Eupatilin exerts neuroprotective effects in mice with transient focal cerebral ischemia by reducing microglial activation.
Microglial activation and its-driven neuroinflammation are characteristic pathogenetic features of neurodiseases, including focal cerebral ischemia. The Artemisia asiatica (Asteraceae) extract and its active component, eupatilin, are well-known to reduce inflammatory responses. But the therapeutic potential of eupatilin against focal cerebral ischemia is not known, along with its anti-inflammatory activities on activated microglia. In this study, we investigated the neuroprotective effect of eupatilin on focal cerebral ischemia through its anti-inflammation, particularly on activated microglia, employing a transient middle cerebral artery occlusion/reperfusion (tMCAO), combined with lipopolysaccharide-stimulated BV2 microglia. Eupatilin exerted anti-inflammatory responses in activated BV2 microglia, in which it reduced secretion of well-known inflammatory markers, including nitrite, IL-6, TNF-α, and PGE2, in a concentration-dependent manner. These observed in vitro effects of eupatilin led to in vivo neuroprotection against focal cerebral ischemia. Oral administration of eupatilin (10 mg/kg) in a therapeutic paradigm significantly reduced brain infarction and improved neurological functions in tMCAO-challenged mice. The same benefit was also observed when eupatilin was given even within 5 hours after MCAO induction. In addition, the neuroprotective effects of a single administration of eupatilin (10 mg/kg) immediately after tMCAO challenge persisted up to 3 days after tMCAO. Eupatilin administration reduced the number of Iba1-immunopositive cells across ischemic brain and induced their morphological changes from amoeboid into ramified in the ischemic core, which was accompanied with reduced microglial proliferation in ischemic brain. Eupatilin suppressed NF-κB signaling activities in ischemic brain by reducing IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation. Overall, these data indicate that eupatilin is a neuroprotective agent against focal cerebral ischemia through the reduction of microglial activation.
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
Arjun
A
Sapkota
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
Bhakta Prasad
BP
Gaire
Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
Kyu Suk
KS
Cho
Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
Se Jin
SJ
Jeon
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
Oh Wook
OW
Kwon
Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
Dae Sik
DS
Jang
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
Sun Yeou
SY
Kim
Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
Jong Hoon
JH
Ryu
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
Ji Woong
JW
Choi
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*
D016207:Cytokines; D005419:Flavonoids; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; C045325:eupatilin