Epidermal growth factor receptor inhibitors promote CNS axon growth through off-target effects on glia

Ahmed, Zubair; Jacques, Steven J.; Berry, Martin; Logan, Ann

doi:10.1016/j.nbd.2009.07.016

Cited by 27 publications

(30 citation statements)

References 40 publications

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“…Results of a regeneration-based screen of known bioactive compounds have implicated cPKC- and epidermal growth factor receptor (EGFR) -mediated signaling events in the activities of glial-derived inhibitors (Sivasankaran et al, 2004; Koprivica et al, 2005; see Ahmed et al, 2009). In particular, inhibition of PKC, or of the EGFR, blocked the neurite-inhibitory effects of both myelin and CSPGs.…”

Section: Resultsmentioning

confidence: 99%

A Chemical Screen Identifies Novel Compounds That Overcome Glial-Mediated Inhibition of Neuronal Regeneration

Usher¹,

Johnstone²,

Ertürk³

et al. 2010

J. Neurosci.

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A major barrier to regeneration of CNS axons is the presence of growth-inhibitory proteins associated with myelin and the glial scar. To identify chemical compounds with the ability to overcome the inhibition of regeneration, we screened a novel triazine library, based on the ability of compounds to increase neurite outgrowth from cerebellar neurons on inhibitory myelin substrates. The screen produced four "hit compounds," which act with nanomolar potency on several different neuronal types and on several distinct substrates relevant to glial inhibition. Moreover, the compounds selectively overcome inhibition rather than promote growth in general. The compounds do not affect neuronal cAMP levels, PKC activity, or EGFR (epidermal growth factor receptor) activation. Interestingly, one of the compounds alters microtubule dynamics and increases microtubule density in both fibroblasts and neurons. This same compound promotes regeneration of dorsal column axons after acute lesions and potentiates regeneration of optic nerve axons after nerve crush in vivo. These compounds should provide insight into the mechanisms through which glial-derived inhibitors of regeneration act, and could lead to the development of novel therapies for CNS injury.

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Section: Resultsmentioning

confidence: 99%

A Chemical Screen Identifies Novel Compounds That Overcome Glial-Mediated Inhibition of Neuronal Regeneration

Usher¹,

Johnstone²,

Ertürk³

et al. 2010

J. Neurosci.

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“…These findings provide new light to a continuing controversy regarding the role of EGFR signaling on axonal regeneration. In prior work, EGFR activation has been shown to inhibit growth in the presence of myelin or chondroitin sulfate proteoglycans (Koprivica et al, 2005; Ahmed et al, 2009), and fibrinogen (Schachtrup et al, 2007), and blocking EGFR activation can promote growth on these substrates. However, after injury, the EGFRs are expressed primarily on astrocytes and not on axons, and EGFR inhibition alone does not enhance axon growth on permissive substrates (Koprivica et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, we demonstrate here that TGFα does not inhibit growth of DRG axons plated on laminin. It has been shown that growth promoting effects of EGFR inhibitors in some models may be mediated by off-target actions of these compounds on surrounding glial cells that then promote growth cone extension (Ahmed et al, 2009; Douglas et al, 2009). At the site of traumatic injury, growing axons that come from the central nervous system encounter a basal lamina and additional inhibitory cues at the astrocyte border.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor α Transforms Astrocytes to a Growth-Supportive Phenotype after Spinal Cord Injury

White

Rao²,

Gensel³

et al. 2011

J. Neurosci.

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Astrocytes are both detrimental and beneficial for repair and recovery after spinal cord injury (SCI). These dynamic cells are primary contributors to the growth-inhibitory glial scar, yet they are also neuroprotective and can form growth-supportive bridges upon which axons traverse. We have shown that intrathecal administration of transforming growth factor alpha (TGFα) to the contused mouse spinal cord can enhance astrocyte infiltration and axonal growth within the injury site, but the mechanisms of these effects are not well understood. The present studies demonstrate that the epidermal growth factor receptor (EGFR) is upregulated primarily by astrocytes and glial progenitors early after SCI. TGFα directly activates the EGFR on these cells in vitro, inducing their proliferation, migration, and transformation to a phenotype that supports robust neurite outgrowth. Overexpression of TGFα in vivo by intraparenchymal adeno-associated virus injection adjacent to the injury site enhances cell proliferation, alters astrocyte distribution and facilitates increased axonal penetration at the rostral lesion border. To determine if endogenous EGFR activation is required after injury, SCI was also performed on Velvet (C57BL/6J-EgfrVel/J) mice, a mutant strain with defective EGFR activity. The affected mice exhibited malformed glial borders, larger lesions, and impaired recovery of function, indicating that intrinsic EGFR activation is necessary for neuroprotection and normal glial scar formation after SCI. By further stimulating precursor proliferation and modifying glial activation to promote a growth permissive environment, controlled stimulation of EGFR at the lesion border may be considered in the context of future strategies to enhance endogenous cellular repair following injury.

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“…There have been reports in the literature of off-target neuroprotective effects of AG1478. 31, 32 Specifically, studies suggest that AG1478 may also act independently of EGFR and affects other signaling pathways in the cells. Therefore, the regenerative effects we see could be due to these off-target effects.…”

Section: Discussionmentioning

confidence: 99%

Nanospheres Delivering the EGFR TKI AG1478 Promote Optic Nerve Regeneration: The Role of Size for Intraocular Drug Delivery

et al. 2011

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Promoting nerve regeneration involves not only modulating the post-injury microenvironment but also ensuring survival of injured neurons. Sustained delivery of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been shown to promote the survival and regeneration of neurons, but systemic administration is associated with significant side effects. We fabricated poly(lactic-co-glycolic acid) (PLGA) microspheres and nanospheres containing the EGFR TKI 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) for intravitreal administration in a rat optic nerve crush injury model. Upon administration, less backflow from the injection site was observed when injecting nanospheres compared to microspheres. Two weeks after intravitreal delivery, we were able to detect microspheres and nanospheres in the vitreous using coumarin-6 fluorescence, but fewer microspheres were observed compared to the nanospheres. At four weeks only nanospheres could be detected. AG1478 microspheres and nanospheres promoted optic nerve regeneration at two weeks, and at four weeks evidence of regeneration was found only in the nanosphere-injected animals. This observation could be attributed to the ease of administration of the nanospheres versus the microspheres, which in turn led to an increased amount of spheres delivered to the vitreous in the nanosphere group compared to the microsphere group. These data provide evidence for use of PLGA nanospheres to deliver AG1478 intravitreally in a single administration to promote nerve regeneration.

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Epidermal growth factor receptor inhibitors promote CNS axon growth through off-target effects on glia

Cited by 27 publications

References 40 publications

A Chemical Screen Identifies Novel Compounds That Overcome Glial-Mediated Inhibition of Neuronal Regeneration

A Chemical Screen Identifies Novel Compounds That Overcome Glial-Mediated Inhibition of Neuronal Regeneration

Transforming Growth Factor α Transforms Astrocytes to a Growth-Supportive Phenotype after Spinal Cord Injury

Nanospheres Delivering the EGFR TKI AG1478 Promote Optic Nerve Regeneration: The Role of Size for Intraocular Drug Delivery

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