A new concept affecting restoration of inflammation-reactive astrocytes

Block, Linda; Björklund, Ulrika; Westerlund, Anna; Jörneberg, Per; Biber, Björn; Hanssoń, Elisabeth

doi:10.1016/j.neuroscience.2013.07.033

Cited by 36 publications

(48 citation statements)

References 54 publications

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“…Such a therapy could assist in the prevention of secondary injury due to enduring inflammation and closely related post-traumatic epilepsy discussed above. Opioid antagonists and agonists may also be potent regulators of astrocyte reactivity (Block et al, 2013). As we learn more about the specific astrocyte roles and underlying mechanisms regulating TBI pathophysiology additional potential therapeutic targets will emerge.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte roles in traumatic brain injury

Burda

Bernstein

Sofroniew

2016

Experimental Neurology

628

479

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Astrocytes sense changes in neural activity and extracellular space composition. In response, they exert homeostatic mechanisms critical for maintaining neural circuit function, such as buffering neurotransmitters, modulating extracellular osmolarity and calibrating neurovascular coupling. In addition to upholding normal brain activities, astrocytes respond to diverse forms of brain injury with heterogeneous and progressive changes of gene expression, morphology, proliferative capacity and function that are collectively referred to as reactive astrogliosis. Traumatic brain injury (TBI) sets in motion complex events in which noxious mechanical forces cause tissue damage and disrupt central nervous system (CNS) homeostasis, which in turn trigger diverse multi-cellular responses that evolve over time and can lead either to neural repair or secondary cellular injury. In response to TBI, astrocytes in different cellular microenvironments tune their reactivity to varying degrees of axonal injury, vascular disruption, ischemia and inflammation. Here we review different forms of TBI-induced astrocyte reactivity and the functional consequences of these responses for TBI pathobiology. Evidence regarding astrocyte contribution to post-traumatic tissue repair and synaptic remodeling is examined, and the potential for targeting specific aspects of astrogliosis to ameliorate TBI sequelae is considered.

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Section: Discussionmentioning

confidence: 99%

Astrocyte roles in traumatic brain injury

Burda

Bernstein

Sofroniew

2016

Experimental Neurology

628

479

View full text Add to dashboard Cite

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“…Western blotting was done as earlier described (Block et al, 2013). Cytoplasmic protein and nucleoprotein was extracted from the primary culture cells in every group.…”

Section: Methodsmentioning

confidence: 99%

Inhibitive Effects of FGF2/FGFR1 Pathway on Astrocyte-Mediated Inflammation in vivo and in vitro After Infrasound Exposure

Shi

Xiao

et al. 2018

Front. Neurosci.

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Infrasound, a kind of ambient noise, can cause severe disorders to various human organs, specially to central nervous system (CNS). Our previous studies have shown that infrasound-induced CNS injury was closely related with astrocytes activation and astrocytes-mediated neuroinflammation, but the underlying molecular mechanisms are still largely unclear. FGF2/FGFR1 (Fibroblast growth factor 2/Fibroblast growth factor receptor 1) pathway was reported to play an important role in anti-inflammation in CNS disorders. To further study the possible roles of FGF2/FGFR1 pathway in infrasound-induced CNS injury, here we exposed Sprague-Dawley rats or cultured astrocytes to 16 Hz, 150 dB infrasound, and explored the effects of FGF2 on infrasound-induced astrocytes activation and neuroinflammation. Western blotting, immunofluorescence and liquid chip method were used in this experiment. Our results showed that after 3- or 7-day exposure (2 h/day) of rats as well as 2 h exposure of cultured astrocytes to 16 Hz, 150 dB infrasound, astrocyte-expressed FGFR1 was downregulated in vivo and in vitro. FGF2 pretreatment not only inhibited infrasound-induced astrocyte activation in rat hippocampal CA1 region, but also reduced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-18, IL-6, and IFN-γ in vitro and in vivo. However, FGF2 significantly upregulated the expression of FGFR1. Furthermore, we showed that FGF2 could attenuate IκBα phosphorylation, NF-κB p65 translocation, pro-inflammatory cytokines levels, and neuronal loss in the CA1 region induced by infrasound. On the contrary, PD173074, a special antagonist of FGFR1, could reverse the effects above in vitro and in vivo. Taken together, our findings showed that FGF2/FGFR1 pathway may exert inhibitive effects on astrocyte-mediated neuroinflammation in vitro and in vivo after infrasound exposure.

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“…The cellular changes that occur during experimental neuroinflammation render the astrocyte network unable to interact appropriately with neurons and synaptic transmission [94]. To restore the cellular changes caused by the experimental neuroinflammation described above, we searched the literature for substances with possible anti-inflammatory properties that are usually used for other purposes in medicine.…”

Section: Reversing Glial Dysfunction (Fig 3)mentioning

confidence: 99%

“…The combination of the endogenous -opioid agonist endomorphin-1, the -opioid antagonist naloxone at ultralow concentrations and the anti-epileptic drug levetiracetam yielded promising results as regards restoration of cellular changes caused by experimentally induced inflammation [94].…”

Section: Experimental Studies Of the Combination Endomorphin-1 Naloxmentioning

confidence: 99%

Glial dysfunction and persistent neuropathic postsurgical pain

Block

2016

Scandinavian Journal of Pain

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AbstractBackgroundAcute pain in response to injury is an important mechanism that serves to protect living beings from harm. However, persistent pain remaining long after the injury has healed serves no useful purpose and is a disabling condition. Persistent postsurgical pain, which is pain that lasts more than 3 months after surgery, affects 10–50% of patients undergoing elective surgery. Many of these patients are affected by neuropathic pain which is characterised as a pain caused by lesion or disease in the somatosen-sory nervous system. When established, this type of pain is difficult to treat and new approaches for prevention and treatment are needed.A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system (CNS), glial dysfunction and subsequently an imbalance in the neuron–glial interaction that causes enhanced and prolonged pain transmission.AimThis topical review aims to highlight the contribution that inflammatory activated glial cell dysfunction may have for the development of persistent pain.MethodRelevant literature was searched for in PubMed.Results Immediately after an injury to a nerve ending in the periphery such as in surgery, the inflammatory cascade is activated and immunocompetent cells migrate to the site of injury. Macrophages infiltrate the injured nerve and cause an inflammatory reaction in the nerve cell. This reaction leads to microglia activation in the central nervous system and the release of pro-inflammatory cytokines that activate and alter astrocyte function. Once the astrocytes and microglia have become activated, they participate in the development, spread, and potentiation of low-grade neuroinflammation. The inflammatory activated glial cells exhibit cellular changes, and their communication to each other and to neurons is altered. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocyte dysfunction can be experimentally restored using the combined actions of a μ–opioid receptor agonist, a μ–opioid receptor antagonist, and an anti-epileptic agent. To find these agents we searched the literature for substances with possible anti-inflammatory properties that are usually used for other purposes in medicine. Inflammatory induced glial cell dysfunction is restorable in vitro by a combination of endomorphine-1, ultralow doses of naloxone and levetiracetam. Restoring inflammatory-activated glial cells, thereby restoring astrocyte-neuron interaction has the potential to affect pain transmission in neurons. ConclusionSurgery causes inflammation at the site of injury. Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflammation can cause an imbalance in the glial-neuron interaction and communication. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocytic dysfunction can be restored in vitro by a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam. This restoration is essential for the interaction between astrocytes and neurons and hence also for modulation of synaptic pain transmission.ImplicationsLarger studies in clinical settings are needed before these findings can be applied in a clinical context. Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened.

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A new concept affecting restoration of inflammation-reactive astrocytes

Cited by 36 publications

References 54 publications

Astrocyte roles in traumatic brain injury

Astrocyte roles in traumatic brain injury

Inhibitive Effects of FGF2/FGFR1 Pathway on Astrocyte-Mediated Inflammation in vivo and in vitro After Infrasound Exposure

Glial dysfunction and persistent neuropathic postsurgical pain

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