Inhibition of c-Jun N-terminal Kinase Ameliorates Early Brain Injury After Subarachnoid Hemorrhage Through Inhibition of a Nur77 Dependent Apoptosis Pathway

Abstract

Nur77 is a potent pro-apoptotic member of the orphan nuclear receptor superfamily. Our previous study revealed Nur77-mediated apoptotic also involved in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). Previous researches show that c-Jun N-terminal kinase (JNK) positively regulates Nur77 nuclear export and apoptosis by phosphorylating Nur77. To determine whether activation of JNK is directly associated with Nur77 dependent apoptosis pathway. We hypothesized that SP600125, a chemical inhibitor of JNK, may effectively ameliorate EBI by inhibiting Nur77 phosphorylation and its transcriptional activity. Hence, in this study was designed to explore the neuroprotective effects of SP600125 in EBI after SAH. Adult male SD rats were randomly assigned to four groups: control; SAH + DMSO; SAH + SP10 and SAH + SP30, a dose of 10 and 30 mg/kg SP600125 was directly administered intraperitoneally 30 min before and 2 h after SAH induction. SP600125 markedly decreased expressions of p-JNK, p-Nur77, Bcl-2, cyto C, caspase-3 and inhibited apoptosis. Improvement of neurological deficit, alleviation of brain edema and amelioration of EBI were obtained after treatment of SP600125. Transferase-mediated dUTP nick end labeling-positive cells were reduced markedly in brain cortex by SP600125. Our studies indicate JNK plays important roles in Nur77 activation. These findings strongly support the hypothesis that SP600125 treatment can ameliorate EBI after experimentally induced SAH by inhibiting a Nur77-dependent apoptotic pathway.

c‑Jun N‑terminal kinase inhibition attenuates early brain injury induced neuronal apoptosis via decreasing p53 phosphorylation and mitochondrial apoptotic pathway activation in subarachnoid hemorrhage rats

“…Thereafter, it was inferred that the downregulation of JNK1 may strengthen the hypoxic endurance of the neurons. These results are comparable with those from a study comprising a JNK1 inhibitor that led to an improvement in the survival time of neurons in an EBI model via the suppression of Nur77-dependent apoptosis pathways (15). However, that study lacked data associated with any effects observable 24 h following SAH.…”

“…Furthermore, a subsequent study on chemically-induced apoptosis in rat livers suggested that the JNK1 gene was associated with p53 activation (14). In the case of EBI, Dai et al (15) demonstrated that sp600125, a JNK-specific inhibitor, was able to ameliorate EBI by decreasing levels of neuronal apoptosis in the brain tissue of rats. However, the association between JNK1 and p53 in the EBI process remains unclear.…”

Retracted:Sex and Age Differences in Epinephrine Mechanisms and Outcomes after Brain Injury

“…16 The JNK isoform contributes to deleterious outcome in other CNS pathologies, such as subarachnoid hemorrhage, cardiac arrest, and stroke. 24 Our data indicate that inhibition of phosphorylated JNK MAPK upregulation by EPI improves outcome after TBI. Nonetheless, early activation of JNK may also be protective because it mediates hypothermic prevention of cell death after FPI in the rat.…”

Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage

“…The previous studies have reported that MyD88 is a critical regulator of apoptosis, which is mainly mediated by the downstream pathways NF-κB p65, p38 MAPKK, JNK and ERK-1/2 28 , 30 , 39 . Evidences show that the activation of the NF-κB and MAPK pathways contributes to EBI after SAH, and inhibition of these pathways offer neuroprotective effects against SAH 21 , 27 , 34 . To identify the molecular mechanisms by which MyD88 inhibition provides neuroprotection after SAH, we first focused on the activation of the NF-κB pathway.…”

“…Additionally, activation of mitogen-activated protein kinases (MAPKs), particularly c-jun-N-terminal kinases (JNK) and p38, could exacerbate EBI by provoking pro-apoptotic and pro-inflammatory cellular signaling 24 . On the other hand, inhibition of p38 and JNK may ameliorate EBI after SAH 25 – 27 . Thus, NF-κB and MAPK pathways have been considered to be targets therapeutically.…”