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The specific protective mechanism of mitophagy and Nrf2 in brain injury has not been fully clarified. This study aimed to reveal the effect of Nrf2 on hydraulic shock brain injury in mice, and explore its possible mechanism. Twenty-four Nrf2 knockout (Nrf2-/-) and wild-type mice (WT) of C57BL/6J were randomly divided into two groups: control group (C) and brain injury group (TBI). Hematoxylin-eosin staining (HE) assay was used for the histomorphological observation. The apoptotic state of brain tissue was detected by TUNEL. Mechanical damage in vitro models of glial cells were prepared. The wild-type (WT) and Nrf2 knockout (KO) mice were constructed to investigate the changes of mitophagy and apoptosis-related indicators by Western blotting. The experimental results showed that 24 h after TBI, the tissue structure was highly porous, the cells were highly edema, the neuronal space increased significantly, the neuron degeneration, and the cell vacuolation was obvious. Meanwhile, the number of apoptotic cells and the apoptosis rate of glial cells increased significantly. After injury, the relative expression of Parkin, Pink, Beclin and LC-3II proteins were significantly decreased in all mice. The protein expressions of Caspase3 and Caspase12 were significantly increased. However, in the TBI group, KO mice were more impaired than WT mice. In conclusion, Nrf2 plays a protective role by promoting mitophagy to inhibit apoptosis in the process of brain injury caused by hydraulic shock in mice, which provides a new idea for the effective treatment of brain injury.

Microglial activation and subsequent inflammatory responses are critical processes in aggravating secondary brain injury after intracerebral hemorrhage (ICH). Pterostilbene (3', 5'-dimethoxy-resveratrol) features antioxidant and anti-inflammation properties and has been proven neuroprotective. In this study, we aimed to explore whether Pterostilbene could attenuate neuroinflammation after experimental ICH, as well as underlying molecular mechanisms. Here, a collagenase-induced ICH in mice was followed by intraperitoneal injection of Pterostilbene (10 mg/kg) or vehicle once daily. PTE-treated mice performed significantly better than vehicle-treated controls in the neurological behavior test after ICH. Furthermore, our results showed that Pterostilbene reduced lesion volume and neural apoptosis, and alleviated blood-brain barrier (BBB) damage and brain edema. RNA sequencing and subsequent experiments showed that ICH-induced neuroinflammation and microglial proinflammatory activities were markedly suppressed by Pterostilbene treatment. With regard to the mechanisms, we identified that the anti-inflammatory effects of Pterostilbene relied on remodeling mitochondrial dynamics in microglia. Concretely, Pterostilbene reversed the downregulation of OPA1, promoted mitochondrial fusion, restored normal mitochondrial morphology, and reduced mitochondrial fragmentation and superoxide in microglia after OxyHb treatment. Moreover, conditionally deleting microglial OPA1 in mice largely countered the effects of Pterostilbene on alleviating microglial inflammation, BBB damage, brain edema and neurological impairment following ICH. In summary, we provided the first evidence that Pterostilbene is a promising agent for alleviating neuroinflammation and brain injury after ICH in mice, and uncovered a novel regulatory relationship between Pterostilbene and OPA1-mediated mitochondrial fusion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Hu, Wang, Cheng, Yu, Li, Luo, Zhang, Wu and Zhang.)

Aquaporin 4 (AQP4), usually expressed at astrocytes end-feet, is a main component of the lymph-lymphatic system and promotes paravascular cerebrospinal fluid-interstitial fluid exchange. Moreover, angiotensin II type 1 (AT1) receptor affects amyloid β (Aβ) levels. This study aimed to detect the effect of AT1 receptor deficiency on the blood-brain barrier (BBB) of traumatic brain injury (TBI) mice and the effect on Aβ level and glial lymphatic circulation. TBI model was built using AT1 receptor knockout mice (AT1-KO) and C57BL/6 mice (wild type, WT). BBB integrity was detected by Evans blue extravasation. The expression of the astrocytic water channel AQP4 and astrocyte activation were evaluated with immunofluorescence. The expressions of amyloid precursor protein (APP), junction protein zonula occludens protein-1 (ZO-1) and occludin in mice brain were detected by Western blot (WB). Aβ levels were assayed by enzyme-linked immunosorbent assay (ELISA). AT1 receptor deficiency defended BBB integrity and rescued occludin and ZO-1 decrease in mice brain induced by TBI. AT1-KO mice had less increase of APP expression and Aβ 1–42, Aβ 1–40 levels compared to WT mice under TBI. Moreover, AT1 receptor deficiency was found to significantly inhibit AQP4 depolarization after TBI. T1 receptor deficiency attenuated TBI-induced impairments of BBB by rescuing tight junction proteins and inhibited AQP4 polarization, thus improving the function of glymphatic system to enhance interstitial Aβ clearance in TBI mice brain. [ABSTRACT FROM AUTHOR]

Background: The glymphatic pathway has been shown to be impaired in traumatic brain injury (TBI). Omega-3 polysaturated fatty acids (Omega-3, PUFAs) are involved in the clearance of amyloid-ß through the glymphatic system and this effect is Aquaporin-4 (AQP4) dependent. We hypothesize that Omega-3 PUFAs can alleviate neurological impairment in TBI by protecting the glymphatic pathway. Methods: We pretreated mice with Omega-3 PUFAs rich fish oil and introduced TBI in the mice. Neurological functions were assessed through the modified neurological severity score (mNSS) system and Rota-rod test. Aß42 levels and radioisotope clearance were examined to determine the function of glymphatic system. AQP4 protein and mRNA expressions and its polarity were examined in fish oil treated TBI mice or control mice. Finally, the integrity of blood-brain barrier was determined by Evans blue extravasation and measurement of tight junction proteins (ZO-1 and Occludin) levels. Results: TBI surgery induced significant neurological functional impairment, Omega-3 PUFAs attenuated TBI-induced neurological impairment, as evidenced by reduced mNSS, improved performance in the Rota-rod test. Furthermore, Omega-3 PUFAs improved glymphatic clearance after induction of TBI in mice, reduced Aß42 accumulation, partially restored the clearance of both 3H-mannitol and 14C-Inulin. Omega-3 PUFAs also suppressed AQP4 expression and partially prevented loss of AQP4 polarity in mice undergoing TBI. Finally, Omega-3 PUFAs protected mice from TBI induced blood-brain barrier disruption. Conclusion: Omaga-3 PUFAs attenuate neurological function by partially restoring the AQP4 dependent glymphatic system in mice with TBI. [ABSTRACT FROM AUTHOR]

The aim of the present study was to was investigate the treatment efficacy of hyperbaric oxygen (HBO) combined with nimodipine on diffuse brain injury. AA total of 80 patients with diffuse brain injury were randomly divided into four groups: Group A, conventional treatment; Group B, conventional treatment + nimodipine; Group C, conventional treatment + HBO therapy and Group D, conventional treatment + nimodipine + HBO therapy. The Glasgow Coma Scale (GCS) score and serum tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels were assessed before treatment and at 8, 24, 48 and 72 h after treatment. The bilateral middle cerebral arterial blood flow velocity (VmMCA) was measured by transcranial Doppler ultrasound. The results indicated that serum TNF-α and IL-1β were significantly decreased in all groups at 24, 48 and 72 h after treatment, compared with 8 h after treatment (P<0.05), with Group D exhibiting the largest decrease. The serum TNF-α, IL-1β and VmMCA peaked at 8 h and gradually decreased over the treatment period. VmMCA was decreased in Group B and D compared with Group A and C, and the decrease rate was higher in Group D compared with Group B (P<0.05). GCS scores were significantly increased in all groups at 24, 48 and 72 h after treatment compared with 8 h after treatment (P<0.05), with Group D exhibiting the largest increase. Serum TNF-α and IL-1β levels were positively correlated with VmMCA (P<0.05) and negatively correlated with GCS (P<0.05). Punctate hemorrhage was observed in all groups on CT before treatment, with a value of 66±3 HU. Punctate hemorrhage was observed to decrease over time in CT images, and CT values were signifi- cantly decreased in all groups at 8, 24, 48 and 72 h compared with before treatment (P<0.05). CT values were significantly lower in group D compared with groups A, B and C (P<0.05) at all time points. Serum TNF-α and IL-1β levels were positively correlated with CT value (P<0.05). In conclusion, HBO combined with nimodipine exhibited increased efficacy in the treatment of brain injury compared with either treatment alone. [ABSTRACT FROM AUTHOR]