Brazilian Journal of Anesthesiology
Brazilian Journal of Anesthesiology
Experimental Trials

The antioxidant effect of preischemic dexmedetomidine in a rat model: increased expression of Nrf2/HO-1 via the PKC pathway

O efeito antioxidante da dexmedetomidina pré-isquêmica em um modelo de rato: aumento da expressão de Nrf2/HO-1 via via PKC

Yong-Hee Park, Hee-Pyoung Park, Eugene Kim, Hannah Lee, Jung-Won Hwang, Young-Tae Jeon, Young-Jin Lim

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The precise underlying mechanism of antioxidant effects of dexmedetomidine-induced neuroprotection against cerebral ischemia has not yet been fully elucidated. Activation of Nuclear factor erythroid 2-related factor (Nrf2) and Heme Oxygenase-1 (HO-1) represents a major antioxidant-defense mechanism. Therefore, we determined whether dexmedetomidine increases Nrf2/HO-1 expression after global transient cerebral ischemia and assessed the involvement of Protein Kinase C (PKC) in the dexmedetomidine-related antioxidant mechanism.

Thirty-eight rats were randomly assigned to five groups: sham (n = 6), ischemic (n = 8), chelerythrine (a PKC inhibitor; 5 IV administered 30 min before cerebral ischemia) (n = 8), dexmedetomidine (100 µ IP administered 30 min before cerebral ischemia (n = 8), and dexmedetomidine + chelerythrine (n = 8). Global transient cerebral ischemia (10 min) was applied in all groups, except the sham group; histopathologic changes and levels of nuclear Nrf2 and cytoplasmic HO-1 were examined 24 hours after ischemia insult.

We found fewer necrotic and apoptotic cells in the dexmedetomidine group relative to the ischemic group (p < 0.01) and significantly higher Nrf2 and HO-1 levels in the dexmedetomidine group than in the ischemic group (p < 0.01). Additionally, chelerythrine co-administration with dexmedetomidine attenuated the dexmedetomidine-induced increases in Nrf2 and HO-1 levels (p < 0.05 and p < 0.01, respectively) and diminished its beneficial neuroprotective effects.

Preischemic dexmedetomidine administration elicited neuroprotection against global transient cerebral ischemia in rats by increasing Nrf2/HO-1 expression partly via PKC signaling, suggesting that this is the antioxidant mechanism underlying dexmedetomidine-mediated neuroprotection.


Antioxidant;  Cerebral ischemia;  Dexmedetomidine;  Nuclear factor erythroid 2-related factor;  Protein kinase C



O mecanismo subjacente preciso dos efeitos antioxidantes da neuroproteção induzida pela dexmedetomidina contra a isquemia cerebral ainda não foi totalmente elucidado. A ativação do fator nuclear eritroide 2 relacionado (Nrf2) e da heme oxigenase-1 (HO-1) representa um importante mecanismo de defesa antioxidante. Portanto, determinamos se a dexmedetomidina aumenta a expressão de Nrf2/HO-1 após isquemia cerebral transitória global e avaliamos o envolvimento da proteína quinase C (PKC) no mecanismo antioxidante relacionado à dexmedetomidina.


Trinta e oito ratos foram distribuídos aleatoriamente em cinco grupos: sham (n=6), isquêmico (n=8), queleritrina (um inibidor de PKC; IV administrado 30min antes da isquemia cerebral) (n=8) , dexmedetomidina (100µ IP administrado 30min antes da isquemia cerebral (n=8) e dexmedetomidina + queleritrina (n=8). Isquemia cerebral transitória global (10min) foi aplicada em todos os grupos, exceto no grupo sham As alterações histopatológicas e os níveis de Nrf2 nuclear e HO-1 citoplasmático foram examinados 24 horas após o insulto de isquemia.


Encontramos menos células necróticas e apoptóticas no grupo dexmedetomidina em relação ao grupo isquêmico (p<0,01) e níveis significativamente maiores de Nrf2 e HO-1 no grupo dexmedetomidina do que no grupo isquêmico (p<0,01). Além disso, a coadministração de queleritrina com dexmedetomidina atenuou os aumentos induzidos por dexmedetomidina nos níveis de Nrf2 e HO-1 (p<0,05 e p<0,01, respectivamente) e diminuiu seus efeitos neuroprotetores benéficos.


A administração pré-isquêmica de dexmedetomidina provocou neuroproteção contra isquemia cerebral transitória global em ratos, aumentando a expressão de Nrf2/HO-1 parcialmente via sinalização PKC, sugerindo que este é o mecanismo antioxidante subjacente à neuroproteção mediada por dexmedetomidina.


Antioxidante; Isquemia cerebral; Dexmedetomidina; Fator nuclear relacionado ao fator eritroide 2; Proteína quinase C


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