Apolipoprotein E Deficiency Aggravates Neuronal Injury by Enhancing Neuroinflammation via the JNK/c-Jun Pathway in the Early Phase of Experimental Subarachnoid Hemorrhage in Mice

Abstract

Neuronal injury is the primary cause of poor outcome after subarachnoid hemorrhage (SAH). The apolipoprotein E (APOE) gene has been suggested to be involved in the prognosis of SAH patients. However, the role of APOE in neuronal injury after SAH has not been well studied. In this study, SAH was induced in APOE-knockout (APOE-/-) and wild-type (WT) mice to investigate the impact of APOE deficiency on neuronal injury in the early phase of SAH. The experiments of this study were performed in murine SAH models in vivo and primary cultured microglia and neurons in vitro. The SAH model was induced by endovascular perforation in APOE-/- and APOE WT mice. The mortality rate, weight loss, and neurological deficits were recorded within 72 h after SAH. The neuronal injury was assessed by detecting the neuronal apoptosis and axonal injury. The activation of microglia was assessed by immunofluorescent staining of Iba-1, and clodronate liposomes were used for inhibiting microglial activation. The expression of JNK/c-Jun was evaluated by immunofluorescent staining or western blotting. The expression of TNF-α, IL-1β, and IL-6 was evaluated by ELISA. Primary cultured microglia were treated with hemoglobin (Hb) in vitro for simulating the pathological process of SAH. SP600125, a JNK inhibitor, was used for evaluating the role of JNK in neuroinflammation. Nitrite production was detected for microglial activation, and flow cytometry was performed to detect apoptosis in vitro. The results suggested that SAH induced early neuronal injury and neurological deficits in mice. APOE deficiency resulted in more severe neurological deficits after SAH in mice. The neurological deficits were associated with exacerbation of neuronal injury, including neuronal apoptosis and axonal injury. Moreover, APOE deficiency enhanced microglial activation and related inflammatory injury on neurons. Inhibition of microglia attenuated neuronal injury in mice, whereas inhibition of JNK inhibited microglia-mediated inflammatory response in vitro. Taken together, JNK/c-Jun was involved in the enhancement of microglia-mediated inflammatory injury in APOE-/- mice. APOE deficiency aggravates neuronal injury which may account for the poor neurological outcomes of APOE-/- mice. The possible protective role of APOE against EBI via the modulation of inflammatory response indicates its potential treatment for SAH.

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“…To evaluate the antitumor effects of the varying drug formulations in vivo, lung cancer cell xenograft mice model was established. When the average tumor volume reached about 70 mm 3 , the mice were randomly divided into 5 groups (8 mice per group), and the varying drug formulations (7.5 mg/kg dioscin and 0.4 mg/kg vinorelbine), and saline were injected into mice via tail vein at day 14, 16, 18 and 20. Body weights and tumor volumes were monitored every 2 days, Tumor volume was measured using the formula: tumor volume = 0.5 (a × b 2 ), where "a" and "b" refer to the largest and smallest diameter, respectively.…”

“…Usually, tumor cells shift through the vasculature, stagnate in distant capillaries, penetrate into surrounding tissues, and eventually spread into distant organs into tumors. 3 In order to prevent NSCLC metastasis to prolong the survival of patients, several approaches have been proposed, such as traditional Chinese medicine therapy, the development of new compounds, chemo-immunotherapy, etc. [4][5][6] Among them, the chemo-immunotherapy combinations will become the first-line treatment for NSCLC, which significantly improved the progression-free survival (PFS) and overall survival (OS) rates of these patients.…”

Ergosta-7,9(11),22-trien-3β-ol Alleviates Intracerebral Hemorrhage-Induced Brain Injury and BV-2 Microglial Activation

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Irisin Contributes to Neuroprotection by Promoting Mitochondrial Biogenesis After Experimental Subarachnoid Hemorrhage

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