1, 3, and 7 days after middle cerebral artery occlusion. Meanwhile, we examined the effects of Apelin-13 on neurological function, infarct volume, and BBB disruption owing to cerebral ischemia in wild type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the possible signal transduction pathways activated by Apelin-13 to regulate AQP4 expression via astrocyte cultures. Results: It was found that Apelin-13 highly increased AQP4 expression as well as reduced neurological scores and infarct volume. Importantly, Apelin-13 played a role of BBB protection in both types of mice by reducing BBB permeability, increased vascular endothelial growth factor, upregulated endothelial nitric oxide synthase, and downregulated inducible NOS. In morphology, we demonstrated Apelin-13 suppressed tight junction opening and endothelial cell swelling via electron microscopy detection. Meanwhile, Apelin-13 also alleviated apoptosis of astrocytes and promoted angiogenesis. Interestingly, effects of AQP4 on neurological function and infarct volume varied with time course, while AQP4 elicited protective effects on BBB at all time points. Statistical analysis of 2-way analysis of variance with replication indicated that AQP4 was required for these effects. In addition, Apelin-13 upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and Akt as well as AQP4 protein in cultured astrocytes. The latter was inhibited by ERK and phosphatidylinositol 3′-kinase (PI3K) inhibitors. Conclusion: Our data suggest that Apelin-13 protects BBB from disruption after cerebral ischemia both morphologically and functionally, which is highly associated with the increased levels of AQP4, possibly through the activation of ERK and PI3K/Akt pathways. This study provides double targets to protection of ischemic BBB damage, which can present new insights to drugs development.

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