RT Journal Article
SR Electronic
T1 Amlexanox inhibits cerebral ischemia-induced delayed astrocytic high-mobility group box 1 release and subsequent brain damage
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.117.245340
DO 10.1124/jpet.117.245340
A1 Sebok Kumar Halder
A1 Hiroshi Ueda
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/01/12/jpet.117.245340.abstract
AB High-mobility group box 1 (HMGB1) is increased in the cerebrospinal fluid (CSF) and serum during the early- and late-phases of brain ischemia and is known to contribute to brain damage. However, detailed characterization underlying cell type-specific HMGB1 release and pathophysiological roles of extracellularly released HMGB1 in ischemic brain remain unclear. Here, we examined cell type-specific HMGB1 release and therapeutic potential of amlexanox, an inhibitor of non-classical release, and an anti-HMGB1 antibody against ischemic brain damage. HMGB1 depletion from neuronal nuclei was observed within 3 h after transient middle cerebral artery occlusion (tMCAO), whereas the intracerebroventricular (i.c.v.) pretreatment with amlexanox blocked HMGB1 release from neurons, resulting in HMGB1 redistribution in the nuclei and cytoplasm. HMGB1 was selectively released from astrocytes 27 h after tMCAO and this HMGB1 release was blocked by the late-treatment of amlexanox (i.c.v.) 24 h after tMCAO. Proximity extension assay revealed that HMGB1 level was elevated in the CSF at 3 and 27 h after tMCAO. This late-treatment of amlexanox significantly protected the brain from ischemic damage, but its pretreatment 30 min before tMCAO failed to show any protection. The late-treatment (i.c.v.) of anti-HMGB1 antibody 24 h after tMCAO also ameliorated ischemic brain damage 48 h after tMCAO. Thus, the inhibition of brain damage by late-treatment of amlexanox or anti-HMGB1 antibody indicates that late HMGB1 release plays a role in the maintenance of stroke-induced brain damage, and the inhibition of this release would be a novel therapeutic target for protection of ischemic brain damage.