Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice.
Glial scarring is traditionally thought to be detrimental after stroke. But emerging studies now suggest that reactive astrocytes may also contribute to neurovascular remodeling. Here, we assessed the effects and mechanisms of metabolic inhibition of reactive astrocytes in a mouse model of stroke recovery. Five days after stroke onset, astrocytes were metabolically inhibited with fluorocitrate (FC, 1 nmol). Markers of reactive astrocytes (glial fibrillary acidic protein (GFAP), HMGB1), markers of neurovascular remodeling (CD31, synaptophysin, PSD95), and behavioral outcomes (neuroscore, rotarod latency) were quantified from 1 to 14 days. As expected, focal cerebral ischemia induced significant neurological deficits in mice. But over the course of 14 days after stroke onset, a steady improvement in neuroscore and rotarod latencies were observed as the mice spontaneously recovered. Reactive astrocytes coexpressing GFAP and HMGB1 increased in peri-infarct cortex from 1 to 14 days after cerebral ischemia in parallel with an increase in the neurovascular remodeling markers CD31, synaptophysin, and PSD95. Compared with stroke-only controls, FC-treated mice demonstrated a significant decrease in HMGB1-positive reactive astrocytes and neurovascular remodeling, as well as a corresponding worsening of behavioral recovery. Our results suggest that reactive astrocytes in peri-infarct cortex may promote neurovascular remodeling, and these glial responses may aid functional recovery after stroke.
Hayakawa
Kazuhide
K
Department of Neuropharmacology, Fukuoka University, Fukuoka, Japan.
Nakano
Takafumi
T
Irie
Keiichi
K
Higuchi
Sei
S
Fujioka
Masayuki
M
Orito
Kensuke
K
Iwasaki
Katsunori
K
Jin
Guang
G
Lo
Eng H
EH
Mishima
Kenichi
K
Fujiwara
Michihiro
M
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D002951:Citrates / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism; D008297:Male; D051379:Mice; D009416:Nerve Regeneration / Q000502:physiology*; D009483:Neuropsychological Tests; D020127:Recovery of Function
D015415:Biomarkers; D002951:Citrates; D024243:HMGB1 Protein; C007744:fluorocitrate