Shock/Sepsis/Trauma/Critical CareRapamycin protects against apoptotic neuronal death and improves neurologic function after traumatic brain injury in mice via modulation of the mTOR-p53-Bax axis
Introduction
Traumatic brain injury (TBI) is a serious public health problem affecting millions of people worldwide. Each year approximately 10 million people are hospitalized for TBI worldwide [1]. TBI causes primary mechanical injury of cerebral cells and also initiates secondary damage, which occurs immediately after the primary damage. The secondary nonmechanical injury is progressive and lasts from hours, days to months [2]. There are several pathologic processes that have been reported to be responsible for the neuronal death observed in the secondary damage of TBI, such as inflammation, disruption of the blood–brain barrier, apoptosis, and oxidative stress [3], [4], [5], [6], [7], [8], [9], [10]. Among these processes, apoptosis plays a key role in secondary injury [6], [7]. Apoptosis, which is also known as programmed cell death, has been observed in the injured brain in an experimental model [11], [12] and humans [13], [14] after TBI. Its phenotypic features include DNA fragmentation and chromatin condensation, cell shrinkage, and formation of apoptotic bodies, which are cleared by phagocytosis without initiating a systemic inflammatory response [15]. It has been reported that approximately two-third of cell death might be attributable to apoptosis and one-third to necrosis in experimental models of TBI [15]. Apoptotic neuronal death presents within a time window that may be responsive to targeted therapies, and an increasing number of researchers have focused on it to retard the pathologic process related to apoptosis after TBI [6], [7], [16], [17], [18].
Rapamycin is a macrolide antibiotic obtained from Streptomyces hygroscopicus that can specifically inhibit the activity of mammalian target of rapamycin (mTOR). The function of rapamycin has been intensively investigated in cancer research, development, metabolism, and central nervous system diseases [19]. Rapamycin has also been investigated for its neuroprotective effects in closed head injury models. Injection of rapamycin increased the survival of neurons and significantly improved brain functional recovery [20]. However, the effect of rapamycin on apoptosis after TBI has not been extensively investigated. Thus, we present the hypothesis that rapamycin can inhibit the mTOR-p53-Bax axis, thereby decreasing the number of apoptotic neuronal death after TBI.
Section snippets
Animals
Male imprinting control region mice (Experiment Animal Centre of Nanjing Medical University, Jiangsu, China) aged 6–8 wk and weighing 28–32 g were used in this study. The experimental protocols were approved by the Animal Care and Use Committee of Nanjing University and conformed to the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health. The mice were housed on a 12 h light–dark cycle with free access to food and water.
Model of TBI
The model of TBI used in the present
Effects of rapamycin on neurobehavioral scores after TBI
As shown in Figure 1, mice in the sham group presented no neurologic dysfunction. The NSS scores of the other three groups were gradually improved from 1 h to 7 d post-TBI. At 24 h after TBI, the NSS score of the rapamycin-treated mice was significantly lower compared with vehicle-treated mice (P < 0.01). At 72 h, a significant difference was still detectable (P < 0.05). At 1 h and 7 d, no significant difference was observed between the TBI + DMSO group and TBI + rapamycin group (P > 0.05).
Effects of rapamycin on the neuronal death in the pericontusive cortex after TBI
Discussion
In this study, we examined the protective effect of rapamycin against apoptotic neuronal death and neurologic deficits in an experimental mice model of TBI. Our data showed that 24 h after TBI, (1) the mTOR-p53-Bax axis was activated, (2) rapamycin improved neurobehavioral deficits and increased the number of neurons in the pericontusive cortex, (3) rapamycin decreased neuronal apoptosis, and (4) rapamycin inactivated the mTOR-p53-Bax axis induced by TBI. These findings suggested that early
Conclusions
In summary, to the best of our knowledge, this is the first study to suggest the potential involvement of rapamycin in protecting neurons from apoptotic neuronal death via modulation of the mTOR-p53-Bax axis after TBI. These findings extend our current understanding of the mechanisms underlying the neuroprotective effect of rapamycin in TBI. We demonstrated that treatment with rapamycin resulted in a significant decrease in apoptotic neuronal death after TBI. This neuroprotective effect was
Acknowledgment
This work was supported by grants obtained from the Natural Science Fund of China (Nos. 81271377 and 81371357) and the Research Project of Jinling Hospital (No. 2014040).
The authors declare that they have no competing interests.
Authors' contributions: K.D. and L.Z. performed most of the experiments. J.X. performed the Western blotting experiments. T.L. and Y.D. performed analysis on the IHC data and statistical analyses and provided the discussion of the results. L.Z. and J.H. performed the IHC
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