S-oxiracetam protect against ischemic stroke via alleviating blood brain barrier dysfunction in rats

Wang

et al. 2018

Front. Cell. Neurosci.

The blood-brain barrier (BBB) is a physical and biochemical barrier that maintains cerebral homeostasis. BBB dysfunction in an ischemic stroke, results in brain injury and subsequent neurological impairment. The aim of this study was to determine the possible protective effects of 1, 25-dihydroxyvitamin D3 [1, 25(OH)2D3, 1, 25-D3, vit D] on BBB dysfunction, at the early stages of an acute ischemic brain injury. We analyzed the effects of 1, 25-D3 on BBB integrity in terms of histopathological changes, the neurological deficit, infarct size and the expression of brain derived neurotrophic factor (BDNF), in a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model. BBB permeability and the expression of permeability-related proteins in the brain were also evaluated by Evans blue (EB) staining and Western blotting respectively. To determine the possible mechanism underlying the role of 1, 25-D3 in BBB maintenance, after MCAO/R, the rats were treated with the specific peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor GW9662. Supplementation with 1, 25-D3 markedly improved the neurological scores of the rats, decreased the infarct volume, prevented neuronal deformation and upregulated the expression of the tight junction (TJ) and BDNF proteins in their brains. Furthermore, it activated PPARγ but downregulated neuro-inflammatory cytokines such as nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α), after MCAO/R. Taken together, 1, 25-D3 protects against cerebral ischemia by maintaining BBB permeability, upregulating the level of BDNF and inhibiting PPARγ-mediated neuro-inflammation.

Section: Introductionmentioning

confidence: 99%

RETRACTED: 1, 25-D3 Protects From Cerebral Ischemia by Maintaining BBB Permeability via PPAR-γ Activation

Wang

et al. 2018

Front. Cell. Neurosci.

“…In this regard, ischemic and hemorrhagic stroke are life-threatening conditions whose outcomes include severe BBB disruption ( Knowland et al, 2014 ; Keep et al, 2018 ). In rodent models of ischemic stroke, based on middle cerebral artery occlusion (MCAO), an increase in brain water content and a decrease in the expression of TJ proteins, including occludin and claudin-5, have been observed ( Huang et al, 2017 ). In functional terms, the cited reports demonstrated an increase in BBB permeability, i.e., increased brain levels of drugs transported through the paracellular pathway.…”

Section: How Blood-brain Barrier Endothelial Dysfunction Could Alter mentioning

confidence: 99%

“…Preeclampsia is associated with impaired systemic endothelial function ( Roberts et al, 1989 ) and, in the brain of preeclamptic women, this endothelial dysfunction presents in the form of impaired integrity of the BBB ( Bergman et al, 2018 ), which is apparently maintained even post-partum ( Bergman et al, 2016 ). The influence of endothelial dysfunction on drug disposition in the brain has been studied in disease states, including stroke ( Huang et al, 2017 ) however there is a lack of studies investigating the effect of endothelial dysfunction on brain drug disposition in pregnancy-related disorders. The latter issue is extremely important and needs to be addressed since preeclamptic women may need to receive medications to control symptoms within pregnancy, and/or at some point post-partum, particularly for treatment of chronic conditions, e.g., epilepsy, depression and HIV-infection.…”

Section: Introductionmentioning

confidence: 99%

Drug Transport at the Brain and Endothelial Dysfunction in Preeclampsia: Implications and Perspectives

Torres-Vergara

Escudero²,

Penny

2018

Front. Physiol.

Transport of drugs across biological barriers has been a subject of study for decades. The discovery and characterization of proteins that confer the barrier properties of endothelia and epithelia, including tight junction proteins and membrane transporters belonging to the ATP-binding cassette (ABC) and Solute Carrier (SLC) families, represented a significant step forward into understanding the mechanisms that govern drug disposition. Subsequently, numerous studies, including both pre-clinical approaches and clinical investigations, have been carried out to determine the influence of physiological and pathological states on drug disposition. Importantly, there has been increasing interest in gaining a better understanding of drug disposition during pregnancy, since epidemiological and clinical studies have demonstrated that the use of medications by pregnant women is significant and this condition embodies a series of significant anatomical and physiological modifications, particularly at excretory organs and barrier sites (e.g., placenta, breast) expressing transporter proteins which influence pharmacokinetics. Currently, most of the research in this field has focused on the expression profiling of transporter proteins in trophoblasts and endothelial cells of the placenta, regulation of drug-resistance mechanisms in disease states and pharmacokinetic studies. However, little attention has been placed on the influence that the cerebrovascular dysfunction present in pregnancy-related disorders, such as preeclampsia, might exert on drug disposition in the mother’s brain. This issue is particularly important since recent findings have demonstrated that preeclamptic women suffer from long-term alterations in the integrity of the blood-brain barrier (BBB). In this review we aim to analyze the available evidence regarding the influence of pregnancy on the expression of transporters and TJ proteins in brain endothelial cells, as well the mechanisms that govern the pathophysiological alterations in the BBB of women who experience preeclampsia. Future research efforts should be focused not only on achieving a better understanding of the influence of preeclampsia-associated endothelial dysfunction on drug disposition, but also in optimizing the pharmacological treatments of women suffering pregnancy-related disorders, its comorbidities and to develop new therapies aiming to restore the integrity of the BBB.

“…Furthermore, ORC remarkably reverses cognitive decline in older human subjects ( 20 ). Another study has suggested that ORC reduces the release of inflammatory cytokines in a rat model of stroke ( 21 ). However, whether ORC improves cognitive decline by preventing Aβ-induced inflammation and oxidative stress in AD models remains unknown; moreover, the mechanisms underlying its effects should be explored in more detail.…”

Section: Introductionmentioning

confidence: 99%

Oxiracetam Offers Neuroprotection by Reducing Amyloid β-Induced Microglial Activation and Inflammation in Alzheimer's Disease

Zhang

Jia

2020

Front. Neurol.

Background: Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) accumulation in the brain, which triggers the activation of microglia; in turn, microglia release neuroinflammatory factors capable of damaging neurons. Thus, a therapeutic approach targeting this sustained microglia-induced inflammatory response deserves investigation. Here, we examined whether oxiracetam (ORC), a nootropic of the racetam family, can indirectly prevent Aβ-induced neurotoxicity by attenuating microglial activation. Methods: Aβ42 oligomers were used to stimulate BV2 microglial cells, and the morphological changes and phagocytic capacity of BV2 cells were evaluated using fluorescence microscopy. We used quantitative reverse transcription polymerase chain reaction to assess the inhibitory effects of ORC on Aβ-induced mRNA levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α); enzyme-linked immunosorbent assay was used to examine the productions of these cytokines. We also assessed the mRNA level of inducible nitric oxide synthase and the production of nitric oxide (NO). The conditioned medium from BV2 cells was used to culture hippocampal HT22 cells to assess indirect toxicity using the MTT assay. Results: ORC prevented the Aβ-induced activation of BV2 cells, as reflected by reduced morphological changes and phagocytic ability. In addition, ORC downregulated the expression of Aβ-induced cytokines (IL-1β, IL-6, and TNF-α) and the production of NO in BV2 cells. Furthermore, ORC protected HT22 cells from indirect damage evoked by Aβ-treated BV2 cell-conditioned medium, but not from direct Aβ-induced toxicity. Conclusions: ORC suppressed the activation of BV2 cells, decreased the production of Aβ-induced inflammatory molecules and NO in BV2 cells, and protected HT22 cells against indirect toxicity mediated by Aβ-treated BV2 cell-conditioned medium. Thus, ORC may exert a protective role in AD through attenuating the damage caused by inflammation and oxidative stress.