Possible mechanisms of Cyclosporin A ameliorated the ischemic microenvironment and inhibited mitochondria stress in tree shrews’ hippocampus

Li, Shuqing; Zhang, Ying; Tang, Daibin

doi:10.1016/j.pathophys.2009.02.014

Cited by 4 publications

(1 citation statement)

References 14 publications

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“…It has been demonstrated that CytC released into the cytosol binds to apoptotic protease activating factor-1, which leads to activation of caspase-9 which is important in neuronal cell death following ischemia ( Kluck et al, 1997 ; Yang et al, 1997 ; Love, 2003 ; Jiang and Wang, 2004 ; Suen et al, 2008 ; Lana et al, 2014 , 2016 , 2017a , b ; Martínez-Fábregas et al, 2014 ). In turn, caspase-9 is activated by high glutamate levels, as occurs during ischemia ( Li et al, 2009 ). As reported in the literature, activation of mTOR, which has multiple roles in cells among which local protein synthesis at the dendritic and spine level ( Frey and Morris, 1997 ; Tsokas et al, 2007 ; Thoreen et al, 2012 ), can be modified in ischemic conditions ( Dennis et al, 2001 ; Laplante and Sabatini, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

The Selective Antagonism of Adenosine A2B Receptors Reduces the Synaptic Failure and Neuronal Death Induced by Oxygen and Glucose Deprivation in Rat CA1 Hippocampus in Vitro

et al. 2018

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Ischemia is a multifactorial pathology characterized by different events evolving in time. Immediately after the ischemic insult, primary brain damage is due to the massive increase of extracellular glutamate. Adenosine in the brain increases dramatically during ischemia in concentrations able to stimulate all its receptors, A1, A2A, A2B, and A3. Although adenosine exerts clear neuroprotective effects through A1 receptors during ischemia, the use of selective A1 receptor agonists is hampered by their undesirable peripheral side effects. So far, no evidence is available on the involvement of adenosine A2B receptors in cerebral ischemia. This study explored the role of adenosine A2B receptors on synaptic and cellular responses during oxygen and glucose deprivation (OGD) in the CA1 region of rat hippocampus in vitro. We conducted extracellular recordings of CA1 field excitatory post-synaptic potentials (fEPSPs); the extent of damage on neurons and glia was assessed by immunohistochemistry. Seven min OGD induced anoxic depolarization (AD) in all hippocampal slices tested and completely abolished fEPSPs that did not recover after return to normoxic condition. Seven minutes OGD was applied in the presence of the selective adenosine A2B receptor antagonists MRS1754 (500 nM) or PSB603 (50 nM), separately administered 15 min before, during and 5 min after OGD. Both antagonists were able to prevent or delay the appearance of AD and to modify synaptic responses after OGD, allowing significant recovery of neurotransmission. Adenosine A2B receptor antagonism also counteracted the reduction of neuronal density in CA1 stratum pyramidale, decreased apoptosis at least up to 3 h after the end of OGD, and maintained activated mTOR levels similar to those of controls, thus sparing neurons from the degenerative effects caused by the simil-ischemic conditions. Astrocytes significantly proliferated in CA1 stratum radiatum already 3 h after the end of OGD, possibly due to increased glutamate release. A2Breceptor antagonism significantly prevented astrocyte modifications. Both A2B receptor antagonists did not protect CA1 neurons from the neurodegeneration induced by glutamate application, indicating that the antagonistic effect is upstream of glutamate release. The selective antagonists of the adenosine A2B receptor subtype may thus represent a new class of neuroprotective drugs in ischemia.

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Section: Discussionmentioning

confidence: 99%

The Selective Antagonism of Adenosine A2B Receptors Reduces the Synaptic Failure and Neuronal Death Induced by Oxygen and Glucose Deprivation in Rat CA1 Hippocampus in Vitro

et al. 2018

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Prevention of Cyclophilin D-Mediated mPTP Opening Using Cyclosporine-A Alleviates the Elevation of Necroptosis, Autophagy and Apoptosis-Related Markers Following Global Cerebral Ischemia-Reperfusion

et al. 2016

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The mitochondrial permeability transition pore (mPTP) is a complex channel of the inner membrane, the opening of which leads to mitochondrial swelling and dissipation of mitochondrial membrane potential (MMP). Here, we aimed to evaluate the role of the cyclophilin D (CypD) as a prominent mediator of mPTP, on necroptosis and autophagy as well as apoptosis, beyond the global cerebral ischemia-reperfusion (I/R) injury. We showed that while cerebral I/R injury is accompanied by loss of MMP, mitochondrial swelling and programmed cell death, pretreatment with cyclosporine-A (CsA) as a potent inhibitor of CypD, led to partial but significant reduction in necroptosis markers, RIP1 and RIP3 as well as activity of glutamate-ammonia ligase (GLUL) and glutamate dehydrogenase 1 (GLUD1), downstream enzymes of RIP3. Administration of CsA also partially decreased autophagy associated proteins. Furthermore, we demonstrated that Bax/Bcl-2 ratio as well as caspase-3 activation, as the executioner of apoptosis, noticeably decreased by CsA pretreatment. Taken together, our results suggest that the CypD alongside the apoptosis regulation plays a partial role in inducing necroptosis and autophagy.

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Establishment of brain ischemia model in tree shrew

et al. 2019

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Possible mechanisms of Cyclosporin A ameliorated the ischemic microenvironment and inhibited mitochondria stress in tree shrews’ hippocampus

Cited by 4 publications

References 14 publications

The Selective Antagonism of Adenosine A2B Receptors Reduces the Synaptic Failure and Neuronal Death Induced by Oxygen and Glucose Deprivation in Rat CA1 Hippocampus in Vitro

The Selective Antagonism of Adenosine A2B Receptors Reduces the Synaptic Failure and Neuronal Death Induced by Oxygen and Glucose Deprivation in Rat CA1 Hippocampus in Vitro

Prevention of Cyclophilin D-Mediated mPTP Opening Using Cyclosporine-A Alleviates the Elevation of Necroptosis, Autophagy and Apoptosis-Related Markers Following Global Cerebral Ischemia-Reperfusion

Establishment of brain ischemia model in tree shrew

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