Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease
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Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease. / Wang, Minghuan; Qin, Chuan; Luo, Xiang; Wang, Jie; Wang, Xuxia; Xie, Minjie; Hu, Jing; Cao, Jie; Hu, Ting; Goldman, Steven A.; Nedergaard, Maiken; Wang, Wei.
In: Theranostics, Vol. 9, No. 15, 2019, p. 4474-4493.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease
AU - Wang, Minghuan
AU - Qin, Chuan
AU - Luo, Xiang
AU - Wang, Jie
AU - Wang, Xuxia
AU - Xie, Minjie
AU - Hu, Jing
AU - Cao, Jie
AU - Hu, Ting
AU - Goldman, Steven A.
AU - Nedergaard, Maiken
AU - Wang, Wei
PY - 2019
Y1 - 2019
N2 - Rational: Myelin loss is a characteristic feature of both ischemic white matter disease and its associated vascular dementia, and is a hallmark of chronic cerebral hypoperfusion due to carotid artery stenosis. Yet the cellular mechanisms involved in ischemic dysmyelination are not well-understood, and no effective treatment has emerged to prevent or slow hypoperfusion-related demyelination. In a study employing the bilateral common carotid artery stenosis (BCAS) mouse model, we found reduced cerebral blood flow velocity and arteriolar pulsatility, and confirmed that prolonged BCAS provoked myelin disruption. These pathological features were associated with marked cognitive decline, in the absence of evident damage to axons. Methods: To assess the role of astroglial communication in BCAS-associated demyelination, we investigated the effect of deleting or inhibiting connexin 43 (Cx43), a constituent of astroglial gap junctions and hemichannels. Results: Genetic deletion and pharmacological inhibition of gap junctions both protected myelin integrity and rescued cognitive decline in the BCAS-treated mice. Gap junction inhibition also suppressed the transient increase in extracellular glutamate observed in the callosal white matter of wild-type mice exposed to BCAS. Conclusion: These findings suggest that astrocytic Cx43 may be a viable target for attenuating the demyelination and cognitive decline associated with chronic cerebral hypoperfusion.
AB - Rational: Myelin loss is a characteristic feature of both ischemic white matter disease and its associated vascular dementia, and is a hallmark of chronic cerebral hypoperfusion due to carotid artery stenosis. Yet the cellular mechanisms involved in ischemic dysmyelination are not well-understood, and no effective treatment has emerged to prevent or slow hypoperfusion-related demyelination. In a study employing the bilateral common carotid artery stenosis (BCAS) mouse model, we found reduced cerebral blood flow velocity and arteriolar pulsatility, and confirmed that prolonged BCAS provoked myelin disruption. These pathological features were associated with marked cognitive decline, in the absence of evident damage to axons. Methods: To assess the role of astroglial communication in BCAS-associated demyelination, we investigated the effect of deleting or inhibiting connexin 43 (Cx43), a constituent of astroglial gap junctions and hemichannels. Results: Genetic deletion and pharmacological inhibition of gap junctions both protected myelin integrity and rescued cognitive decline in the BCAS-treated mice. Gap junction inhibition also suppressed the transient increase in extracellular glutamate observed in the callosal white matter of wild-type mice exposed to BCAS. Conclusion: These findings suggest that astrocytic Cx43 may be a viable target for attenuating the demyelination and cognitive decline associated with chronic cerebral hypoperfusion.
KW - Astrocyte
KW - Connexin 43
KW - Ischemic white matter disease
KW - Myelin injury
U2 - 10.7150/thno.31942
DO - 10.7150/thno.31942
M3 - Journal article
C2 - 31285774
AN - SCOPUS:85069288583
VL - 9
SP - 4474
EP - 4493
JO - Theranostics
JF - Theranostics
SN - 1838-7640
IS - 15
ER -
ID: 228250070