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Folia Neuropathologica
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Original paper

Resveratrol attenuates autophagy and inflammation after traumatic brain injury by activation of PI3K/Akt/mTOR pathway in rats

Yan Feng
1
,
Yaru Ju
2
,
Zhongjie Yan
1
,
Mingjun Ji
3
,
Jingchen Li
1
,
Qiang Wu
1
,
Ming Yang
1
,
Guozhu Sun
1

1.
The Second Hospital of Hebei Medical University, China
2.
The Fourth Hospital of Shijiazhuang, China
3.
Linxi County People’s Hospital, China
Folia Neuropathol 2022; 60 (2): 153-164
Online publish date: 2022/06/30
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Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability in young adults, and a major health and socio-economic issue of modern life. Due to a shortage of effective therapeutic agents, TBI survivors often suffer long-term disability in sensorimotor functions, and neurological and cognitive deficits. In TBI, neurological impairment is caused by a direct destruction of brain tissue (primary injury) as well as a series of complex and aggravating pathological processes (secondary injury), which further aggravate the primary neuronal damage [7]. Primary injury can initiate secondary brain injuries, such as a release of neuro-transmitters, formation of oxygen-free radicals, lipid peroxidation of cell membranes, mitochondrial dysfunction, calciummediated damage, and initiation of inflammatory and immune responses. Therefore, these pathological lesions may lead to neuronal cell death in the form of necrosis and/or apoptosis [24]. It is worth noting that neuronal autophagy and inflammation play a crucial role in the management of TBI, and are depicted as an important source of secondary brain injury in experimental conditions.
Resveratrol (RV, 3,5,40-trihydroxystilbene) is a powerful antioxidant, enriched in vegetables, fruits, grains, grape skin, flowers, nuts, tea, and red wine [4]. Resveratrol was shown to be neuro-protective against various neurological disorders, including Parkinson’s disease, Huntington’s disease, ischemic stroke, and Alzheimer’s disease [32,33,36]. Autophagy is a ‘self-eating’ phenomenon in cells, and is a highly conserved degradation pathway in several organisms. Moreover, autophagy is a formation of double membrane autophagosomes, in which cells wrap part of their cytoplasm or damaged organelles and transport them to lysosomes for degradation [5,17]. Autophagy is mainly used to remove and degrade damaged cellular structures, senescent organelles, and biological macromolecules that are no longer needed. Several studies have demonstrated that the activation of autophagy can directly cause cell damage or its’ death, and is involved in the pathophysiology of various diseases [31,35]. Indeed, Clark et al. [6] reported LC3 II and autophagosomes in human brain tissues after TBI. Lai et al. [18] demonstrated that autophagy occurs in experimental TBI, while treatment with g-glutamylcysteine ethyl ester (GCEE) reduced neuronal autophagy and improved neurological outcomes in mice subjected to TBI. More recently, previous reports from our group have suggested that the suppression of neuronal autophagy can be neuro-protective in the rat’s hippocampus [10,11]. Interestingly, Lin et al. demonstrated in adult rats that resveratrol increased cell survival after TBI through the inhibition of GSK-3b-mediated autophagy and apoptosis [23]. Resveratrol has been reported to regulate several different signaling pathways after brain injury, such as mating-type information regulating 2 homolog 1 (SIRT1), AMP-activated kinase (AMPK), and NF-E2-related factor 2 (NRF2) [22,34,40]. Moreover, a previous study showed that neuronal apoptosis was attenuated by resveratrol treatment in SAH rat brain, which could be partially mediated by the activation of PI3K/Akt signaling pathway [41]. However, it remains unclear whether resveratrol treatment is protective against autophagic neuronal death and inflammation after TBI through PI3K/Akt signaling pathway.
Therefore, in this study, we performed intra-peritoneal injections of resveratrol in rats subjected to brain injury, and evaluated if resveratrol could provide neuro-protection against TBI. In addition, we also investigated a possible underlying mechanism of resveratrol through the activation of PI3K/Akt/mTOR pathway to inhibit neuronal autophagy and inflammatory response.

Material and methods

Animals

In the present study, 150 adult male SpragueDawley rats were purchased from the Laboratory Animal Center of Hebei Medical University (aged 12-16 weeks, weight 300-330 g; Shijiazhuang, China). Rats were kept in a standard 12 : 12 hour light/dark cycle environment, with free access to laboratory standard water and food before TBI or sham surgery. All experimental procedures were approved by the Ethics Committee of the Hebei Medical University (Permit number: 20201086). Every effort was employed to minimize animals’ suffering during experiments.

CCI model

CCI procedure was performed according to a previously published procedure. Specifically, rats were anesthetized under intra-peritoneal 10% chloral hydrate (300 mg/kg), with no side effects reported. Their heads were fixed onto a brain stereoscope and body temperature was continuously monitored by a rectal probe to ensure that the temperature was kept at 36.5°C. After cleaning with betadine, the skin at the top of the skull was cut to identify the bregma. An approximate 6 mm bone window was made with a portable drill under aseptic conditions, centered 3.0 mm from the bregma and 2.0 mm lateral (right) from the midline. Rat was impacted with a CCI device using a 3 mm flat-tip impactor (impact velocity = 5 m/s, impact duration = 150 ms, depth = 2.5 mm). Then, the bone window was closed with bone wax and the skin was stitched. In the control group, the bone flap was removed, but CCI was not performed. Humane end points were established following the guideline of assessment for humane end points in animal experiments (People’s Republic of China: RB/T 173-2018) in order to minimize pain or distress in experimental animals. Rats were intra-peritoneally deep anesthetized by chloral hydrate (400 mg/kg) prior to euthanasia by cervical vertebra dislocation. Death was confirmed by cessation of the heartbeat.

Grouping and administration

Rats were randomly divided into three different experimental groups by random number table as described previously [10,11]: sham-operated group (n = 30), TBI group (n = 60), and TBI + resveratrol treatment group (n = 60). Five rats in each sub-group were sacrificed at 12, 24, or 48 hours after TBI. Resveratrol (50 mg/kg body weight; Sigma Aldrich, Yorba Linda, CA, USA) was administered by intra-peritoneal injection immediately after brain injury. Sham and TBI rats were given the same amount of 0.9% saline by intra-peritoneal injection.

Evaluation of brain edema

Brain water content was measured in rat cerebral tissues. Rats (n = 5 in each group) were sacrificed by cervical vertebra dislocation under deep anesthesia. After craniotomy, the brain was removed, the surface moisture was dried, and the brain tissue was weighed immediately (wet weight). The brain was placed in an oven at 100°C for 24 hours, and was re-weighed (dry weight). Finally, the water content was calculated as: brain water content = (wet weight – dry weight)/wet weight × 100%.

Morris water maze

Morris water maze (MWM) was used to examine the spatial learning and memory ability of rats. There were five rats in each group following sham or TBI. Morris water maze consists of heated swimming pool, platform, and computer analysis software. The pool (1.8 m in diameter, 0.5 m high) was filled with water at 25°C, and divided into four equivalent quadrants: East (E), South (S), West (W), and North (N). The platform (12 cm in diameter, 28 cm high) was placed 2 cm below the surface and in the middle of any quadrant. Rats were put in the pool near the edge and facing the wall of the pool, and one of the four starting positions (East, West, South, or North) was randomly selected. Latency (seconds) was recorded as the time taken for rats to find the underwater platform. If the time exceeded 60 seconds, rats were gently put on the platform and allowed to stay on the platform for 20 seconds and returned to the cage for a new trial (time interval, 10 minutes). Movement trajectory of rats in Morris water maze experiment was extracted using video tracking technology (HVS Imaging, Hampton, UK). Rats were tested five times from the same starting point. This test was conducted at 7, 8, 9, and 10 days after trauma or sham surgery.

Evaluation of neurological impairment

The degree of behavioral functional damage after brain injury was evaluated 1 to 5 days after injury. The scoring system included motor tests, sensory tests, reflexes, and balance functions, and the full score was 18 points. Failing to complete a task gave 1 point; thus, 0 = minimum deficit and 18 = maximum deficit. Two double-blinded and independent researchers carried out neuro-behavioral tests.

Immunofluorescence

Brain tissue was collected and immersed in 4% paraformaldehyde for 24 hours, and then transferred to a 30% sucrose solution (0.1 M PBS, pH = 7.4) for 3 days. Brain tissue was embedded in OCT medium (Leica 020106926, Germany) in a cryo-embedding machine and stored at –80°C. Frozen brain tissues were sliced (15 µm) with a frozen slicer, blocked with 0.4% triton X-100 for 40 minutes and 5% donkey serum for 1 hour. Tissue sections were washed with PBS, and incubated with primary antibodies. For double-labeling, polyclonal rabbit anti-LC3 antibody (dilution 1 : 100; MBL) and polyclonal mouse anti-NeuN antibody (dilution 1 : 100; Millipore) were incubated simultaneously overnight at 4˚C. Sections were then washed 3 times with fresh PBS and incubated with fluorescent secondary antibodies tagged with FITC 488 (donkey anti-rabbit IgG, 1 : 200, Santa Cruz Biotechnology) or 594 (donkey anti-mouse IgG, 1 : 200, Santa Cruz Biotechnology) for 2 hours at room temperature in dark. All cell nuclei were counterstained with 4’,6-diamidino-2-phenylindole (DAPI). After washing with PBS, images were collected using a laser confocal microscope (Olympus FV950).

Western blot

Rats were sacrificed by decapitation, and the hippocampus from the injured side of the brain was collected at different time points after TBI. Frozen tissue was placed in complete RIPA buffer, minced, and centrifuged for 15 minutes at 12,000 × g at 4˚C. Protein concentration of the supernatant was determined using a bicinchoninic acid (BCA) protein assay kit (SolarBio, Beijing, China), then proteins (50 mg of protein) were separated by 10% sodium dodecylsulfate-polyacrylamide gel electrophoresis (PAGE). Proteins were transferred to a polyvinylidene fluoride (PVDF) membrane with a semi-dry transfer (Bio-Rad, Hercules, CA, USA), and blocked with 5% non-fat dry milk for 2 hours at room temperature. PVDF membranes were incubated with appropriate primary antibodies at 4˚C overnight. Primary antibodies were as follows: rabbit polyclonal anti-LC3 (MBL, Japan; diluted 1 : 1000), rabbit polyclonal anti-p62 (Antibody Revolution; diluted 1 : 1000), rabbit polyclonal antiBeclin-1 (MBL, Japan; diluted 1 : 1000), rabbit polyclonal anti-IL-1b (Affinity; diluted 1 : 500), rabbit polyclonal anti-TNF-a (Affinity; diluted 1 : 500), rabbit polyclonal anti-p-PI3K (MyBioSource; diluted 1 : 500), rabbit polyclonal anti-PI3K (Abcam; diluted 1 : 500), rabbit polyclonal anti-p-Akt (Invitrogen; diluted 1 : 500), rabbit polyclonal anti-Akt (Invitrogen; diluted 1 : 500), mouse monoclonal anti-p-mTOR (Invitrogen; diluted 1 : 500), rabbit polyclonal anti-mTOR (Abcam; diluted 1 : 500), and rabbit monoclonal anti-b-actin (Affinity; diluted 1 : 1000). On the following day, membranes were rinsed with PBS, and goat anti-rabbit or anti-mouse secondary antibodies conjugated with horseradish peroxidase were incubated for 2 hours at 37˚C. Grey intensity of each protein was observed using an enhanced chemiluminescence (ECL) system (Pierce, Rockford, USA). Band intensities were quantified using Image J (Image Lab 4.1, Bio-Rad Laboratories), and b-actin was used as an internal control.

Statistical analysis

SPSS v. 17.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis of the data. All experimental data were expressed as mean ± standard deviation (SD). Differences among groups were evaluated by one-way analysis of variance (ANOVA) followed by Student and Newman-Keuls post-hoc tests. P < 0.05 was considered statistically significant.

Results

Resveratrol treatment attenuated brain edema

We evaluated the effect of resveratrol on brain edema after injury by dry-wet specific weight method. Compared with the sham operation group, the brain water content induced by TBI was dramatically increased at 12, 24, and 48 hours (Fig. 1), whereas the level of brain water content was significantly reduced after TBI by treatment with resveratrol.

Resveratrol treatment ameliorated the cognitive dysfunction

Morris water maze was designed to test behavioral changes of laboratory animals. We used this approach to investigate whether resveratrol could improve spatial memory deficits in rats at 7, 8, 9, and 10 days after brain injury. As shown in Figure 2, compared with the sham operation group, the escape latency was increased in the TBI group at days 7, 8, 9, and 10, depicting significant spatial learning deficits. Of note, the escape latency was significantly reduced in resveratrol-treated rats subjected to TBI.

Resveratrol treatment attenuated TBI-induced sensorimotor deficits

Sensorimotor function was evaluated by mNSS scores. As presented in Figure 3, the mNSS scores were significantly increased in rats after 1-4 days of TBI when compared with those of the sham group. Interestingly, treatment with resveratrol reduced the mNSS scores, suggesting a recovery of sensorimotor function in injured rats.

Resveratrol treatment ameliorated the neuronal autophagy in the hippocampus

A previous study has shown that the expression of LC3-autophagy-associated proteins was significantly increased 24 hours after brain injury [35]; therefore, we assessed the co-localization of NeuN and LC3 by immunofluorescence analysis 24 hours after TBI. Images presented in Figure 4A show that neuronal autophagy occurred after brain trauma, and the co-localization of NeuN and LC3 was significantly increased in the TBI group. Then, we detected proteins expression levels of LC3 II, Beclin-1, and P62 in the hippocampus using Western blot (Fig. 4B, C, Fig. 5). As expected, LC3 II and Beclin-1 were significantly increased in the TBI group compared with the sham group, while resveratrol significantly down-regulated these proteins at 12, 24, and 48 hours after TBI. In addition, P62 protein expression was significantly reduced in the injured hippocampus, while resveratrol treatment restored P62 levels.

Resveratrol treatment reduced the levels of inflammatory factors in the hippocampus

The expression levels of tumor necrosis factor a (TNF-a) and interleukin 1b (IL-1b) in rat hippocampal tissues were detected using Western blot at 12, 24, and 48 hours after brain injury. As shown in Figure 6, the expression of TNF-a and IL-1b were significantly increased in the TBI group when compared with those of the sham group at every time point. Compared with the TBI group, TNF-a and IL-1b were significantly down-regulated at their corresponding times in resveratrol-treated rats. These results suggest that resveratrol can significantly reduce the production of inflammatory cytokines in the hippocampus of rats subjected to TBI.

Resveratrol treatment activated PI3K/Akt/mTOR signaling pathway in the hippocampus

Finally, to elucidate the potential effects of resveratrol in ameliorating brain injury, the PI3K/Akt/mTOR signaling pathway in the hippocampus was determined. We detected the phosphorylation levels of PI3K, Akt, and mTOR by using Western blot. The results showed in Figure 7A, compared with the sham group, phosphorylation levels of PI3K, Akt, and mTOR were raised in the TBI group (#p < 0.05 vs. sham group). Interestingly, the expression levels of p-PI3K, p-Akt, and p-mTOR were further increased by resveratrol treatment (Fig. 7B; *p < 0.05 vs. TBI group), which corroborate that the PI3K/Akt/mTOR signaling pathway was activated upon treatment with resveratrol.

Discussion

Traumatic brain injury is the major cause of disability and death among young individuals in developed countries, and is a predominant medical problem. Therefore, investigation of the pathogenesis of TBI as well as the identification of effective interventions and/or treatments has been a topic of intense scientific output in the field of neuro-medicine. Although some mechanisms of brain injury have been proposed, the mechanical destruction of neurons may lead to a series of pathological events that can potentiate neuronal damage and cell death upon brain injury [25]. Extensive pre-clinical animal research has been conducted to develop effective treatments for TBI. Despite these efforts, no treatment was demonstrated to improve the prognosis of patients with TBI. This may be due to biological differences between animals and humans, and/or pathophysiological differences in patients with severe brain injury. In this regard, studies have demonstrated that resveratrol present neuro-protective proprieties against a variety of diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease [32,33].
In the present study, we further evaluated the neuro-protective effect of resveratrol on a rat model of TBI. Our results showed that resveratrol treatment (50 mg/kg) could decrease brain edema, improve learning and memory ability, and improve neurological deficits in TBI rats. MWM test is a hippocampus-dependent memory task that is frequently used for examining cognitive deficits, and demonstrating permanent spatial learning ability and reference memory in rodents [20]. A finding that severity of post-mTBI deficits correlates with endogenous opioid system activity, and mTBI resulted in a significant deterioration of spatial memory performance and severity of depressive-like behavior in low analgesia (LA) mouse line [19]. In the present study, we confirmed that administration of resveratrol resulted in a significant reduction in escape latency, enhanced cognitive performance, and amelioration of the memory deficits associated with TBI. It is unclear, however, if the beneficial effects of resveratrol on memory deficits are related to enhanced endogenous opioid system activity after TBI in rats. Previous studies have found that the administration of resveratrol alleviated the degree of brain injury, since rats treated with this compound presented reduced brain water content and attenuated cognitive dysfunction after TBI [10,34], which is consistent with our findings. Moreover, since resveratrol can cross the blood-brain barrier and prevent brain damage caused by cerebral ischemia, we speculate that this compound is a potentially promising therapeutic option for TBI patients [3,37].
To further explore the molecular mechanisms of the neuro-protective effect of resveratrol, we evaluated the levels of autophagy markers with Western blotting. Autophagy is a deleterious process, in which cells dispose of misfolded proteins and damaged organelles into vesicles fused with lysosomes to form autophagy lysosomes, to accomplish metabolic needs of cells and renewal of organelles [30]. Interestingly, the exact functional role of autophagy after TBI has not been fully elucidated. Erlich et al. [8] showed that rapamycin, which induces neuronal autophagy by inhibiting its’ mammalian target protein, improved neurological prognosis after TBI. On the other hand, accumulating evidence suggests that the activation of the neuronal autophagy pathway is related to the pathological mechanism of post-traumatic brain injury, and inhibition of this pathway can alleviate brain injury and functional defects [10,15,21]. In our current study, treatment with resveratrol suppressed the expression levels of LC3 II and Beclin-1, and increased P62 in the hippocampus at 12, 24, and 48 hours after injury. Armour et al. [2] demonstrated that rapamycin-induced autophagy in multiple cell lines (NIH/3T3 cells or HEK293 cells) can be dramatically reduced by resveratrol treatment. Lin et al. [23] shown that TBI leads to glutamateinduced astrocyte death through the activation of a ROS-mediated GSK-3b signaling pathway. These authors reported that resveratrol improved cell survival against TBI by inhibiting GSK-3b-mediated autophagy and apoptosis. Recently, Fan et al. [9] observed that resveratrol could activate autophagy and inhibit apoptosis of neurons by the PI3K signaling pathway; thus, promoting the recovery of neuronal function in spinal cord injury rats. Taken together, it seems reasonable to assume that the neuro-protection of resveratrol in TBI-subjected rats may be related to a decreased neuronal autophagy.
Furthermore, increasing evidence suggests that neuro-inflammatory responses mediated by inflammatory mediators may play an important role in the establishment or secondary injury development of multiple brain conditions [26]. Our data showed that resveratrol reduced the expression levels of TNF-a and IL-1b in the hippocampus of rats at 12, 24, and 48 hours after injury. Indeed, previous studies indicated that resveratrol reduced protein levels of TNF-a and Iba-1 in the hippocampus of high-fat diet (HFD)-fed mice, reversed obesity-related neuroinflammation and metabolic derangements, and enhanced cognitive function [13,29]. Another study has observed that resveratrol attenuated the inflammatory response and alleviated the degree of TBI in rats, which may occur through the reduction of reactive oxygen species and inhibition of NLRP3 [42]. Moreover, there is evidence that TNF-a induces the up-regulation of macro-autophagy in vitro in human skeletal muscle cells and murine macrophages [1,16]. In particular, in human atherosclerotic vascular smooth cells, the expression of autophagy genes can be influenced by TNF-a, in a process mediated by Jun kinase (JNK) or Akt pathways [14]. However, the mechanism of autophagy induced by TNF-a is still not fully understood, and there may be differences among various cell types or injury models. We hypothesized that resveratrol might influence autophagy pathways by down-regulating inflammatory cytokines to some extent, and we will investigate other pathways in the future.
Many studies have shown that activation of the PI3K/AKT signaling pathway is neuro-protective in TBI through the induction of anti-apoptosis and autophagy signaling [12,27]. Previous evidence indicated that mTOR signaling pathway is the key to improving the internal regeneration ability of neurons, while mTOR activation can effectively promote the regeneration of nerve fibers [28]. Wang et al. reported that the PI3K/Akt/mTOR signaling pathway was closely associated with the initiation of autophagy, and the inhibition of this pathway by LY294002 (a PI3K-specific inhibitor) could significantly promote autophagy, which protects against mitochondrial-related apoptosis [39]. Another recent study has shown that homer1a expression is protective against neuronal injury in a traumatic neuronal injury model in vitro, acting through increased neuron autophagy and decreased expression of pro-apoptosis proteins, which may be involved in the PI3K/AKT/mTOR signaling pathway [38]. Our results showed that treatment with resveratrol induced the activation of PI3K/AKT/mTOR pathway, in which the protein expression levels of p-PI3K, p-AKT, and p-mTOR were further increased when compared with those of the TBI group. Therefore, we hypothesized that TBI might induce neuronal autophagy, aggravating inflammatory responses, while resveratrol treatment weakens TBI-induced autophagy and inflammation, thus being neuro-protective through the activation of PI3K/AKT/mTOR signal pathway.
In conclusion, the experimental data presented herein corroborates that resveratrol treatment decreases brain edema, improves spatial learning and memory, and improves the recovery of sensorimotor function of rats subjected to TBI. At the molecular level, resveratrol attenuates neuronal autophagy and inflammation in the injured hippocampus, and the activation of the PI3K/Akt/mTOR signaling pathway is involved in this neuro-protective effect (Fig. 8). Therefore, we propose that resveratrol is a promising therapeutic agent, which might provide a clinical alternative for the treatment of TBI.

Funding

The National Natural Science Foundation of China (Grant No.: 81401032), the Natural Science Foundation of Hebei Province (Grant No.: H2020206437), the Medical Science Research Project of Hebei Province (Grant No.: 20220112, 20221677, and 20190063), and the Hebei Medical University “Department-School Consultation Fund – Science and Technology Innovation” – Frontier Cross Discipline Research (Grant No.: 2020TXJC02) have all supported this work.

Ethics approval and consent to participate

The present study was approved by the Animal Ethics Committee of Hebei Medical University Animal Center.

Disclosure

The authors report no conflict of interest.

References

1. Andrade RM, Wessendarp M, Gubbels MJ, Striepen B, Subauste CS. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J Clin Invest 2006; 116: 2366-2377.
2. Armour SM, Baur JA, Hsieh SN, Land-Bracha A, Thomas SM, Sinclair DA. Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging 2009; 1: 515-528.
3. Atalay T, Gulsen I, Colcimen N, Alp HH, Sosuncu E, Alaca I, Ak H, Ragbetli MC. Resveratrol treatment prevents hippocampal neurodegeneration in a rodent model of traumatic brain injury. Turk Neurosurg 2017; 27: 924-930.
4. Borriello A, Bencivenga D, Caldarelli I, Tramontano A, Borgia A, Zappia V, Della Ragione F. Resveratrol: from basic studies to bedside. Cancer Treat Res 2014; 159: 167-184.
5. Cao W, Li J, Yang K, Cao D. An overview of autophagy. Mechanism, regulation and research progress. Bull Cancer 2021; 108: 304-322.
6. Clark RS, Bayir H, Chu CT, Alber SM, Kochanek PM, Watkins SC. Autophagy is increased in mice after traumatic brain injury and is detectable in human brain after trauma and critical illness. Autophagy 2008; 4: 88-90.
7. Davis AE. Mechanisms of traumatic brain injury: biomecha-nical, structural and cellular considerations. Crit Care Nurs Q 2000; 23: 1-13.
8. Erlich S, Alexandrovich A, Shohami E and Pinkas-Kramarski R. Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol Dis 2007; 26: 86-93.
9. Fan Y, Li YL, Huang SL, Xu HL, Li H, Liu BX. Resveratrol-primed exosomes strongly promote the recovery of motor function in SCI rats by activating autophagy and inhibiting apoptosis via the PI3K signaling pathway. Neurosci Lett 2020; 736: 135262.
10. Feng Y, Cui Y, Gao JL, Li MH, Li R, Jiang XH, Tian YX, Wang KJ, Cui CM, Cui JZ. Resveratrol attenuates neuronal autophagy and inflammatory injury by inhibiting the TLR4/NF-kB signaling pathway in experimental traumatic brain injury. Int J Mol Med 2016; 37: 921-930.
11. Feng Y, Gao JL, Cui Y, Li MH, Li R, Cui CM, Cui JZ. Neuroprotective effects of resatorvid against traumatic brain injury in rat: involvement of neuronal autophagy and TLR4 signaling pathway. Cell Mol Neurobiol 2017; 37: 155-168.
12. Gao Y, Li J, Wu L, Zhou C, Wang Q, Li X, Zhou ML, Wang HD. Tetrahydrocurcumin provides neuroprotection in rats after traumatic brain injury: autophagy and the PI3K/AKT pathways as a potential mechanism. J Surg Res 2016; 206: 67-76.
13. Jeon BT, Jeong EA, Shin HJ, Lee Y, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS. Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet. Diabetes 2012; 61: 1444-1454.
14. Jia G, Cheng G, Gangahar DM, Agrawal DK. Insulin-like growth factor-1 and TNF-a regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells. Immunol Cell Biol 2006; 84: 448-454.
15. Jing CH, Wang L, Liu PP, Wu C, Ruan D, Chen G. Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage. Neuroscience 2012; 213: 144-153.
16. Keller CW, Fokken C, Turville SG, Lünemann A, Schmidt J, Münz C, Lünemann JD. TNF-a induces macroautophagy and regulates MHC class II expression in human skeletal muscle cells. J Biol Chem 2011; 286: 3970-3980.
17. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441: 880-884.
18. Lai Y, Hickey RW, Chen Y, Bayir H, Sullivan ML, Chu CT, Kochanek PM, Dixon CE, Jenkins LW, Graham SH, Watkins SC, Clark RSB. Autophagy is increased after traumatic brain injury in mice and is partially inhibited by the antioxidant g-glutamylcysteinyl ethyl ester. J Cereb Blood Flow Metab 2008; 28: 540-550.
19. Lesniak A, Leszczynski P, Bujalska-Zadrozny M, Pick CG, Sacharczuk M. Naloxone exacerbates memory impairments and depressive-like behavior after mild traumatic brain injury (mTBI) in mice with upregulated opioid system activity. Behav Brain Res 2017; 326: 209-216.
20. Lesniak A, Pick CG, Misicka A, Lipkowski AW, Sacharczuk M. Biphalin protects against cognitive deficits in a mouse model of mild traumatic brain injury (mTBI). Neuropharmacology 2016; 101: 506-518.
21. Li L, Huang J. Rapamycin pretreatment alleviates cerebral ischemia/reperfusion injury in dose-response manner through inhibition of the autophagy and NFκB pathways in rats. Dose Response 2020; 18: 1559325820946194.
22. Li Z, Han X. Resveratrol alleviates early brain injury following subarachnoid hemorrhage: possible involvement of the AMPK/SIRT1/autophagy signaling pathway. Biol Chem 2018; 399: 1339-1350.
23. Lin CJ, Chen TH, Yang LY, Shih CM. Resveratrol protects astrocytes against traumatic brain injury through inhibiting apoptotic and autophagic cell death. Cell Death Dis 2014; 5: e1147.
24. Loane DJ, Stoica BA, Faden AI. Neuroprotection for traumatic brain injury. Handb Clin Neurol 2015; 127: 343-366.
25. Luo CL, Chen XP, Yang R, Sun YX, Li QQ, Bao HJ, Cao QQ, Ni H, Qin ZH, Tao LY. Cathepsin B contributes to traumatic brain injury‐induced cell death through a mitochondria‐mediated apoptotic pathway. J Neurosci Res 2010; 88: 2847-2858.
26. Banjara M, Ghosh C. Sterile neuroinflammation and strategies for therapeutic intervention. Int J Inflam 2017; 2017: 8385961.
27. Miao J, Wang L, Zhang X, Zhu CH, Cui LL, Ji H, Liu Y, Wang XL. Protective effect of Aliskiren in experimental ischemic stroke: up-regulated p-PI3K, p-AKT, Bcl-2 expression, attenuated Bax expression. Neurochem Res 2016; 41: 2300-2310.
28. Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu BG, Connolly L, Kramvis I, Sahin M, He ZG. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 2008; 322: 963-966.
29. Poulsen MM, Fjeldborg K, Ornstrup MJ, Kjær TN, Nøhr MK, Pedersen SB. Resveratrol and inflammation: Challenges in translating pre-clinical findings to improved patient outcomes. Biochim Biophys Acta 2015; 1852: 1124-1136.
30. Pozuelo-Rubio M. 14-3-3ζ binds class III phosphatidylinositol3-kinase and inhibits autophagy. Autophagy 2011; 7: 240-242.
31. Puyal J, Ginet V, Grishchuk Y, Truttmann AC, Clarke PG. Neuronal autophagy as a mediator of life and death: contrasting roles in chronic neurodegenerative and acute neural disorders. Neuroscientist 2012; 18: 224-236.
32. Rahman MH, Akter R, Bhattacharya T, Abdel-Daim MM, Alkahtani S, Arafah MW, Al-Johani NS, Alhoshani NM, Alkeraishan N, Alhenaky A, Abd-Elkader OH, El-Seedi HR, Kaushik D, Mittal V. Resveratrol and neuroprotection: impact and its therapeutic potential in Alzheimer’s disease. Front Pharmacol 2020; 11: 619024.
33. Saiko P, Szakmary A, Jaeger W, Szekeres T. Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat Res 2008; 658: 68-94.
34. Shi Z, Qiu W, Xiao G, Cheng J, Zhang N. Resveratrol attenuates cognitive deficits of traumatic brain injury by activating p38 signaling in the brain. Med Sci Monit 2018; 24: 1097-1103.
35. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, Tsujimoto Y. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 2004; 6: 1221-1228.
36. Simão F, Matté A, Pagnussat AS, Netto CA, Salbego CG. Resveratrol prevents CA1 neurons against ischemic injury by parallel modulation of both GSK-3β and CREB through PI3-K/Akt pathways. Eur J Neurosci 2012; 36: 2899-2905.
37. Walle T. Bioavailability of resveratrol. Ann N Y Acad Sci 2011; 1215: 9-15.
38. Wang Y, Zhao MM, Shang L, Zhang YG, Huang CG, He ZQ, Luo M, Wu B, Song P, Wang MY, Duan F. Homer1a protects against neuronal injury via PI3K/AKT/mTOR signaling pathway. Int J Neurosci 2020; 130: 621-630.
39. Wang Z, Zhou L, Zheng X, Chen G, Pan RF, Li JH, Liu WG. Autophagy protects against PI3K/Akt/mTOR-mediated apoptosis of spinal cord neurons after mechanical injury. Neurosci Lett 2017; 656: 158-164.
40. Zhang Z, Li D, Xu L, Li HP. Sirt1 improves functional recovery by regulating autophagy of astrocyte and neuron after brain injury. Brain Res Bull 2019; 150: 42-49.
41. Zhou XM, Zhou ML, Zhang XS, Zhuang Z, Li T, Shi JX, Zhang X. Resveratrol prevents neuronal apoptosis in an early brain injury model. J Surg Res 2014; 189: 159-165.
42. Zou P, Liu XX, Li G, Wang YG. Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1. Mol Med Rep 2018; 17: 3212-3217.
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