TY - JOUR
T1 - Inhibition of Brain Epidermal Growth Factor Receptor Activation
T2 - A Novel Target in Neurodegenerative Diseases and Brain Injuries
AU - Tavassoly, Omid
AU - Sato, Takashi
AU - Tavassoly, Iman
N1 - Publisher Copyright:
© 2020 American Society for Pharmacology and Experimental Therapy. All rights reserved.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Several reports have been published recently demonstrating a beneficial effect of epidermal growth factor receptor (EGFR) inhibitors in improving pathologic and behavioral conditions in neurodegenerative diseases (NDDs) such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS) as well as the brain and spinal cord injuries (SCI). Despite successful therapeutic effects of EGFR inhibition in these pathologic conditions, there is still no report of proof-of-concept studies in well-characterized animal models using recently developed blood-brain barrier (BBB)-penetrating EGFR inhibitors, which is due to previous conflicting reports concerning the level of EGFR or activated EGFR in normal and pathologic conditions that caused target engagement to be a concern in any future EGFR inhibition therapy. In this review, the level of EGFR expression and activation in the developing central nervous system (CNS) compared with the adult CNS will be explained as well as how neuronal injury or pathologic conditions, especially inflammation and amyloid fibrils, induce reactive astrocytes leading to an increase in the expression and activation of EGFR and, finally, neurodegeneration. Furthermore, in this review, we will discuss two main molecular mechanisms that can be proposed as the neuroprotective effects of EGFR inhibition in these pathologic conditions. We will also review the recent advances in the development of BBB-penetrating EGFR inhibitors in cancer therapy, which may eventually be repositioned for NDDs and SCI therapy in the future.
AB - Several reports have been published recently demonstrating a beneficial effect of epidermal growth factor receptor (EGFR) inhibitors in improving pathologic and behavioral conditions in neurodegenerative diseases (NDDs) such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS) as well as the brain and spinal cord injuries (SCI). Despite successful therapeutic effects of EGFR inhibition in these pathologic conditions, there is still no report of proof-of-concept studies in well-characterized animal models using recently developed blood-brain barrier (BBB)-penetrating EGFR inhibitors, which is due to previous conflicting reports concerning the level of EGFR or activated EGFR in normal and pathologic conditions that caused target engagement to be a concern in any future EGFR inhibition therapy. In this review, the level of EGFR expression and activation in the developing central nervous system (CNS) compared with the adult CNS will be explained as well as how neuronal injury or pathologic conditions, especially inflammation and amyloid fibrils, induce reactive astrocytes leading to an increase in the expression and activation of EGFR and, finally, neurodegeneration. Furthermore, in this review, we will discuss two main molecular mechanisms that can be proposed as the neuroprotective effects of EGFR inhibition in these pathologic conditions. We will also review the recent advances in the development of BBB-penetrating EGFR inhibitors in cancer therapy, which may eventually be repositioned for NDDs and SCI therapy in the future.
UR - http://www.scopus.com/inward/record.url?scp=85086345820&partnerID=8YFLogxK
U2 - 10.1124/mol.120.119909
DO - 10.1124/mol.120.119909
M3 - Review article
C2 - 32350120
AN - SCOPUS:85086345820
SN - 0026-895X
VL - 98
SP - 13
EP - 22
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 1
ER -