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1.
Eur J Drug Metab Pharmacokinet ; 49(1): 23-32, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38001303

ABSTRACT

AIM: 4-Hydroxybenzaldehyde (4-HBd) is used for the treatment of headaches, dizziness, and convulsions. The objective of this study was to characterize the pharmacokinetics of 4-HBd in cerebral ischemia-reperfusion injury (CIRI) rats by microdialysis technology with high-performance liquid chromatography with diode-array detection (HPLC-DAD) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). METHODS: Microdialysis was used to collect blood, feces, and urine of normal and CIRI model rats. Pharmacokinetic parameters were determined using HPLC-DAD and 4-HBd metabolites were determined using UPLC-MS. RESULTS: After gavage of 4-HBd in normal and middle cerebral artery occlusion/reperfusion (MCAO/R) rats, it was widely distributed to all tissues (heart, liver, spleen, lung, kidney, and brain) in both the equilibrium and elimination phases, and the distribution pattern was basically the same; the highest concentration was found in the brain. The absolute bioavailability of 4-HBd was 5.33%; however, after intragastric administration in normal and MCAO/R rats, fecal and urinary excretion of 4-HBd accounted for 0.02% and 0.01% and for 0.01% and 0.03% of the dosage, respectively. Furthermore, 4-HBd was rapidly metabolized into 4-hydroxybenzoic acid (4-HBA) after administration in both the control and MCAO/R groups. Compared with the control, the peak time of 4-HBd plasma concentration in the MCAO/R rats decreased from 10.67 min to 8.83 min, the area under the concentration-time curve decreased significantly, and the half-life increased from 31.81 min to 78.85 min. CONCLUSIONS: The rapid absorption and low absolute bioavailability of 4-HBd by gavage in rats are followed by rapid and wide distribution to various tissues and organs, including the brain. The prototype drug is excreted in the feces and urine in low amounts, and it is metabolized to 4-HBA in large amounts in vivo; the pathological state of the MCAO/R model mainly affects its absorption degree and metabolism rate.


Subject(s)
Benzaldehydes , Brain Ischemia , Butyrates , Reperfusion Injury , Rats , Animals , Chromatography, Liquid , Tandem Mass Spectrometry/methods , Microdialysis , Infarction, Middle Cerebral Artery , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism
2.
Can J Physiol Pharmacol ; 99(12): 1253-1263, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34283928

ABSTRACT

Angiogenesis facilitates the formation of microvascular networks and promotes neurological deficit recovery after cerebral ischemia-reperfusion injury (CIRI). This study investigated the angiogenesis effects of 4-methoxy benzyl alcohol (4-MA) on CIRI. The angiogenesis effects of 4-MA and the potential underlying mechanisms were assessed based on a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model and a hind limb ischemic (HLI) mouse model. Immunofluorescence was conducted to detect microvessel density, and Western blotting and polymerase chain reaction were performed to determine the expression of angiogenesis-promoting factors. In addition, we investigated whether the angiogenesis effects of 4-MA caused damage to the blood-brain barrier (BBB). After treatment with 4-MA (20 mg/kg) for 7 days, the neurological deficits recovered and microvessel density in the cerebral cortex increased in the MCAO/R rats. Additionally, 4-MA also regulated the expression of angiogenesis factors, with an increase in vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) expression and a decrease in angiopoietin 1 (Ang-1), Ang-2, and Tie-2 expression in both MCAO/R rats and HLI mice. Moreover, 4-MA increased the expression of angiogenesis-promoting factors without exacerbating BBB cascade damage in MCAO/R rats. Our results indicated that 4-MA may contribute to the formation of microvascular networks, thus promoting neurological deficit recovery after CIRI.


Subject(s)
Angiogenesis Inducing Agents , Benzyl Alcohol/administration & dosage , Benzyl Alcohol/pharmacology , Brain Ischemia/drug therapy , Reperfusion Injury/drug therapy , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Angiopoietin-1/genetics , Angiopoietin-1/metabolism , Angiopoietin-2/genetics , Angiopoietin-2/metabolism , Animals , Blood-Brain Barrier/metabolism , Brain Ischemia/genetics , Brain Ischemia/metabolism , Disease Models, Animal , Gene Expression/drug effects , Gene Expression/genetics , Male , Mice , Rats, Sprague-Dawley , Receptor, TIE-2/genetics , Receptor, TIE-2/metabolism , Reperfusion Injury/genetics , Reperfusion Injury/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-2/genetics
3.
Fitoterapia ; 151: 104879, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33689876

ABSTRACT

Swertia mileensis, known as Qing-Ye-Dan (QYD), has been documented in Chinese Pharmacopoeia to cure hepatitis. Interestingly, its announced main active component, swertiamarin, could not be detected in the decoction, which indicated that the efficacy of QYD might be attributed to heat-transformed products of swertiamarin (HTPS). Further investigation on HTPS led to the isolation of sweritranslactone D (1), a novel secoiridoid dimer possessing a tetracyclic lactone skeleton, with better hepatoprotective activity than N-acetyl-L-cysteine in vitro.


Subject(s)
Chemical and Drug Induced Liver Injury/drug therapy , Hot Temperature , Iridoid Glucosides/chemistry , Lactones/chemistry , Protective Agents/pharmacology , Pyrones/chemistry , Animals , Cell Line , Drugs, Chinese Herbal , Humans , Mice , Molecular Structure , Protective Agents/isolation & purification , Swertia/chemistry
4.
Int Immunopharmacol ; 82: 106353, 2020 Mar 03.
Article in English | MEDLINE | ID: mdl-32143007

ABSTRACT

BACKGROUND: Increasing evidence from human and animal studies suggests that cerebral ischemic diseases are associated with nerve dysfunction and neuroinflammation. Therefore, alleviating neuroinflammation is a potential way to treat ischemic stroke. Gastrodia elata Blume (GEB) is a traditional Chinese medicine used to treat central nervous system diseases and related conditions, such as vertigo, headache, epilepsy. We have previously shown that GEB has a protective effect in ischemic stroke, and that the underlying mechanism is related to anti-neuroinflammation. 3,4-Dihydroxybenzaldehyde (DBD) is a phenolic component of GEB and may be responsible for the neuroprotective effect of GEB; however, the detailed molecular mechanisms underlying the effects of DBD are unknown. METHODS: The anti-neuroinflammatory effect of DBD and the potential mechanisms underlying it were assessed. We using a rat model of middle cerebral artery occlusion/reperfusion and lipopolysaccharide-treated BV2 microglial cells. RESULTS: DBD (10 mg/kg) significantly decreased infarct volume. Additionally, it alleviated neurological deficits in the rats by inhibiting microglia activation. DBD (0.01, 0.1, and 1 µM) also significantly decreased the levels of inflammatory mediators and cytokines such as tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, prostaglandin E2. Furthermore, phenotypic analysis of the BV2 cells showed that DBD significantly down-regulated the expression of M1 marker but significantly up-regulated the expression of M2 marker. Moreover, it suppressed nuclear factor (NF)-κB activation and inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase, and extracellular signal-regulated protein kinases 1/2. CONCLUSIONS: The neuroprotective and anti-inflammatory effects of DBD are associated with selective modulation of microglia polarization and reduction in the production of inflammatory mediators and cytokines through inhibition of MAPK and NF-κB activation. These findings suggest that DBD may be a potential treatment for ischemic stroke and other neuroinflammatory diseases.

5.
Biomed Pharmacother ; 118: 109260, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31548176

ABSTRACT

OBJECTIVE: Cerebral ischemia reperfusion injury (CIRI) is a major cause of ischemic stroke (IS) deterioration. Considering the intricate mechanism of the pathological process of CIRI, most drugs only work on one target. The neurovascular unit (NVU) puts forward the concept of neuroprotection from nerve protection to global stabilization. The NVU plays an important role in maintaining the brain microenvironment. This would promote neuronal survival and overall neurological recovery, which would likely lead to the reduction of mortality rate. Previous studies have shown that 4-methoxy benzyl alcohol (4-MA) ameliorated neurological score and cerebral infarct volume and reduced the concentration of Evans blue (EB) in brain tissue. In this research, we investigated the effects of 4-MA on NVU microenvironment improvement in rats impaired by middle cerebral artery occlusion/reperfusion (MCAO/R). METHODS: First, we established a rat model of middle cerebral artery occlusion (MCAO) so as to use Western blot analysis, immunofluorescence and transmission electron microscopy (TEM) evaluating the NVU's protection of 4-MA. Then we established a primary cortical neuron model of oxygen glucose deprivation and re-oxygenation (OGD/R) with the objective of identifying whether 4-MA exhibited anti-oxidant and anti-apoptotic effects on neurons. RESULTS: NVU ultra structural changes were improved by 4-MA. Immunofluorescence and western blot showed that 4-MA protected NVUs through enhancement of the expression of the symbolic neuronal proteins Microtubule Associated Protein-2(MAP-2), and attenuation of protein expression of Asy symbolic protein Glial Fibrillary Acidic Protein(GFAP). Furthermore, in the OGD/R model of I/R injury in vitro, 4-MA significantly increased Superoxide dismutase(SOD), Nitric Oxide(NO), B-cell lymphoma-2(Bcl-2), decreased Bcl-2-Associated X(Bax) and increased Bcl-2/Bax. CONCLUSION: 4-MA can play the role of anti-ischemic stroke drug by ameliorating the microenvironment of NVUs while its neuroprotective effects will contribute towards the inhibition of the antioxidant and anti-apoptotic activities.


Subject(s)
Benzyl Alcohol/pharmacology , Neuroprotective Agents/pharmacology , Reperfusion Injury/drug therapy , Animals , Antioxidants/pharmacology , Apoptosis/drug effects , Brain Ischemia/drug therapy , Brain Ischemia/metabolism , Cell Survival/drug effects , Glial Fibrillary Acidic Protein/metabolism , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/metabolism , Male , Microtubule-Associated Proteins/metabolism , Neurons/drug effects , Neurons/metabolism , Rats , Rats, Sprague-Dawley , Reperfusion Injury/metabolism , Stroke/drug therapy , Stroke/metabolism
6.
Oxid Med Cell Longev ; 2018: 7642158, 2018.
Article in English | MEDLINE | ID: mdl-29765502

ABSTRACT

Pharmacological or spontaneous thrombolysis in ischemic stroke triggers an outbreak of reactive oxygen species and results in neuron death. Nrf2-mediated antioxidation in cells has been proved as a pivotal target for neuroprotection. This research reports that phenolic components of Gastrodia elata Blume (PCGE), a traditional Chinese medicine, can alleviate the pathological lesions in the penumbra and hippocampus by increasing the survival of neurons and astrocytes and improve neurofunction and cognition after reperfusion in a rat model of middle cerebral artery occlusion. LDH assay indicated that pretreatment of cells with PCGE (25 µg/ml) for 24 h significantly reduced H2O2-induced cell death in astrocytes and SH-SY5Y cells. Western blot showed that the nucleus accumulation of Nrf2 and the expression of cellular HO-1 and NQO-1, two of Nrf2 downstream proteins, were increased in both cells. BDNF, an Nrf2-dependent neurotrophic factor, was also upregulated by PCGE in astrocytes. These results illustrated that PCGE can reduce the cerebral ischemia/reperfusion injury and improve prognosis by remedying the cell damage within affected tissues. The protective effects of PCGE seem to be via activation of a Nrf2-mediated cellular defense system. Therefore, PCGE could be a therapeutic candidate for ischemic stroke and other oxidative stress associated neurological disorders.


Subject(s)
Antioxidants/therapeutic use , Gastrodia/chemistry , Phenols/therapeutic use , Reperfusion Injury/prevention & control , Animals , Antioxidants/chemistry , Antioxidants/pharmacology , Astrocytes/cytology , Astrocytes/drug effects , Astrocytes/metabolism , Behavior, Animal/drug effects , Brain Ischemia/etiology , Gastrodia/metabolism , Hippocampus/metabolism , Hippocampus/pathology , Humans , Hydrogen Peroxide/pharmacology , Infarction, Middle Cerebral Artery/complications , L-Lactate Dehydrogenase/metabolism , Male , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Phenols/chemistry , Phenols/pharmacology , Prognosis , Rats , Rats, Sprague-Dawley , Recovery of Function/drug effects , Reperfusion Injury/metabolism , Reperfusion Injury/pathology
7.
J Stroke Cerebrovasc Dis ; 26(6): 1258-1265, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28396190

ABSTRACT

Damage of the blood-brain barrier (BBB) during the process of cerebral ischemic injury is a key factor that influences the therapeutic efficacy to the cerebral ischemic injury. This work was designed to investigate the mechanisms underlying the protective effects of 4-methoxy benzyl alcohol (4-MA) on the BBB by developing a cerebral ischemia/reperfusion model of rats (MCAO/R). The MCAO/R was developed through a thread embolism method. The neurologic scales, the brain infarct rate, and the Evans blue (EB) contents of the brains were detected. Meanwhile, the release of nitric oxide (NO) and activities of NO synthase (NOS) in brain tissues were measured. Western blotting analyses were also used to assess the protein expressions of aquaporin-4 (AQP-4), occludin, and claudin-5 in brain tissue. After rats were pretreated with different concentrations of 4-MA, the neurologic scores, the infarct rate, and the EB contents in the brain tissues were significantly decreased. The release of NO and the activities of neuronal NOS and inducible NOS were notably inhibited. Furthermore, the protein expression of AQP-4 was markedly decreased, whereas the protein expressions of claudin-5 and occludin were significantly increased. In conclusion, the 4-MA decreases the permeability of BBB when focal cerebral ischemia occurs. The inhibition of the NOS pathways, the attenuation of the protein expression of AQP-4, and the enhancement of the expressions of the tight junction proteins might contribute to the protective effects of 4-MA on the BBB.


Subject(s)
Anisoles/pharmacology , Blood-Brain Barrier/drug effects , Capillary Permeability/drug effects , Infarction, Middle Cerebral Artery/prevention & control , Neuroprotective Agents/pharmacology , Reperfusion Injury/prevention & control , Animals , Aquaporin 4/metabolism , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Claudin-5/metabolism , Cytoprotection , Disease Models, Animal , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/pathology , Male , Nitric Oxide/metabolism , Nitric Oxide Synthase Type I/metabolism , Nitric Oxide Synthase Type II/metabolism , Occludin/metabolism , Rats, Sprague-Dawley , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Tight Junctions/drug effects , Tight Junctions/metabolism , Tight Junctions/pathology
8.
Afr J Tradit Complement Altern Med ; 13(4): 199-209, 2016.
Article in English | MEDLINE | ID: mdl-28852737

ABSTRACT

BACKGROUND: Damage of the blood brain barrier (BBB) during the process of cerebral ischemic injury is a key factor which influences the therapeutic efficacy to the cerebral ischemic injury. The present study was designed to verify the mechanisms underlying the protective effects of the ethyl acetate (EtOAc) extraction from Gastrodia elata Blume (GEB) on the BBB by developing a model of cerebral ischemia-reperfusion in rats. MATERIAL AND METHODS: MCAO/R model in rats was developed through a thread embolism method. The neurological scales, the moisture and the evans blue (EB) contents of brains were detected. Meanwhile, the release of nitric oxide (NO) and activities of NO synthase (NOS) in brain tissues were measured. Western blotting analyses were also performed to assess the protein expressions of AQP-4, Occludin and Claudin-5 in brain tissue. RESULTS: After rats were pretreated with different concentrations of EtOAc extractions from GEB, the neurologic scores, the EB contents in the brain tissues and the moisture of the brains were significantly decreased. Meanwhile, the release of NO, the activities of nNOS and iNOS were notably inhibited. Furthemore, the protein expression of AQP-4 was markedly decreased, but the protein expressions of -5 and Occludin were significantly increased. CONCLUSION: the EtOAc extracts of GEB may decrease the permeability of BBB when focal cerebral ischemia occurs. The inhibition of the NOS pathways, the attenuation of the protein expression of AQP-4 and the enhancement of the expressions of the tight junction proteins may contribute to the protective effects of the EtOAc extracts from GEB on BBB.


Subject(s)
Blood-Brain Barrier/drug effects , Drugs, Chinese Herbal/administration & dosage , Gastrodia/chemistry , Protective Agents/administration & dosage , Reperfusion Injury/prevention & control , Acetates/chemistry , Animals , Aquaporin 4/genetics , Aquaporin 4/metabolism , Blood-Brain Barrier/metabolism , Brain Ischemia/surgery , Humans , Male , Nitric Oxide/metabolism , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Occludin/genetics , Occludin/metabolism , Rats , Rats, Sprague-Dawley , Reperfusion Injury/genetics , Reperfusion Injury/metabolism
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