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The mitochondrial permeability transition pore is a nonspecific transmembrane channel. Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling, calcium overload, and axonal degeneration. Cyclophilin D is an important component of the mitochondrial permeability transition pore. Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear. In this study, we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice, in which pyramidal neurons and axons express yellow fluorescent protein. We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin. We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening. We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage. We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury. In addition, inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage. Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage; inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage. Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.

Background: Animal studies have confirmed that statins have neuroprotective effects during and following a subarachnoid hemorrhage; however, the therapeutic effect of statins in humans remains controversial. The interpretation of data currently available on the clinical application of statins to spontaneous subarachnoid hemorrhage is limited by the small sample sizes used in the studies, making it difficult to draw valid conclusions regarding the multiple neuroprotective effects of statins. Thus, we propose to perform a randomized double-blind placebo-controlled parallel-group clinical trial to determine the effects of atorvastatin on spontaneous subarachnoid hemorrhage, apoptosis-related factors, and serum inflammatory factors in cerebrospinal fluid and to observe its neuroprotective effect mediated by relieving vasospasm. Methods/Design: This is a randomized parallel-group placebo-controlled double-blind clinical trial. This trial will recruit 300 patients with spontaneous subarachnoid hemorrhage from the Department of Neurosurgery, 101 st Hospital of PLA (Wuxi Taihu Hospital). These patients will be equally and randomly assigned to atorvastatin (40 mg/day) and placebo control groups. Outcomes will be evaluated at baseline, 3, 5, and 14 days after hemorrhage, and 6 months after discharge. The primary outcomes will be the results of computed tomography (CT) angiography combined with CT perfusion imaging and conventional CT. The secondary outcomes will be cerebrospinal fluid analysis, blood testing (tumor necrosis factor α, vascular endothelial growth factor, interleukin-6, and C-reactive protein levels), and the Hunt-Hess classification, the results of transcranial Doppler ultrasonography, and the scores on the Glasgow Coma Scale, the Glasgow Outcome Scale, and the National Institutes of Health Stroke Scale. Discussion: The results of this trial will provide data on the clinical application and neuroregenerative effect of atorvastatin in the acute stage of spontaneous subarachnoid hemorrhage. Trial registration: This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005395) on 18 May 2014.

Background: Traumatic brain injury is a high-incidence condition that can cause severe cognitive impairment. At present, functional magnetic resonance imaging is used to analyze changes in brain function and network connectivity at different stages of injury. In addition, tau protein expression in nerve cells may reflect cognitive function. However, the combined use of functional magnetic resonance imaging and tau measurement to assess cognitive function following traumatic brain injury has not yet been investigated. Methods/Design: A prospective inception cohort study will be performed at the 101 st Hospital of PLA, Wuxi, China. We will conduct a follow-up visit in 100 patients with traumatic brain injury. Cognitive function will be assessed within 24 hours of injury and 0.5, 1, and 2 years after injury. Primary outcomes will be the Montreal Cognitive Assessment score, functional magnetic resonance imaging results, and tau protein level in the cerebrospinal fluid. Secondary outcomes will include Mini-Mental State Examination Scale and Hamilton Depression Scale scores. We will assess cognitive function in patients with traumatic brain injury and analyze its correlation with functional imaging indexes and tau levels in the cerebrospinal fluid. Discussion: This trial has been designed to determine whether functional imaging indexes and tau level in the cerebrospinal fluid can predict recovery of cognitive function in patients with traumatic brain injury. It will provide objective evidence for the clinical prevention and treatment of cognitive dysfunction following traumatic brain injury. Trial registration: This trial was registered at Chinese Clinical Trial Registry (registration number: ChiCTR-OOC-16008574) on 31 May 2016. Ethics: Approved by the Ethics Committee of the 101 st Hospital of PLA, China (approval number: L2016002), the study protocol will be performed in accordance with the guidelines of the Declaration of Helsinki , formulated by the World Medical Association. Informed consent: Written informed consent will be obtained from participants or their guardians.