Propentofylline protects neurons in culture from death triggered by macrophage or microglial secretory products

Flavin, Michael P.; Ho, Lam T.

doi:10.1002/(sici)1097-4547(19990401)56:1<54::aid-jnr7>3.0.co;2-2

Cited by 23 publications

(4 citation statements)

References 29 publications

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“…2 Microglia are stimulated within hours after ischemia onset, 27,28 followed by upregulation of a variety of inflammatory factors. Microglia can generate similar substances under ischemia-like 3,29 and ischemic 30 conditions. Lynch et al 31 correlated microglial activation to BBB disruption in a model of 3-chlorpropanediol toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 When activated, microglia undergo proliferation, chemotaxis, morphological alterations, and generate immunomodulatory molecules. Microglia release proteases, lipases, and glutamate 3,4 and are sensitive to hypoxia-and ischemia-like insults in vitro with a vulnerability greater than oligodendrocytes 5 and similar to or less than astrocytes, 6 depending on the model and species used. Their role in maintaining or interfering with BBB integrity in the context of ischemia is not well studied.…”

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confidence: 99%

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Microglia Potentiate Damage to Blood–Brain Barrier Constituents

Yenari

Tang

et al. 2006

Stroke

335

264

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Background-Blood-brain barrier (BBB) disruption after stroke can worsen ischemic injury by increasing edema and causing hemorrhage. We determined the effect of microglia on the BBB and its primary constituents, endothelial cells (ECs) and astrocytes, after ischemia using in vivo and in vitro models. Methods and Results-Primary astrocytes, ECs, or cocultures were prepared with or without added microglia. Primary ECs were more resistant to oxygen-glucose deprivation/reperfusion than astrocytes. ECs plus astrocytes showed intermediate vulnerability. Microglia added to cocultures nearly doubled cell death. This increase was prevented by minocycline and apocynin. In vivo, minocycline reduced infarct volume and neurological deficits and markedly reduced BBB disruption and hemorrhage in mice after experimental stroke. Conclusions-Inhibition of microglial activation may protect the brain after ischemic stroke by improving BBB viability and integrity. Microglial inhibitors may prove to be an important treatment adjunct to fibrinolysis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Microglia Potentiate Damage to Blood–Brain Barrier Constituents

Yenari

Tang

et al. 2006

Stroke

335

264

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“…However, it does not allow stating that microglial A 2A Rs play a key role in controlling the involvement of A 2A Rs in neuronal damage. In fact, studies with cultured cells showed that adenosine can directly attenuate neuronal damage caused by administration to neurons of medium from activated microglia cultures [98]. The development of a neuro-inflammatory process depends not only on microglia activation, but also on the participation of astrocytes (e.g., [288]) and neurons (e.g., [289]), as well as on the involvement of infiltrating myeloid cells (see [282,290,291]).…”

Section: A 2a Receptor Blockade Confers Robust Neuroprotectionmentioning

confidence: 99%

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

Purinergic Signalling

484

432

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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“…Microglia are among the first cells to respond to brain injury [199,200]. When stimulated, microglia undergo proliferation, chemotaxis, morphological alterations, and release of immunomodulatory molecules including proteases, lipases, glutamate and generate reactive oxygen species [201,202]. Blocking microglial activation may limit BBB disruption and reduce edema and hemorrhagic transformation.…”

Section: Minocyclinementioning

confidence: 99%

Chronic Inflammatory Pain and the Neurovascular Unit: A Central Role for Glia in Maintaining BBB Integrity?

Willis

Davis²

2008

CPD

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Pain is a complex phenomenon involving both a peripheral innate immune response and a CNS response as well as activation of the hypothalamic-pituitary-adrenal axis. The peripheral innate immune response to injury involves the rapid production and local release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-/alpha), interleukin-1 (IL-1) and IL-6. Recent studies into the CNS response to peripheral chronic inflammatory pain strongly implicates a role for glia, and local synthesis of proinflammatory cytokines and growth factors. A characteristic feature of CNS inflammation is gliosis, in which inflammatory mediators activate glial cells (e.g. astrocytes and microglia, macrophages and leukocytes) which have been shown to induce and maintain hyperalgesia. In addition, inflammatory pain induces changes in blood-brain barrier (BBB) permeability and alters transport of clinically relevant drugs used to treat pain into the brain. Despite the increasing body of evidence for the involvement of glia in chronic pain and the role of glia in maintaining the BBB, few studies have addressed glial/endothelial interactions and the mechanisms by which glia may regulate the BBB during inflammatory pain. Further studies into the cellular mechanisms of glial/endothelial interactions may identify novel therapeutic targets for reversing chronic inflammatory induced BBB dysfunction and innovate therapies for modulating the severity of chronic inflammatory pain.

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Propentofylline protects neurons in culture from death triggered by macrophage or microglial secretory products

Cited by 23 publications

References 29 publications

Microglia Potentiate Damage to Blood–Brain Barrier Constituents

Microglia Potentiate Damage to Blood–Brain Barrier Constituents

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Chronic Inflammatory Pain and the Neurovascular Unit: A Central Role for Glia in Maintaining BBB Integrity?

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