Neuroprotective Effects of Long-Term Metformin Preconditioning on Rats with Ischemic Brain Injuries

2021 ◽  
pp. 1-7
Author(s):  
Lu Wang ◽  
Aqian Wang ◽  
Hongtao Guo ◽  
Zhenxian Zhang ◽  
Shenghai Wang ◽  
...  
Keyword(s):  
Sham Group ◽  
Brain Injuries ◽  
Beclin 1 ◽  
Pathological Changes ◽  
Neuroprotective Effects ◽  
Ischemic Brain ◽  
Infarct Area ◽  
The Brain ◽  
Apoptosis Level

<b><i>Introduction:</i></b> This study is to analyze the neuroprotective effects of long-term metformin (Met) preconditioning on rats with ischemic brain injuries and the related mechanisms. <b><i>Methods:</i></b> Twenty-five Sprague-Dawley rats were randomly divided into 5 groups: sham group, middle cerebral artery occlusion (MCAO) group, normal saline + MCAO group, pre- Met + MCAO group, and 3-MA + Met + MCAO group. Pathological changes of brain were observed by hematoxylin-eosin staining. Neurobehavior scores were calculated. Infarct area was assessed by 2,3,5-triphenyltetrazolium chloride staining. Apoptosis of neurons was detected by TdT-mediated dUTP Nick-End Labeling (TUNEL). Western blot tested the expression of LC3 (microtubule-associated protein 1 light chain 3), Beclin-1, adenosine 5′-monophosphate ([AMP]-activated protein kinase [AMPK]), and p-AMPK in hippocampal CA1 region. <b><i>Results:</i></b> Compared with the sham group, the MCAO group induced severe pathological changes in the brain. The neurobehavior scores and infarct area in the brain were increased in the MCAO group than in the sham group. The apoptosis level in the MCAO group was also higher than in the sham group. However, after pretreatment with Met, the pathological changes in the brain were attenuated. Compared with the MCAO group, the pre-Met + MCAO group also had decreased neurobehavior scores and infarct area in the brain. Additionally, the apoptosis level in the pre-Met + MCAO group was lower than in the MCAO group. Moreover, the MCAO group had increased levels of LC3 and Beclin-1 than in the sham group. In the pre-Met + MCAO group, their levels were decreased than in the MCAO group. The p-AMPK level in the pre-Met + MCAO group was also increased than in the MCAO group, suggesting activation of p-AMPK by Met. <b><i>Conclusion:</i></b> Long-term Met pretreatment has neuroprotective effect on ischemic brain injury, which may be related to the regulation of autophagy-related protein expression and apoptosis.

scholarly journals Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Shufeng Yu ◽  
Desislava Met Doycheva ◽  
Marcin Gamdzyk ◽  
Yijun Yang ◽  
Cameron Lenahan ◽  
...  
Keyword(s):  
Brain Injury ◽  
Neurological Deficits ◽  
Ischemic Brain Injury ◽  
Neuroprotective Effects ◽  
Ischemic Brain ◽  
Expression Levels ◽  
Infarct Area ◽  
Short And Long Term ◽  
Hypoxic Ischemic Brain Injury

Abstract Background Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of hypoxic-ischemic (HI)-induced brain injury. Activation of melanocortin-1 receptor (MC1R) has been shown to exert anti-inflammatory and neuroprotective effects in several neurological diseases. In the present study, we have explored the role of MC1R activation on neuroinflammation and the potential underlying mechanisms after neonatal hypoxic-ischemic brain injury in rats. Methods A total of 169 post-natal day 10 unsexed rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. BMS-470539, a specific selective MC1R agonist, was administered intranasally at 1 h after HI induction. To elucidate the potential underlying mechanism, MC1R CRISPR KO plasmid or Nurr1 CRISPR KO plasmid was administered via intracerebroventricular injection at 48 h before HI induction. Percent brain infarct area, short- and long-term neurobehavioral tests, Nissl staining, immunofluorescence staining, and Western blot were conducted. Results The expression levels of MC1R and Nurr1 increased over time post-HI. MC1R and Nurr1 were expressed on microglia at 48 h post-HI. Activation of MC1R with BMS-470539 significantly reduced the percent infarct area, brain atrophy, and inflammation, and improved short- and long-term neurological deficits at 48 h and 28 days post-HI. MC1R activation increased the expression of CD206 (a microglial M2 marker) and reduced the expression of MPO. Moreover, activation of MC1R with BMS-470539 significantly increased the expression levels of MC1R, cAMP, p-PKA, and Nurr1, while downregulating the expression of pro-inflammatory cytokines (TNFα, IL-6, and IL-1β) at 48 h post-HI. However, knockout of MC1R or Nurr1 by specific CRISPR reversed the neuroprotective effects of MC1R activation post-HI. Conclusions Our study demonstrated that activation of MC1R with BMS-470539 attenuated neuroinflammation, and improved neurological deficits after neonatal hypoxic-ischemic brain injury in rats. Such anti-inflammatory and neuroprotective effects were mediated, at least in part, via the cAMP/PKA/Nurr1 signaling pathway. Therefore, MC1R activation might be a promising therapeutic target for infants with hypoxic-ischemic encephalopathy (HIE).

scholarly journals Replicating infant astrocyte behavior in the adult after brain injury improves outcomes

2020 ◽  
Author(s):  
Leon Teo ◽  
Anthony G. Boghdadi ◽  
Jihane Homman-Ludiye ◽  
Iñaki Carril-Mundiñano ◽  
William C. Kwan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Brain Injuries ◽  
Adult Patients ◽  
Long Term Outcomes ◽  
Neuroprotective Effects ◽  
Age Dependent ◽  
Underlying Mechanisms ◽  
Glial Scarring

AbstractInfants and adults respond differently to brain injuries. Specifically, improved neuronal sparing along with reduced astrogliosis and glial scarring often observed earlier in life, likely contributes to improved long-term outcomes. Understanding the underlying mechanisms could enable the recapitulation of neuroprotective effects, observed in infants, to benefit adult patients after brain injuries. We reveal that in primates, Eph/ ephrin signaling contributes to age-dependent reactive astrocyte behavior. Ephrin-A5 expression on astrocytes was more protracted in adults, whereas ephrin-A1 was associated only with infant astrocytes. Furthermore, ephrin-A5 exacerbated major hallmarks of astrocyte reactivity via EphA2 and EphA4 receptors, which was subsequently alleviated by ephrin-A1. Rather than suppressing reactivity, ephrin-A1 signaling shifted astrocytes towards GAP43+ neuroprotection, accounting for improved neuronal sparing in infants. Reintroducing ephrin-A1 after middle-aged ischemic stroke significantly attenuated glial scarring, improved neuronal sparing and preserved circuitry. Therefore, beneficial infant mechanisms can be recapitulated in adults to improve outcomes after CNS injuries.

scholarly journals New cerebrovascular agent with hypotensive activity

2019 ◽  
Vol 5 (2) ◽  
pp. 71-77
Author(s):  
Galina A. Kim ◽  
Tamara S. Gan’shina ◽  
Elena V. Kurza ◽  
Ilya N. Kurdyumov ◽  
Denis V. Maslennikov ◽  
...  
Keyword(s):  
Blood Flow ◽  
Antihypertensive Agent ◽  
Brain Injuries ◽  
Cerebrovascular Disorders ◽  
Male Rats ◽  
Hypotensive Activity ◽  
Duration Of Action ◽  
Ischemic Brain ◽  
Cerebrovascular Activity ◽  
The Brain

Introduction: In cerebrovascular disorders, special attention is paid to a hypertensive cerebrovascular crisis, which combines a vascular injury of the brain and hypertension. The paper studies the cerebrovascular properties of the calcium channel blocker of S-Amlodipine nicotinate antihypertensive agent. Materials and methods: Tests were performed on 96 nonlinear male rats, measuring local blood flow in the cerebral cortex in 36 awake animals, using a laser Doppler flowmeter. Cerebral circulation was recorded in the animals when modeling ischemic and hemorrhagic brain injuries. Results and discussion: S-Amlodipine nicotinate (0.1 mg/kg i/v) shows a pronounced cerebrovascular activity in the models of ischemic and hemorrhagic injuries of the brain. In terms of the vasodilating effect in ischemic brain injury, the drug is comparable to mexidol, nimodipine, picamilon, but is superior to nimodipine and picamilon in terms of duration of action, and in the model of hemorrhagic stroke, S-Amlodipine nicotinate is superior to nimodipine and is comparable to picamilon and mexidol. The analysis of the mechanism of action of the agent revealed the participation of GABA A-receptors in the implementation of cerebrovascular properties of the agent. Conclusion: Significant cerebrovascular activity of S-Amlodipine nicotinate (0.1 mg/kg i/v) antihypertensive agent was revealed. The presence of GABAergic mechanism on cerebral blood flow in the agent action along with blockade of slow calcium channels ensures its high efficacy in treatment of both ischemic and hemorrhagic brain injuries.

scholarly journals Endogenous THBD (Thrombomodulin) Mediates Angiogenesis in the Ischemic Brain—Brief Report

2020 ◽  
Vol 40 (12) ◽  
pp. 2837-2844 ◽  
Author(s):  
Jan Wenzel ◽  
Dimitrios Spyropoulos ◽  
Julian Christopher Assmann ◽  
Mahtab Ahmad Khan ◽  
Ines Stölting ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Soluble Form ◽  
Stroke Outcome ◽  
Brain Endothelial Cells ◽  
Ischemic Brain ◽  
Infarct Area ◽  
The Brain

Objective: THBD (thrombomodulin) is part of the anticoagulant protein C-system that acts at the endothelium and is involved in anti-inflammatory and barrier-stabilizing processes. A recombinant soluble form of THBD was shown to have protective effects in different organs, but how the endogenous THBD is regulated during ischemia, particularly in the brain is not known to date. The aim of this study was to investigate the role of THBD, especially in brain endothelial cells, during ischemic stroke. Approach and Results: To induce ischemic brain damage, we occluded the middle cerebral artery of mice. We found an increased endothelial expression of Thbd in the peri-infarct area, whereas in the core of the ischemic tissue Thbd expression was decreased compared with the contralateral side. We generated a novel Cre/loxP-based mouse line that allows for the inducible deletion of Thbd specifically in brain endothelial cells, which worsened stroke outcome 48 hours after middle cerebral artery occlusion. Unexpectedly, we found no signs of increased coagulation, thrombosis, or inflammation in the brain but decreased vessel diameters and impaired angiogenesis in the peri-infarct area that led to a reduced overall vessel length 1 week after stroke induction. Conclusions: Endogenous THBD acts as a protective factor in the brain during ischemic stroke and enhances vessel diameter and proliferation. These previously unknown properties of THBD could offer new opportunities to affect vessel function after ischemia and thereby improve stroke outcome.

Brain Grafting as a Treatment for Parkinson's Disease

Neurosurgery ◽  
1987 ◽  
Vol 20 (2) ◽  
pp. 335-342 ◽  
Author(s):  
Mark J. Perlow
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Manifestations ◽  
Dopamine Neurons ◽  
Clinical Aspects ◽  
Pathological Changes ◽  
Pharmacological Treatments ◽  
The Central Nervous System ◽  
The Brain

Abstract Parkinson's disease is an illness with neuropathological and neuroanatomical abnormalities in many areas of the central nervous system. Some clinical manifestations of this illness are correlated with pathological changes in the substantia nigra and with a loss of dopamine in the nigra and striatum. The most effective pharmacological treatments have used agents that either replace the lost dopamine or act as agonists on dopamine receptors. Recent studies in animal models of Parkinson's disease demonstrate that the loss of dopamine and many clinical manifestations of dopamine reduction can be reversed by transplantation of fetal dopamine-containing cells to specific dopamine-depleted areas of the brain. Long term viability of these transplants has also been demonstrated. The author suggests that the transplantation of dopamine neurons, even across species barriers, is a reasonable consideration for the treatment of human Parkinson's disease. This article reviews in detail the results of recent experiments and how the experience in these models might be utilized in determining a transplantation strategy for the treatment of specific clinical aspects of this illness.

scholarly journals Traumatic Injury to the Developing Brain: Emerging Relationship to Early Life Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaila N. Parker ◽  
Michael H. Donovan ◽  
Kylee Smith ◽  
Linda J. Noble-Haeusslein
Keyword(s):  
Brain Injury ◽  
Life Stress ◽  
Early Life ◽  
Brain Injuries ◽  
Traumatic Injury ◽  
Early Life Stress ◽  
Early Age ◽  
Functional Impairments ◽  
The Brain

Despite the high incidence of brain injuries in children, we have yet to fully understand the unique vulnerability of a young brain to an injury and key determinants of long-term recovery. Here we consider how early life stress may influence recovery after an early age brain injury. Studies of early life stress alone reveal persistent structural and functional impairments at adulthood. We consider the interacting pathologies imposed by early life stress and subsequent brain injuries during early brain development as well as at adulthood. This review outlines how early life stress primes the immune cells of the brain and periphery to elicit a heightened response to injury. While the focus of this review is on early age traumatic brain injuries, there is also a consideration of preclinical models of neonatal hypoxia and stroke, as each further speaks to the vulnerability of the brain and reinforces those characteristics that are common across each of these injuries. Lastly, we identify a common mechanistic trend; namely, early life stress worsens outcomes independent of its temporal proximity to a brain injury.

scholarly journals Violation in the axis of the "microbiota of the digestive tract-brain" under conditions of ischemia-reperfusion of the brain (literature review)

2021 ◽  
Vol 11 (5) ◽  
pp. 325-332
Author(s):  
O. Tkachuk ◽  
S. Tkachuk ◽  
M. Povar ◽  
O. Denysenko ◽  
V. Shtefaniuk
Keyword(s):  
Literature Review ◽  
Intestinal Microbiota ◽  
Brain Injuries ◽  
Ischemia Reperfusion ◽  
T Cell Homeostasis ◽  
Ischemic Brain ◽  
Intestinal Lymphocytes ◽  
And Migration ◽  
The Brain

The aim of the study is to analyze current views concerning interrelations between the state of intestinal microbiota and the course of ischemic-reperfusion brain injury.   Conclusion. Literary data are indicative of disputable scientific opinions existing nowadays concerning the role of dysbacteriosis (neuroprotective or neurodegenerative) in the course of ischemic brain injuries. Meanwhile, the studies are in common concerning the evidenced role of the intestinal microbiota in disturbances of T-cell homeostasis, ratio changes of their Treg-Th17 subpopulations, and migration of intestinal lymphocytes to the ischemic brain.  

scholarly journals Circulating Tight-Junction Proteins Are Potential Biomarkers for Blood-Brain Barrier Function in a Model of Neonatal Hypoxic/Ischemic Brain Injury

2020 ◽  
Author(s):  
Axel Erik Andersson ◽  
Carina Mallard ◽  
Carl Joakim Ek
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Brain Injuries ◽  
Brain Barrier ◽  
Neonatal Brain ◽  
Ischemic Brain ◽  
Blood Brain ◽  
Hypoxia Ischemia ◽  
The Brain ◽  
Junction Proteins

Abstract BackgroundNeonatal hypoxia-ischemia often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal brain pathologies but there is a lack of diagnostic tools to evaluate the brain vascular health of neonates in a clinical setting. Measurement of blood-brain barrier tight-junction proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury.MethodsThe levels of TJ-proteins (occluding, claudin-5, and zonula occludens-1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood-brain barrier function were measured in a clinically relevant hypoxia/ischemia model in neonatal rats.ResultsTemporally acute elevated levels of occludin and claudin-5 could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood-brain barrier-permeability at 6 and 24h after hypoxia/ischemia.ConclusionsLevels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood-brain barrier-impairment and have promise as early biomarkers for cerebral vascular health and as a tool for risk assessment of neonatal brain injuries.

Proinflammatory and Anti-inflammatory Genes in Stroke Pathogenesis

2020 ◽  
Vol 26 (34) ◽  
pp. 4220-4233
Author(s):  
Mengmeng Jiang ◽  
Penglin Yin ◽  
Xiaodan Bai ◽  
Liji Yang ◽  
Junping Zhang ◽  
...  
Keyword(s):  
Inflammatory Process ◽  
Ischemic Brain ◽  
Inflammatory Genes ◽  
Proinflammatory Mediators ◽  
Inflammatory Mechanism ◽  
Ischemic Brain Tissue ◽  
Anti Inflammatory ◽  
The Brain

The brain&#039;s response to ischemic injury is an acute and long-term inflammatory process. This process involves activation of resident cells (mainly microglia, hematogenous macrophages), production of proinflammatory mediators and infiltration of various proinflammatory cells (mainly neutrophils and lymphocytes). These cells play an essential role in ischemic brain tissue by releasing either proinflammatory or anti-inflammatory mediators at different time points. However, the exact pathogenesis of proinflammatory or anti-inflammatory genes in this process has not yet been elucidated. This review aims to investigate the inflammatory process of stroke, especially the role of proinflammatory and anti-inflammatory genes in the pathogenesis of stroke. We also summarize the current clinical trials of drugs that target the inflammatory mechanism for intervention.

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