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Aim To investigate whether alisol A (AA) could improve the blood brain barrier (BBB) mediated cortex cerebral ischemia-repeifusion injury (CIRI) by inhibiting matrix metalloproteinase 9 (MMP-9). Methods The global cerebral ischemia- reperfusion (GCI/R) model in mice was established, and the AA was intragastric injected subsequently for seven days. The modified neurological severity scores (mNSS), open field test and Y-maze test were applied to detect neurological function. Magnetic resonance spectroscopy (MRS) was used to detect relevant neu- rosubstance metabolism in cortex of mice. Transmission electron microscope (TEM) was employed to observe the ultrastructure of BBB in cortex. Western blot and immunohistochemistry were used to detect the MMP-9 level in cortex. The binding possibility of A A and MMP-9 was determined by molecular docking. Results Compared with Sham group, mice in GCI/R group have an increased mNSS score but decreased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test (P<0.01). While mice in GCI/R + AA group have a decreased mNSS score but increased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test (P<0.01) compared with GCI/R group. MRS results found that in cortex of GCI/R group mice, the level of GABA and NAA significantly decreased while the Cho, mI and Tau level increased (P<0.01). Whereas in GCI/R + AA group mice, the GABA and NAA level increased and the Cho, ml and Tau decreased significantly (P<0.01). By TEM we observed that the basilemma of cerebral microvessels collapsed, the lumen narrowed, the endothelial cells were active and plasma membranes ruffled, gaps between cells were enlarged and tight junctions were damaged and the end feet of astrocytes were swollen in GCI/R group mice. While in GCI/R + AA group mice, the lumen was filled, plasma membranes of endothelial cells were smooth, tight junctions were complete and end feet of astrocytes were in normal condition. Western blot and immunohistochemistry both found that the MMP-9 level increased in GCI/R group mice (P < 0.01) and decreased in GCI/R + AA group mice (P < 0.05). Molecular docking proved the binding between aliso A and MMP9 through TYR-50 and ARG-106, and the binding energy was calculated as -6.24 kcal · mol
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ObjectiveTo examine the inhibitory effects of berberine compounds， including columbamine， on acetylcholinesterase from the perspectives of drug-target binding affinity and kinetics and explore the blood-brain barrier （BBB） permeability of these compounds in different multi-component backgrounds. MethodThe median inhibitory concentration （IC50） of acetylcholinesterase by berberine compounds including columbamine was measured using the Ellman-modified spectrophotometric method. The binding kinetic parameters （Koff） of these compounds with acetylcholinesterase were determined using the enzyme activity recovery method. A qualitative analysis of the ability of these components to penetrate the BBB and arrive at the brain tissue in diverse multi-component backgrounds （including medicinal herbs and compound formulas） was conducted using ultra performance liquid chromatography-high resolution mass spectrometry （UPLC-HRMS）. ResultBerberine compounds， including columbamine， exhibited strong inhibition of acetylcholinesterase， with IC50 values in the nanomolar range. Moreover， they displayed better drug-target binding kinetics characteristics （with smaller Koff values） than the positive control of donepezil hydrochloride （P<0.01）， indicating a longer inhibition duration of acetylcholinesterase. Berberine components such as columbamine could penetrate the BBB to arrive at brain tissue in the form of a monomer， as well as in the multi-component backgrounds of Coptis and Phellodendri Chinensis Cortex medicinal extracts and the compound formula Huanglian Jiedutang. ConclusionThese berberine compounds such as columbamine exhibit a strong inhibitory effect on acetylcholinesterase and can arrive at brain tissue in multi-component backgrounds. In the level of pharmacological substance， this supports the clinical efficacy of compound Huanglian Jiedutang in improving Alzheimer's disease， providing data support for elucidating the pharmacological basis of compound Huanglian Jiedutang.
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Objective:To investigate the effect of radiofrequency radiation (RF) from 5G mobile phone communication frequency bands (3.5 GHz and 4.9 GHz) on the permeability of the blood-brain barrier (BBB) in mice.Methods:A total of 24 healthy adult male C57BL/6 mice (6-8 weeks old) were randomly divided into Sham, 3.5 GHz RF and 4.9 GHz RF groups, and 8 mice in each group. Mice in the RF groups were systemically exposed to 5G cell phone radiation for consecutive 35 d(1 h/d) with 50 W/m 2 power density. The BBB permeability of mice was detected by Evans Blue (EB) fluorescence experiment. The expression levels of the BBB tight junction-related proteins (ZO-1, occludin and claudin-11) and the gap junction-related protein Connexin 43 were determined by Western blot. Results:The number of spots, fluorescence intensity and comprehensive score of EB were significantly increased in 3.5 GHz RF group and 4.9 GHz RF group compared with the Sham group ( t=12.98, 17.82, P<0.001). Compared with the Sham group, the content of S100B in mouse serum was significantly increased in 3.5 GHz RF group and 4.9 GHz RF group ( t=19.34, 14.68, P<0.001). The BBB permeability was increased in the RF group. The expression level of occludin protein was significantly reduced in the 3.5 GHz RF group ( t=-3.13, P<0.05), and this decrease was much profound in the 4.9 GHz RF group ( t=-6.55, P<0.01). But the protein levels of ZO-1, Claudin-11 and Connexin 43 in the cerebral cortex of the RF groups had no significantly difference in comparison with the Sham group( P>0.05). Conclusions:The continuous exposure of mobile phone RF at 3.5 GHz or 4.9 GHz for 35 d (1 h/d) induces an increase of BBB permeability in the mouse cerebral cortex, perhaps by reducing the expression of occludin protein.
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OBJECTIVE To identify the role of mixed lineage kinase domain like protein(MLKL)in cerebral small vessel disease(CSVD)and explore the underlying mechanism.METHODS Transient bilateral common carotid artery occlusion(tBCCAO)was used to establish a mouse model of CSVD.Immunofluorescence staining and Western blotting were used to observe the expres-sions of RIPK3/MLKL signaling molecules in brain tissues at 7,14 and 28 d after tBCCAO.Open field test,rotarod test,Y-maze and novel object recognition test were used to observe the effect of MLKL knockout on cognitive func-tion after tBCCAO.Blood-brain barrier(BBB)disruption was observed by sodium fluorescein permeability test and the expressions of tight junction proteins.Immunoflu-orescence staining and Western blotting were used to detect the expression of microglia marker Iba-1,astro-cyte marker GFAP,and NLRP3/Caspase-1 signaling mol-ecules in the hippocampus of CSVD mice.ELISA was used to detect the level of inflammatory factors(TNF-α,IL-1β,IL-18)in hippocampus.RESULTS The expres-sions of RIPK3/MLKL signaling molecules increased in cortex and hippocampus after tBCCAO,especially on day 14.The expression of pMLKL mainly increased in neurons,glia cells and endothelial cells in CSVD mice.MLKL knockout improved the cognitive functions such as motor learning,spatial learning and working memory,and object recognition ability in CSVD mice.MLKL knock-out alleviated the leakage of sodium fluorescein and attenuated the down-regulation of tight junction proteins at 1 d and 14 d after tBCCAO.At 14 d after tBCCAO,MLKL knock out inhibited the activations of microglia and astrocytes,attenuated the expressions of NLRP3/cas-pase-1 molecules,and decreased the levels of inflamma-tory factors in the hippocampus of mice.CONCLUSION Genetic inhibition of MLKL exerts protective effects against cognitive impairment by ameliorating BBB dam-age and neuroinflammation in a mouse cerebral small vessel disease model.
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Alzheimer's disease(AD)is a neurode-generative disease with complex pathological mecha-nism characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain.Increasing evi-dence suggests that vascular dysfunction due to endothe-lial cell injury may have a pathogenic role in the occur-rence and development of AD.Malfunction of the blood-brain barrier caused by endothelial cell dysfunction is associated with the accumulation of several neurotoxic molecules within brain parenchyma,a reduction in cerebral blood flow,amyloid-β transfer and hypoxia,especially at the early stages of the disease.At the same time,it can-not be ignored that the peripheral arterial vascular endo-thelial cell dysfunction also seems to be closely related to the risk and the severity of symptoms of AD.Some mole-cules are thought to be messengers connecting the central and peripheral endothelial cells.Peripheral and central vascular endothelial cells communicate with each other and influence the progression of AD through some common mechanisms.In this review,we provide an ap-praisal of the endothelial cell dysfunction in cerebral and systemic vasculature,and give the evidence that vascular pathology is inextricably linked to disease onset and pro-gression of AD.
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Objective:To observe the effect of ventilator-induced lung injury (VILI) on blood-brain barrier permeability in rats.Methods:Forty-eight healthy clean male Sprague-Dawley (SD) rats were randomly divided into sham operation (Sham) group, low tidal volume (LVT) mechanical ventilation group (LVT group), normal tidal volume (NVT) mechanical ventilation group (NVT group) and high tidal volume (HVT) mechanical ventilation group (HVT group) with 12 rats in each group. After anesthesia, rats in the Sham group were intubated and kept spontaneous breathing. The rats in different tidal volume (VT) groups were mechanically ventilated by endotracheal intubation with VT of 6 mL/kg (LVT group), 10 mL/kg (NVT group), and 20 mL/kg (HVT group), respectively. The inspiration-expiration ratio of the three groups was 1∶1, the ventilation frequency was 40 times/min, and the ventilation time was 3 hours. At the end of the experiment, the bronchoalveolar lavage fluid (BALF) of rats was collected, and the levels of pro-inflammatory factors [tumor necrosis factor-α (TNF-α), interleukins (IL-1β and IL-6)] in BALF were detected by enzyme-linked immunosorbent assay (ELISA). The lung tissues of rats were collected, and the lung wet/dry weight (W/D) ratio was calculated. The pathological changes of lung tissues were observed under light microscopy after hematoxylin-eosin (HE) staining, and lung injury scores were performed. The brain tissue of rats was taken to measure the brain water content, and the Evans blue (EB) content of brain tissue was measured to reflect the permeability of the blood-brain barrier. The tight junction proteins in the brain tissues were detected by Western blotting.Results:After 3 hours of mechanical ventilation, with the increase of VT, the degree of lung injury in VILI rats gradually increased. When VT reached 20 mL/kg, lung tissue structure was significantly injured, alveolar wall edema, alveolar congestion, lung interstitial thickening, a large number of inflammatory cells infiltrated, and the lung injury score, lung W/D ratio, and the levels of TNF-α, IL-1β and IL-6 in BALF were significantly higher than those in the Sham group [lung injury score: 10.6±1.1 vs. 1.4±1.0, lung W/D ratio: 6.6±0.8 vs. 3.7±0.6, TNF-α(ng/L): 832.9±97.9 vs. 103.8±23.3, IL-1β (ng/L): 68.9±14.1 vs. 15.7±2.6, IL-6 (ng/L): 70.8±16.4 vs. 20.3±5.4, all P < 0.05]. Lung injury in rats was accompanied by aggravating brain injury. When VT reached 20 mL/kg, brain water content and EB content in brain tissue were significantly higher than those in the Sham group [brain water content: (85.4±3.6)% vs. (68.7±2.7)%, EB content in brain tissue (μg/g): 887±78 vs. 97±14, both P < 0.05], and the protein expressions of claudin-5, occluding and zonula occluden-1 (ZO-1) in the brain tissue were significantly lower than those in the Sham group [claudin-5 protein (claudin-5/β-actin): 0.67±0.12 vs. 1.45±0.19, occludin protein (occludin/β-actin): 0.48±0.11 vs. 0.99±0.21, ZO-1 protein (ZO-1/β-actin): 0.13±0.03 vs. 0.63±0.12, all P < 0.05]. Conclusion:VILI can induce brain edema and increase blood-brain barrier permeability in rats, which may be related to the down-regulation of tight junction protein expression in the brain tissue.
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Cerebral small vessel disease (CSVD) is an important cause of ischemic stroke and vascular dementia, which brings heavy burden to families and society. The prevention and treatment of CSVD has always been a research hotspot, but its pathogenesis is still not completely clear. This article reviews the pathogenesis of CSVD, including chronic cerebral hypoperfusion, blood-brain barrier dysfunction, vascular endothelial dysfunction, interstitial fluid reflux disorder, inflammatory response, and genetic factors, in order to provide more sufficient theoretical basis for early intervention and treatment of CSVD.
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Objective:To investigate the correlation between paroxysmal slow-wave events (PSWEs) and cerebral small vessel disease (CSVD) and CSVD-related cognitive impairment.Methods:Patients with CSVD visited Weihai Municipal Hospital from March 2021 to April 2022 were included, and sex- and age-matched healthy controls were recruited for cross-sectional analysis. The patients with CSVD were further divided into cognitive impairment group and non-cognitive impairment group. The self-developed Python script was used to detect the PSWE parameters in electroencephalogram records. Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) were used to evaluate cognitive function. Multivariate logistic regression analysis was used to determine whether PWSE parameters were the independent related factors of CSVD and CSVD-related cognitive impairment. Multiple linear regression analysis was used to determine the correlation between the PSWE parameters and overall cognitive function (MoCA total score) in patients with CSVD. Results:A total of 76 patients with CSVD (including 41 patients with cognitive impairment and 35 patients without cognitive impairment) and 45 healthy controls were included. Compared with the healthy control group, PWSEs in the F3 (left frontal area) and O1 (left occipital area) regions of the CSVD group occurred more frequently and lasted longer (all P<0.05). Multivariate logistic regression analysis showed that the frequency (odds ratio [ OR] 1.080, 95% confidence interval [ CI] 1.023-1.140; P=0.005) and duration ( OR 1.006, 95% CI 1.001-1.011; P=0.023) of PWSEs in the left frontal area, as well as the frequency ( OR 1.052, 95% CI 1.010-1.095; P=0.014) and duration ( OR 1.003, 95% CI 1.000-1.006; P=0.028) of PWSEs in the left occipital region were the independent related factors for CSVD. The frequency ( OR 1.106, 95% CI 1.033-1.183; P=0.004) and duration ( OR1.010, 95% CI 1.003-1.017; P=0.004) of PWSEs in the left frontal area were the independent risk factors for cognitive impairment in patients with CSVD. Multiple linear regression analysis showed that the frequency ( β= –0.242, P=0.045) and duration ( β= –0.235, P=0.046) of PWSEs in the left frontal region were negatively correlated with the overall cognitive function score in patients with CSVD. Conclusions:The frequency and duration of PSWEs in some brain regions of patients with CSVD increase, and there is an independent correlation between PSWEs and cognitive impairment, suggesting that the damage of blood-brain barrier may participate in the pathogenesis of cognitive impairment in patients with CSVD.
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Objective To investigate the effect of plateau hypoxia on the blood-brain barrier after subarachnoid hemorrhage (SAH) in rats. Methods Adult male SD rats (n = 78) were randomly divided into 4 groups: sham group (sham), SAH model group (SAH), plateau hypoxia sham group (Hp sham) and plateau hypoxia SAH model group (Hp SAH). The rat model of plateau hypoxia was established through low-pressure simulation chamber (altitude 5000 m), and the SAH model was established by endovascular perforation method. At 24 hours after SAH, neurobehavior score and SAH grade were assessed. The morphological changes of neurons and apoptosis of nerve cells in the CA1 region of hippocampal were observed by the staining of Nissl and TUNEL. The expression of phosphorylated PI3K (p-PI3K), PI3K, phosphorylated Akt (p-Akt), Akt, phosphorylated nuclear factor κB (p-NF-κB), NF-κB, matrix metalloproteinase-9 (MMP-9), occludin and claudin-5 in hippocampal were detected by the method of Western blotting. The expression of occludin and claudin-5 proteins in the CA1 region of hippocampal were observed by immunofluorescent staining. Results At 24 hours after SAH, the neurobehavior score decreased significantly and SAH grade increased significantly in the SAH and Hp SAH group (P< 0.05). Neurobehavior score decreased significantly in the Hp SAH group compared with the SAH group (P < 0.05). In the SAH group, neurons in the CA1 region of hippocampus were atrophied and deformed, the arrangement were disordered, the number of neurons decreased significantly, and the apoptosis of nerve cells increased significantly(P< 0.05). Plateau hypoxia could aggravate the morphological damage of neurons and apoptosis of nerve cells. The expression of p-PI3K/PI3K, p-Akt/Akt, occludin and claudin-5 proteins decreased significantly, while the expression of p-NF-κB/NF-κB and MMP-9 proteins increased significantly in the SAH and Hp SAH group (P< 0.05). The expression of p-PI3K/PI3K and MMP-9 proteins increased significantly in Hp SAH group compared with the SAH group. The expression of claudin-5 protein increased significantly in Hp sham group compared with the sham group (P < 0.05). Immunofluorescent staining showed that the expression of occludin and claudin-5 proteins in the CA1 region of hippocampus decreased in the SAH group. Plateau hypoxia could further decreased the expression of occludin and claudin-5 proteins. Conclusion Plateau hypoxia aggravates blood-brain barrier disruption after subarachnoid hemorrhage in rats through inhibiting PI3K/Akt/NF-κB pathway.
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AIM: To investigate the effects of hyperoside on traumatic brain injury (TBI) rats by regulating the Ras homolog gene family, member A (RhoA)/Rho-associated coiled coil-forming kinase (ROCK) signal pathway. METHODS: The TBI rat model was established by modified Feeney free fall hit method, and was randomly divided into model group, low-dose hyperoside (60 mg / kg) group, high-dose hyperoside (120 mg / kg) group, high-dose hyperoside (120 mg / kg) + no load group, and high-dose hyperoside (120 mg / kg) + RhoA overexpression group, with 10 rats in each group, another 10 healthy rats were set as sham operation group, after hyperoside and plasmid were grouped, the nerve injury was detected by modified neurological deficit score (mNSS) and dark avoidance test; Evans blue (EB) quantitative method was used to detect the permeability of blood brain barrier in rats; ultrastructural damage of blood-brain barrier was observed by transmission electron microscopy; the levels of tumor necrosis factor- α (TNF- α), interleukin-8 (IL-8), superoxide dismutase (SOD) and malondialdehyde (MDA) in serum and brain tissue of rats were measured with the kit; and the expression of RhoA/ROCK pathway related proteins in rat brain was detected by Western blot. RESULTS: Compared with the sham operation group, the blood brain barrier structure of the model group rats was damaged, the step-through latency and SOD level decreased obviously (P0.05). CONCLUSION: Hyperoside can inhibit neuroinflammation and oxidative stress in TBI rats by down-regulating RhoA / ROCK signal pathway, thereby reducing the damage of blood brain barrier and repairing its neural function.
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Aim To develop a ultra-high performance liquid chromatography electrospray-ionization tandem mass spectrometry ( UPLC-MS/MS ) method for the simultaneous determination of salidroside derivative pOBz in rat plasma and brain tissue, and to study the pharmacokinetic profile and penetration of the blood-brain barrier in rats after a single dose intravenous administration of pOBz. Methods SD rats were administered pOBz at a dose of 50 mg • kg
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Aim To investigate the effect of astaxanthin (ASTA) on the blood brain barrier (BBB) injury and cognitive disorders in mice induced by hyperglycemia and the possible mechanism. Methods db/db mice aged eight weeks were administered ASTA (5, 10, 20 mg • kg
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The establishment of the cerebral pharmacokinetic model aims to truly reflect the disposition and course of action of drugs entering brain tissues, to ensure that brain-targeted drugs reach effective intracerebral concentrations, while preventing neurological damage from non-brain-targeted drugs, and to greatly improve effectiveness and safety. With the rapid development of research strategies and analytical techniques in the field of pharmacokinetics, intracerebral pharmacokinetic techniques have evolved from traditional brain tissue homogenization and cerebrospinal fluid extraction to in situ in vivo analysis techniques, from invasive techniques to non-invasive imaging techniques, and from the macroscopic tissue level to the microscopic cellular/subcellular level. A variety of pharmacokinetic research methods in brain are complementing each other and becoming increasingly perfect, gradually forming a comprehensive " subcellular-cellular-tissue" pharmacokinetic research system in brain, laying the foundation for elucidating the dynamic changes of drugs in brain and predicting the course of action of drugs in brain. This paper reviews the evolution and development of pharmacokinetic research strategies in brain, evaluates the advantages and limitations of various techniques and methods, and provides a reference for predicting the pharmacodynamic and toxic effects of drugs in brain tissues.
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The blood-brain barrier (BBB) impairment plays a crucial role in the pathological processes of aging-accompanied neurological diseases (AAND). Meanwhile, circadian rhythms disruption and gut microbiota dysbiosis are associated with increased morbidity of neurological diseases in the accelerated aging population. Importantly, circadian rhythms disruption and gut microbiota dysbiosis are also known to induce the generation of toxic metabolites and pro-inflammatory cytokines, resulting in disruption of BBB integrity. Collectively, this provides a new perspective for exploring the relationship among circadian rhythms, gut microbes, and the BBB in aging-accompanied neurological diseases. In this review, we focus on recent advances in the interplay between circadian rhythm disturbances and gut microbiota dysbiosis, and their potential roles in the BBB disruption that occurs in AAND. Based on existing literature, we discuss and propose potential mechanisms underlying BBB damage induced by dysregulated circadian rhythms and gut microbiota, which would serve as the basis for developing potential interventions to protect the BBB in the aging population through targeting the BBB by exploiting its links with gut microbiota and circadian rhythms for treating AAND.
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In recent years, growing awareness of the role of oxidative stress in brain health has prompted antioxidants, especially dietary antioxidants, to receive growing attention as possible treatments strategies for patients with neurodegenerative diseases (NDs). The most widely studied dietary antioxidants include active substances such as vitamins, carotenoids, flavonoids and polyphenols. Dietary antioxidants are found in usually consumed foods such as fresh fruits, vegetables, nuts and oils and are gaining popularity due to recently growing awareness of their potential for preventive and protective agents against NDs, as well as their abundant natural sources, generally non-toxic nature, and ease of long-term consumption. This review article examines the role of oxidative stress in the development of NDs, explores the 'two-sidedness' of the blood-brain barrier (BBB) as a protective barrier to the nervous system and an impeding barrier to the use of antioxidants as drug medicinal products and/or dietary antioxidants supplements for prevention and therapy and reviews the BBB permeability of common dietary antioxidant suplements and their potential efficacy in the prevention and treatment of NDs. Finally, current challenges and future directions for the prevention and treatment of NDs using dietary antioxidants are discussed, and useful information on the prevention and treatment of NDs is provided.
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Glioblastoma (GBM) is the most aggressive malignant brain tumor and has a high mortality rate. Photodynamic therapy (PDT) has emerged as a promising approach for the treatment of malignant brain tumors. However, the use of PDT for the treatment of GBM has been limited by its low blood‒brain barrier (BBB) permeability and lack of cancer-targeting ability. Herein, brain endothelial cell-derived extracellular vesicles (bEVs) were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB. To enhance PDT efficacy, the photosensitizer chlorin e6 (Ce6) was linked to mitochondria-targeting triphenylphosphonium (TPP) and entrapped into bEVs. TPP-conjugated Ce6 (TPP-Ce6) selectively accumulated in the mitochondria, which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation. Moreover, the encapsulation of TPP-Ce6 into bEVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6, leading to significantly enhanced PDT efficacy in U87MG GBM cells. An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that bEVs containing TPP-Ce6 [bEV(TPP-Ce6)] substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis. As such, bEV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity, suggesting that mitochondria are an effective target for photodynamic GBM therapy.
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The incidence rate of anxiety and depression is significantly higher in patients with inflammatory bowel diseases (IBD) than in the general population. The mechanisms underlying dextran sulfate sodium (DSS)-induced depressive-like behaviors are still unclear. We clarified that IBD mice induced by repeated administration of DSS presented depressive-like behaviors. The paraventricular thalamic nucleus (PVT) was regarded as the activated brain region by the number of c-fos-labeled neurons. RNA-sequencing analysis showed that lipocalin 2 (Lcn2) was upregulated in the PVT of mice with DSS-induced depressive behaviors. Upregulating Lcn2 from neuronal activity induced dendritic spine loss and the secreted protein induced chemokine expression and subsequently contributed to microglial activation leading to blood-brain barrier permeability. Moreover, Lcn2 silencing in the PVT alleviated the DSS-induced depressive-like behaviors. The present study demonstrated that elevated Lcn2 in the PVT is a critical factor for DSS-induced depressive behaviors.
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Mice , Humans , Animals , Lipocalin-2/genetics , Midline Thalamic Nuclei , Brain , Inflammatory Bowel Diseases , Proto-Oncogene Proteins c-fos , Mice, Inbred C57BLABSTRACT
The function of the central nervous system was significantly altered under high-altitude hypoxia, and these changes lead to central nervous system disease and affected the metabolism of drugs in vivo. The blood-brain barrier is essential for maintaining central nervous system stability and plays a key role in the regulation of drug metabolism, and barrier structure and dysfunction affect drug transport to the brain. Changes in the structure and function of the blood-brain barrier and the transport of drugs across the blood-brain barrier under high-altitude hypoxia are regulated by changes in brain microvascular endothelial cells, astrocytes and pericytes, and are regulated by drug metabolism factors such as drug transporters and drug metabolizing enzymes. This article reviews the effects of high-altitude hypoxia on the structure and function of the blood-brain barrier and the effects of changes in the blood-brain barrier on drug metabolism. We investigate the regulatory effects and underlying mechanisms of the blood-brain barrier and related pathways such as transcription factors, inflammatory factors and nuclear receptors on drug transport under high-altitude hypoxia.
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Hepatic encephalopathy (HE) is a common complication and an independent risk factor for death in patients with liver cirrhosis. Brain lactate level is associated with the progression and severity of HE, and research on brain lactate level may help to further explain the pathogenesis of HE. This article summarizes the metabolic process of brain lactate, the association between brain lactate level and HE, and the potential therapeutic targets for HE and provides a reference for clinicians to further systematically evaluate the progression, treatment outcome, and prognosis of patients with HE, in order to reduce the medical burden of patients and improve the prognosis of patients with HE.
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A BBB co-culture cell model consisting of rat brain microvascular endothelial cells (BMEC) and astrocytes (AS) was established to study the effect of Angelica dahurica coumarins on the transport behavior of puerarin across blood-brain barrier (BBB) in vitro and in vivo. The barrier function of this model was evaluated by measuring the transendothelial resistance, phenol red permeability and BBB related protein expression. The permeability assay and western blot methods were performed to study the effects of Angelica dahurica coumarins on the BBB permeability and the expression of BBB related protein. The animal experiment protocols in this study were approved by the Animal Ethics Committee of Xi'an Jiaotong University (Animal Ethics No.: 2021-1329). The results showed that the established BMEC/AS co-culture model could be used to evaluate drug transport across BBB in vitro. After combined with Angelica dahurica coumarins, the transport capacity of puerarin was significantly increased in vitro and in vivo. Additionally, Angelica dahurica coumarins enhanced BBB permeability and inhibited the protein expression of P-glycoprotein (P-gp), zonula occludens-1 (ZO-1) and occludin. Angelica dahurica coumarins might increase BBB permeability by inhibiting the expression of P-gp and tight junction protein, thereby increasing the content of puerarin in brain tissue.