Reactive astrogliosis after basic fibroblast growth factor (bFGF) injection in injured neonatal rat brain

Eclancher, Françoise; Perraud, Frédéric; Faltin, J; Labourdette, G.; Sensenbrenner, M.

doi:10.1002/glia.440030609

Cited by 85 publications

(37 citation statements)

References 43 publications

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“…The nature of the experimental approaches previously used to study the damage response in vivo, which, in most cases, have not been manipulations that target a specific cell type but affect the response as a whole, have made it difficult to tease apart functionally relevant cell-cell interactions. A good example of this is the infusion of FGF2 into the sites of injury, which led to the hypothesis that FGFs promote astrogliosis (13)(14)(15). Here, by specifically targeting astrocytes in the adult, we demonstrate that the FGF pathway directly inhibits the activation of protoplasmic astrocytes in the normal brain and after traumatic injury.…”

Section: Discussionmentioning

confidence: 82%

“…11, 12) and based on increased proliferation and GFAP expression upon injections of high concentrations of FGF2 in different brain areas (e.g., refs. [13][14][15]. However, the role FGF signaling may play in directly regulating astrocyte activation in these experiments is difficult to interpret given the high concentrations of exogenous ligand that was administered and the potential for indirect effects through other cell types affected by FGFs.…”

Section: Significancementioning

confidence: 99%

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Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Kang

Balordi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

117

109

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In the brain, astrocytes are multifunctional cells that react to insults and contain damage. However, excessive or sustained reactive astrocytes can be deleterious to functional recovery or contribute to chronic inflammation and neuronal dysfunction. Therefore, astrocyte activation in response to damage is likely to be tightly regulated. Although factors that activate astrocytes have been identified, whether factors also exist that maintain astrocytes as nonreactive or reestablish their nonreactive state after containing damage remains unclear. By using loss-and gainof-function genetic approaches, we show that, in the unperturbed adult neocortex, FGF signaling is required in astrocytes to maintain their nonreactive state. Similarly, after injury, FGF signaling delays the response of astrocytes and accelerates their deactivation. In addition, disrupting astrocytic FGF receptors results in reduced scar size without affecting neuronal survival. Overall, this study reveals that the activation of astrocytes in the normal and injured neocortex is not only regulated by proinflammatory factors, but also by factors such as FGFs that suppress activation, providing alternative therapeutic targets.brain damage | astrogliosis A strocytes are the most abundant cell type in the mammalian brain. The thin processes of protoplasmic astrocytes (graymatter astrocytes) canvas the neural parenchyma and make contact with several other cell types. Protoplasmic astrocytes carry out a variety of functions, including maintaining the bloodbrain barrier, ion homeostasis, neurotransmitter turnover, and synapse formation (1). Another major function of these astrocytes involves their activation in response to damage. Astrocyte activation, or astrogliosis, plays a central role in the response to most or all neurological insults including trauma, infections, stroke, tumorigenesis, neurodegeneration, and epilepsy. The extent of astrogliosis can influence long-term recovery, and the response of astrocytes to different insults is likely to be graded and complex (2, 3). Nevertheless, in most cases, astrocytes transiently become hypertrophic and express high levels of intermediate filaments such as GFAP, vimentin, tenascin C, and nestin, and, in cases of severe damage, astrocytes can also become proliferative and form a scar.Astrogliosis can have beneficial and detrimental effects on recovery. Astrogliosis is essential for minimizing the spread of damage and inflammation, but it is also inhibitory for axonal and cellular regeneration. For example, in transgenic mice in which reactive astrocytes are ablated or disabled, traumatic injury leads to the lack of normal scar formation, prolonged and more widespread inflammation, and a failure to reconstruct the bloodbrain barrier and maintain tissue integrity (4, 5). However, ablation or impairment of reactive astrocytes also leads to increased nerve fiber growth in the immediate vicinity of the injury site, which could improve axonal regeneration and functional recovery (4, 5). Therefore, levels of astrocy...

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Section: Discussionmentioning

confidence: 82%

Section: Significancementioning

confidence: 99%

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Kang

Balordi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

117

109

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“…bFGF/JNK pathway in astrocytes and persistent pain bFGF (OR FGF-2) is a well-known activator of astrocytes. bFGF is produced by astrocytes and strongly induces their mitosis, growth, differentiation and gliosis (Ferrara et al, 1988;Eclancher et al, 1990). bFGF is induced in the CNS in many injury conditions.…”

Section: Activation Of the Jnk Cascade In Spinal Astrocytes And Neuromentioning

confidence: 99%

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

et al. 2006

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Although pain is regarded traditionally as neuronally mediated, recent progress shows an important role of spinal glial cells in persistent pain sensitization. Mounting evidence has implicated spinal microglia in the development of chronic pain (e.g. neuropathic pain after peripheral nerve injury). Less is known about the role of astrocytes in pain regulation. However, astrocytes have very close contact with synapses and maintain homeostasis in the extracellular environment. In this review, we provide evidence to support a role of spinal astrocytes in maintaining chronic pain. In particular, cJun N-terminal kinase (JNK) is activated persistently in spinal astrocytes in a neuropathic pain condition produced by spinal nerve ligation. This activation is required for the maintenance of neuropathic pain because spinal infusion of JNK inhibitors can reverse mechanical allodynia, a major symptom of neuropathic pain. Further study reveals that JNK is activated strongly in astrocytes by basic fibroblast growth factor (bFGF), an astroglial activator. Intrathecal infusion of bFGF also produces persistent mechanical allodynia. After peripheral nerve injury, bFGF might be produced by primary sensory neurons and spinal astrocytes because nerve injury produces robust bFGF upregulation in both cell types. Therefore, the bFGF/JNK pathway is an important signalling pathway in spinal astrocytes for chronic pain sensitization. Investigation of signaling mechanisms in spinal astrocytes will identify new molecular targets for the management of chronic pain.

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“…It is produced by astrocytes and strongly induces their mitosis, growth, differentiation and gliosis [11]. After SNL, bFGF immunoreactivity increases in reactive astrocytes in the ipsilateral dorsal horn after nerve injury [29].…”

mentioning

confidence: 99%

Activation of JNK pathway in persistent pain

Gao

2008

Neuroscience Letters

129

104

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The c-Jun N-terminal kinase (JNK) is a stress-activated member of MAP kinase family. JNK activation has been strongly implicated in inflammatory responses, neurodegeneration, and apoptosis. Recent evidence shows that JNK pathway is also transiently activated in primary sensory neurons after tissue or nerve injury, which is required for the development of hyperalgesia and allodynia. In particular, JNK is persistently activated in astrocytes of the spinal cord after nerve injury, and this activation can maintain central sensitization and mechanical allodynia. In this mini-review, we will provide evidence for the involvement of JNK pathway in regulating persistent pain sensitization. We will also discuss possible upstream signaling mechanisms that cause JNK activation and downstream signaling mechanisms by which JNK modulates pain sensitivity. Thus, targeting JNK pathway might be a useful strategy to treat both neurodegeneration and chronic pain.Chronic pain, resulting from tissue injury (inflammatory pain) or nerve damage (neuropathic pain) or tumor growth (cancer pain), is a real clinical challenge [10,22,30]. Although it is generally believed that chronic pain is caused by neural plasticity that occurs both in the peripheral nervous system (peripheral sensitization) and central nervous system (central sensitization), the mechanisms underlying the induction and maintenance of chronic pain are incompletely understood [15,46]. Inflammation is a driving force for the pathogenesis of chronic pain by producing multiple inflammatory mediators such as prostaglandin (PGE 2 ), nerve growth factor (NGF), and proinflammatory cytokines [e.g., tumor necrosis factor-α (TNF-α) and interleukin-1beta (IL-1β)] in inflamed or damaged tissues [16,37]. These inflammatory mediators are not only produced by peripheral tissues, but also by glial cells (e.g. microglia and astrocytes) in the central nervous system. Recently, accumulating evidence supports an important role of spinal microglia and astrocytes in promoting chronic pain [8,14,41,43].In particular, mitogen-activated protein kinases (MAPKs) are activated in spinal glia after nerve injury and play an important role in chronic pain sensitization by signaling to the inflammatory mediators. On the one hand, MAPK pathways are activated by different inflammatory mediators. On the other hand, activation of MAPK pathways also increases the synthesis of multiple inflammatory mediators. This positive feedback loop leads to more production of inflammatory mediators [16]. There are three major members in the MAPK family, extracellular signal regulated kinase (ERK), p38, and c-Jun N-terminal kinases (JNK) [19]. Recent studies have demonstrated that ERK and p38 MAPKs play important roles in regulating neuronal plasticity and persistent pain sensitization via both neuronal and glial mechanisms [16,18,32,36]. Although JNK activation in DRG neurons is very prominent in nerve injury conditions, acute inflammation may also cause moderate and transient activation of JNK [9]. Intraplantar i...

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Reactive astrogliosis after basic fibroblast growth factor (bFGF) injection in injured neonatal rat brain

Cited by 85 publications

References 43 publications

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

Activation of JNK pathway in persistent pain

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