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NEURAL REGENERATION RESEARCH
June 2016,Volume 11,Issue 6 Rosiglitazone ameliorates diffuse axonal injury by
reducing loss of tau and up-regulating caveolin-1
expression
Yong-lin Zhao, Jin-ning Song*, Xu-dong Ma, Bin-fei Zhang, Dan-dong Li, Hong-gang Pang
Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China

How to cite this article: Zhao YL, Song JN, Ma XD, Zhang BF, Li DD, Pang HG (2016) Rosiglitazone ameliorates diffuse axonal injury by re-
ducing loss of tau and up-regulating caveolin-1 expression. Neural Regen Res 11(6):944-950.
Funding: This study was funded by the New Century Supporting Programs to Excellent Talents in China, No. NCET-05-0831.
Protective effects and mechanisms of rosiglitazone against diffuse axonal injury
Jin-ning Song, M.D., [email protected]. Intraperitoneal injection of rosiglitazone for 3 Rosiglitazone could induce neuroprotection by attenuating amyloid beta-precusor protein and hyperphosphorylated tau at Ser404 site and decreasing the loss of total tau level Diffuse axonal injury device Diffuse axonal injury rats after diffuse axonal injury.
Abstract
Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postu-
lated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta
precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone
significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser404 (p-tau (S404)),
and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S404) levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury.
Key Words: nerve regeneration; diffuse axonal injury; rosiglitazone; hyperphosphorylated tau; total tau; caveolin-1; rats; amyloid precursor
protein; ser404; cortex; immunocytochemistry; western blot assay; neural regeneration
and morphological changes in axons (Dong et al., 2014; Lv There is an urgent need for more effective treatments for et al., 2014). As a consequence, amyloid-beta precursor pro- traumatic brain injury, including diffuse axonal injury (DAI). tein (β-APP) accumulates rapidly and massively, serving as a In this study, we examined whether rosiglitazone (RSG), a sensitive biomarker for diagnosis of DAI (Li et al., 2010). Al- peroxisome proliferator-activated receptor-γ (PPAR-γ) ago- though there are many promising drug and cell-based ther- nist, may have therapeutic potential for DAI. DAI initiates a apeutic approaches for reducing brain injury and enhancing series of pathophysiological changes including inflammation functional outcome after DAI, the clinical effectiveness of and glutamate excitotoxicity, resulting in neurodegeneration, these approaches is limited (Xiong et al., 2009). Consequent- neuronal death and neurological dysfunction (Chelly et al., ly, further research is needed to explore new therapeutic 2011). During axonal degeneration, hyperphosphorylated strategies for DAI.
microtubule-associated protein tau dissociates from micro- RSG is a Food and Drug Administration-approved drug tubules, leading to total tau loss, microtubule destabilization with few short-term side effects, and is an excellent candidate Zhao YL, et al. / Neural Regeneration Research. 2016;11(6):944-950. for rapid translation to clinical trials. RSG is currently in bars, a head clip and an anterior teeth hole, with its body at Phase III clinical trials for Alzheimer's disease, based on its a 30° angle with respect to the top of the laboratory table. ability to reduce β-amyloid pathology and inflammation (Liu When the trigger was pushed, the rat head was rapidly ro- et al., 2015). RSG has been reported to reduce neuroinflam- tated 90°, involving sudden acceleration and deceleration. mation, oxidative stress, apoptotic markers and lesion vol- All injured rats were in a coma for at least 30 minutes. The ume in mouse models of traumatic brain injury (Yonutas et control group only underwent anesthesia and fixation to the al., 2013; Yao et al., 2015). However, few studies have inves- device. Rats that died because of injury were excluded and tigated whether RSG affects tau phosphorylation or tau loss, later replaced by new rats.
which are pathological features of both Alzheimer's disease and DAI (Xu et al., 2014). Cheng et al. (2014) reported that RSG suppresses the proliferation of vascular smooth muscle To ensure that the animal model of DAI used in this study cells by up-regulating caveolin-1, and that it attenuates cere- was successful, hematoxylin-eosin staining was performed. bral vasospasm following experimental subarachnoid hem- Rats in each group were deeply anesthetized and perfused orrhage. The up-regulation of caveolin-1 by RSG may also with 250 mL of normal saline followed by 400 mL of 40 g/L impact β-APP levels and tau hyperphosphorylation (Hattori paraformaldehyde. The whole brain was removed and post-et al., 2006; Head et al., 2010). However, it remains unknown fixed in paraformaldehyde. All tissues were desiccated, em- whether RSG has therapeutic efficacy for DAI. In the present bedded in paraffin, and sectioned into 5-μm-thick sections. study, we investigated whether intraperitoneal injection of Three sections per animal were processed for hematoxy- RSG rescues the axonal pathology in rats with DAI, and we lin-eosin staining. Hematoxylin-eosin-stained sections were examined the underlying mechanisms.
observed at 400× magnification (BX-40; Olympus, Tokyo, Japan).
Materials and Methods
Animals
A total of 108 male 8–10-week-old Sprague-Dawley rats Brain sections were de-paraffinized in xylene and rehy- weighing 280–320 g were purchased from the Experimental drated in a decreasing graded alcohol series and distilled Animal Center of Xi'an Jiaotong University of China (license water. Endogenous peroxidase activity was quenched with No. SCXK (Shaanxi) 2006-001). Animals were housed and 3% H O for 15 minutes, followed by a wash in phos- fed in a temperature- and humidity-controlled environment phate-buffered saline (PBS). Sections were placed in 0.01 with a standardized 12-hour reversed light-dark cycle for 1 M citrate buffer and heated in a microwave oven at 95°C week. This study was carried out in strict accordance with for 30 minutes. Sections were cooled at room temperature the recommendations in the Guide for the Care and Use of for 40 minutes and rinsed in PBS. Non-specific protein Laboratory Animals of the National Institutes of Health. The binding was blocked with normal goat serum at room tem- protocol was approved by the Biomedical Ethics Committee perature for 30 minutes, followed by incubation with pri- of Medical College of Xi'an Jiaotong University of China mary antibodies—rabbit anti-caveolin-1 monoclonal anti- body (3267P, 1:1,000; Cell Signaling Technology, Danvers, MA, USA), rabbit anti-tau (phospho S404) polyclonal anti- Establishment of a rat model of DAI and RSG
body (ab131338, 1:200; Abcam, Cambridge, UK) or rabbit anti-β-APP monoclonal antibody (ab32136, 1:100; Ab- To investigate changes in levels of β-APP, hyperphosphor- cam)—for 24 hours at 4°C, followed by a 15-minute wash ylated tau (phosphorylated at serine 404 (p-tau (S404)) and in PBS. Sections were then incubated with goat anti-rabbit total tau after DAI, and to evaluate the effect of RSG, 84 rats IgG-biotin for 30 minutes (sp9001, 1:200; ZSGB-BIO Co., were randomly assigned to 7 groups (n = 12 per group) as Beijing, China) followed by streptavidin-horseradish per- follows: control group, DAI 6 hour (h) group, DAI 1 day (d) oxidase for 30 minutes at 37°C. Sections were washed with group, DAI 3 d group, DAI 7 d group, DAI 3 d + saline group PBS for 15 minutes after each step. Diaminobenzidine was (the same as the DAI 3 d group, but given intraperitoneal used as the chromogen, and hematoxylin was used as the injection of saline at 5 minutes, 24 h and 48 h post DAI), and DAI 3 d + RSG group (the same as the DAI 3 d + saline Microscopic observation of the immunohistochemical- group, but administered RSG (Cayman Chemical Co., Ann ly-stained sections was performed by an experienced pathol- Arbor, MI, USA), 10 mg/kg intraperitoneal injection, dilut- ogist blinded to the experimental conditions. Six animals ed with saline to a final concentration of 2 mg/mL prior to in each group and five sections per animal were chosen for injection). Rats were euthanized at the indicated time points quantitative analysis. Under a light microscope (Olympus), post injury.
each section was scored in five random visual fields at 400× The DAI model was established using a lateral head rota- magnification. Immunoreactivity was scored based on the tion device, which was created by our team (Li et al., 2013). number of positive cells and staining intensity using Im- After anesthesia with 30 g/L pentobarbital sodium (intraper- age-Pro Plus 6.0 software (Media Cybernetics, Silver Spring, itoneal injection, 30 mg/kg), the rat's head was horizontally MD, USA). The immunohistochemical score was obtained secured to the lateral head rotation device by two lateral ear by multiplying the staining quantity and intensity scores

Zhao YL, et al. / Neural Regeneration Research. 2016;11(6):944-950. Figure 1 Photomicrographs of the cerebral cortex in the control and DAI groups (hematoxylin-eosin staining).
(A) Control group: no notable abnormality. (B) DAI 6 h group: vacuoles around neurons and pyknosis begin to appear. (C) DAI 1 d group: vacu-
oles are more obvious, and a large number of pyknotic and swollen neurons and distorted axons are observable. (D) DAI 3 d group: the number of
damaged cells appears to be decreased, but pyknotic and swollen neurons and distorted axons are still visible. (E) DAI 7 d group: pyknosis is still
observed, but the tissue appears to be in a recovery stage, scale bars: 100 μm. Figures in the top right corner are magnified images of representative
pathological changes, scale bars: 20 μm. DAI: Diffuse axonal injury; d: day(s); h: hours.
Relative folds of optical density (β-APP) Relative folds of Relative folds of optical density (p-tau) optical density (total tau) Figure 2 Dynamic expression of β-APP, p-tau (S404) and total tau protein in the cortex of control and DAI groups assessed by western blot assay.
Compared with the control group, the levels of β-APP and p-tau (S404) increased at 6 h, peaked at 3 d, and gradually decreased at 7 d after DAI. To- tal tau declined to the lowest level at 6 h, and then gradually increased after DAI. Histograms show the relative fold changes in each group relative to the control group (mean ± SD, n = 6, one-way analysis of variance followed by Tukey's post hoc test). *P < 0.05, vs. control group. DAI: Diffuse axonal injury; β-APP: amyloid-beta precursor protein; p-tau (S404): hyperphosphorylated tau at Ser404; d: day(s); h: hours.
(Soslow et al., 2000). The staining quantity was rated on a 20 buffer (TBST) for 2 hours at room temperature, and scale of 0–4 as follows: 0, no staining; 1, 1–10% cells stained; incubated overnight with rabbit anti-tau (phospho S404) 2, 11–50%; 3, 51–80%; and 4, 81–100%. Staining intensity polyclonal antibody (ab131338, 1:1,000; Abcam), rab- was rated on a scale of 0–3 as follows: 0, negative; 1, weak; 2, bit anti-β-APP monoclonal antibody (ab32136, 1:1,000; moderate; and 3, strong. Theoretically, the scores can range Abcam), mouse anti-tau (tau46) monoclonal antibody from 0 to 12. An immunohistochemical score of 9–12 was (4019P, 1:1,000; Cell Signaling Technology) or monoclonal considered to indicate strong immunoreactivity; 5–8, mod- rabbit anti-caveolin-1 antibody (3267P, 1:1,000; Cell Sig- erate; 1–4, weak; and 0, negative.
naling Technology). Membranes were washed three times with TBST for 10 minutes each, and then incubated with Western blot assay
goat anti-rabbit IgG-horseradish peroxidase secondary Rats were anesthetized, and the cortex was immediately re- antibody (ab6721, 1:3,000; Abcam) or goat anti-mouse moved and stored in liquid nitrogen until processing. Total IgG-horseradish peroxidase secondary antibody (ab97023, protein was purified using radioimmunoprecipitation assay 1:3,000; Abcam) for 1 hour at room temperature, with buffer (Sigma, St. Louis, MO, USA). Protein samples (20 subsequent washing in TBST. β-Actin (ab8227, 1:5,000; Ab- μg) were analyzed with 10% sodium dodecyl sulfate-poly- cam, Cambridge, UK) was used as an internal control for acrylamide gel electrophoresis. Proteins were transferred protein loading. The membranes were visualized using the onto polyvinylidene fluoride membranes (Merck Millipore, ChemiDoc MP System (Bio-Rad, Hercules, CA, USA) with Darmstadt, Germany). The membranes were blocked with enhanced chemiluminescence substrate (Millipore). Densi- 5% skimmed milk powder in Tris-buffered saline/Tween tometric quantification of the bands was performed using

Zhao YL, et al. / Neural Regeneration Research. 2016;11(6):944-950. Relative folds of optical density (p-tau) 5 density (total tau) density (caveolin-1) Relative folds of optical Relative folds of optical Relative folds of optical Control DAI 3 d DAI 3 d+ DAI 3 d+ Control DAI 3 d DAI 3 d+ DAI 3 d+ Control DAI 3 d DAI 3 d+ DAI 3 d+ Figure 3 Treatment with RSG blocks the increases in β-APP and p-tau (S404) levels and up-regulates the expression of total tau and caveolin-1 in
the cortex 3 d after DAI.
Compared with the control group, the levels of β-APP, p-tau (S404) and caveolin-1 were increased, while total tau was significantly decreased in the
DAI 3 d and DAI 3 d + saline groups. There was no significant difference between the DAI 3 d and DAI 3 d + saline groups. Compared with the DAI 3 d and DAI 3 d + saline groups, the DAI 3 d + RSG group showed increased caveolin-1 and total tau expression and decreased p-tau (S404) and β-APP levels. Histograms show the relative fold changes in each group relative to the control group (mean ± SD, n = 6, one-way analysis of variance followed by Tukey's post hoc test). *P < 0.05, vs. the control group; #P < 0.05, vs. the DAI 3 d and DAI 3 d + saline group. DAI: Diffuse axonal inju- ry; RSG: rosiglitazone; β-APP: amyloid beta-precursor protein; p-tau (S404): hyperphosphorylated tau at Ser404; d: days.
Control DAI 3 d DAI 3 d+saline DAI 3 d+RSG Scores of IHC (caveolin-1) Scores of IHC (β-APP) Scores of IHC (p-tau) Control DAI 3 d DAI 3 d+ DAI 3 d+ Control DAI 3 d DAI 3 d+ DAI 3 d+ Control DAI 3 d DAI 3 d+ DAI 3 d+ Figure 4 RSG administration inhibits the increases in β-APP and p-tau (S404) and up-regulates caveolin-1 expression in the rat cortex 3 d after
DAI (immunohistochemical staining).
Compared with the control group, strong staining for β-APP and p-tau (S404), and relatively mild staining for caveolin-1 are visible in the cortex of
the DAI 3 d and DAI 3 d + saline groups (*P < 0.05). There was no significant difference between the DAI 3 d and DAI 3 d + saline groups. Com- pared with the DAI 3 d and DAI 3 d + saline groups, caveolin-1 expression was higher, but p-tau (S404) and β-APP expression was lower in the DAI 3 d + RSG group (#P < 0.05). The histogram shows the immunohistochemical score for each group, determined by multiplying the staining quan- tity and intensity levels (mean ± SD, n = 6, one-way analysis of variance followed by Tukey's post hoc test). A higher immunohistochemical score indicates stronger staining intensity and/or a greater number of positive cells. Scale bars: 100 μm. DAI: Diffuse axonal injury; RSG: rosiglitazone; IHC: immunohistochemistry; β-APP: amyloid beta-precursor protein; p-tau (S404): hyperphosphorylated tau at Ser404; d: days.
Zhao YL, et al. / Neural Regeneration Research. 2016;11(6):944-950. Image J software (version 1.29x, NIH, Bethesda, MD, USA). First, the ratio of the optical density of the protein to that p-tau (S404) levels were significantly higher in the DAI 3 d of β-actin was determined. These values in the experimen- and DAI 3 d + saline groups, with scores of 8.5 and 7.9, re- tal groups were then normalized to the values in the control spectively, compared with the control group, which had a group to obtain relative expression levels.
score of 2.6 (P < 0.05). The DAI 3 d + RSG group showed decreased p-tau (S404) staining with a score of 4.3 (P < 0.05, vs. DAI 3 d or DAI 3 d + saline groups). Similarly, β-APP SPSS 17.0 software (SPSS, Chicago, IL, USA) was used for expression was significantly higher in the DAI 3 d and DAI statistical analyses. All data were expressed as the mean ± SD. 3 d + saline groups, with scores of 7.6 and 8.2, respectively, Comparisons among multiple groups were performed using compared with the control group, which had a score of 1.9 (P one-way analysis of variance, followed by Tukey's post hoc < 0.05). β-APP expression in the DAI 3 d + RSG group was test. A P-value of less than 0.05 was considered statistically decreased, with a score of 3.6 (P < 0.05, vs. DAI 3 d or DAI 3 d + saline groups). Caveolin-1 was mainly expressed in the cell membrane in the cerebral cortex. Caveolin-1 expression was significantly higher in the DAI 3 d and DAI 3 d + saline Histopathological changes in the rat model of DAI
groups, with scores of 3.1 and 3.3, respectively, compared Hematoxylin-eosin-stained sections showed the presence of with the control group, which had a score of 1.5 (P < 0.05). vacuoles around neurons in the cerebral cortex of rats with RSG treatment increased caveolin-1 expression (score of 6.0; DAI. Pyknosis was observed in the DAI 6 h, 1 d, 3 d and 7 d P < 0.05, vs. DAI 3 d or DAI 3 d + saline groups) (Figure 4).
groups (Figure 1B–E). Swollen neurons and distorted axons
were visible in the cerebral cortex of the DAI 6 h and 1 d
groups (Figure 1B, C). Pyknotic, swollen and tangled neu-
Hyperphosphorylation and loss of tau have been implicated rons were clearly visible in the DAI 1 d group (Figure 1C).
in the pathogenesis of DAI. β-APP accumulates rapidly and In contrast, in the cortex of rats in the control group, these massively in axonal bulbs when the axon is damaged (Li et features were absent (Figure 1A).
al., 2010). Therefore, drugs that simultaneously attenuate tau hyperphosphorylation, lower β-APP levels and inhibit Dynamic changes in expression of β-APP and in p-tau (S404)
the decrease in total tau may have therapeutic potential in and total tau levels
the treatment of DAI in patients. In this study, we investi- Compared with the control group, the expression of β-APP gated the pathology and dynamic changes in the levels of was increased 1.6-fold, 2.1-fold, 2.4-fold and 1.9-fold in the β-APP, p-tau (S404) and total tau at different time points in a DAI 6 h, 1 d, 3 d and 7 d groups, respectively (P < 0.05). rat model of DAI. The effects of RSG on β-APP, p-tau (S404), Compared with the control group, the levels of p-tau (S404) total tau and caveolin-1 at 3 d after DAI were also assessed. were increased 6.2-fold, 7.6-fold, 16.7-fold and 7.4-fold, re- The major findings of our study are as follows: (1) the levels spectively. Levels of total tau were decreased to 0.5, 0.6, 0.7 of p-tau (S404) and β-APP peaked 3 d post DAI, while total and 0.9× the levels in the control group in the DAI 6 h, 1 d, 3 tau levels decreased after DAI; (2) RSG treatment attenuated d and 7 d groups, respectively (all P < 0.05) (Figure 2).
DAI-induced increases in β-APP and p-tau (S404) levels; (3) RSG prevented the decrease in total tau levels 3 d after DAI; Effects of RSG on β-APP, p-tau (S404), total tau and
(4) RSG treatment increased caveolin-1 expression.
caveolin-1 levels 3 days after DAI
β-APP can be detected at the site of axonal injury. Mu et al. Western blot assay (2015) reported that following impact acceleration traumatic Compared with the control group, β-APP expression was brain injury, β-APP is detectable in injured axons as early as increased 1.6-fold, 1.8-fold and 1.3-fold in the DAI 3 d, 2 to 6 h after trauma and continues to accumulate 1–3 d post DAI 3 d + saline and DAI 3 d + RSG groups, respectively (all injury. Hyperphosphorylation of tau results in microtubule P < 0.05). p-tau (S404) levels were increased 15.1-fold, 16.2- destabilization. Shultz et al. (2015) showed that in the rat DAI fold and 7.9-fold in the DAI 3 d, DAI 3 d + saline and DAI model created by lateral fluid percussion, there is increased 3 d + RSG groups, respectively (all P < 0.05). Caveolin-1 phosphorylation of tau (p-tau (S198/S262)) in the cortex 24 h expression was increased 1.1-fold, 1.2-fold and 1.6-fold in and 3 d post injury, although total tau levels did not signifi- the DAI 3 d, DAI 3 d + saline and DAI 3 d + RSG groups, cantly differ from the control group (Shultz et al., 2015). In respectively (all P < 0.05). Total tau levels were decreased to the present study, β-APP expression and hyperphosphor- 0.4, 0.4 and 0.8× the level in the control group in the DAI 3 ylation of tau, induced by rapid lateral head rotation, had d, DAI 3 d + saline and DAI 3 d + RSG groups, respectively similar temporal trends, with significantly increased expres- (all P < 0.05). There were no significant differences between sion from 6 h to 3 d, in accordance with the previous study. the DAI 3 d and DAI 3 d + saline groups (all P > 0.05). However, p-tau (S404) was detected soon after DAI, while total Compared with the DAI 3 d or DAI 3 d + saline groups, the tau was significantly decreased at 6 h, 1 d and 3 d post DAI DAI 3 d + RSG group showed increased caveolin-1 expres- in this study. Moreover, the histopathological study revealed sion and decreased p-tau (S404) and β-APP levels (P < 0.05) the presence of axonal injury 6 h post injury, which greatly
(Figure 3).
worsened 1 to 3 h post injury. These findings suggest that Zhao YL, et al. / Neural Regeneration Research. 2016;11(6):944-950. secondary processes contribute to further axonal damage and tection. Interestingly, the inhibition of PPAR-γ results in a de- degeneration after the initial injury.
crease in proliferation and loss of the undifferentiated pheno- RSG is a commonly prescribed insulin-sensitizing drug that type in neural precursor cells (Bernal et al., 2015). Therefore, is a selective agonist of PPAR-γ. It has been shown that RSG RSG treatment may also promote nerve regeneration.
provides neuroprotection in animal models of focal ischemia, In summary, RSG exerts a significant neuroprotective spinal cord injury, and Alzheimer's disease (Madeira et al., effect by suppressing excessive expression of β-APP, by low- 2015). RSG also confers neuroprotection after traumatic brain ering p-tau (S404) levels, and by preventing the decrease in injury via anti-inflammatory, anti-apoptotic, anti-oxidative total tau in a rat model of DAI. Caveolin-1 may be involved mechanisms (Yi et al., 2008).
in the neuroprotection provided by RSG. Our novel findings Researches on the effects of RSG on tau hyperphosphor- suggest that RSG may have therapeutic potential for the ylation have mainly focused on Alzheimer's disease. RSG treatment of DAI. Further studies are required to elucidate alleviates spatial learning deficits in APP/PS1/tau transgenic the molecular mechanisms underlying the neuroprotective mice by reducing tau hyperphosphorylation in the brain effects of RSG.
(Mazanetz and Fischer, 2007; Escribano et al., 2010; Yoon et al., 2010; Tokutake et al., 2012; Song et al., 2014; Yu et al., Author contributions: JNS obtained funding, participated
2014). In addition, there are a few reports on the effects of in the definition of intellectual content of this topic and paper RSG on β-APP and total tau.
review. YLZ and XDM did literature searching, designed the The present study is the first to demonstrate that RSG experiment and collected data. YLZ, XDM, and BFZ wrote treatment attenuates the dramatic rise in β-APP expression the paper and provided critical revision of the paper. DDL and and p-tau (S404) levels after DAI. Furthermore, RSG inhibited HGP made the model and contributed to statistical analysis. the decrease in total tau following DAI, thereby producing a All authors approved the final version of the paper. neuroprotective effect. However, the mechanisms underlying Conflicts of interest: None declared.
these effects of RSG after DAI are still unknown.
Plagiarism check: This paper was screened twice using Cross-
In this study, the down-regulation of β-APP and p-tau Check to verify originality before publication. (S404) induced by RSG was accompanied by increased ex- Peer review: This paper was double-blinded and stringently
pression of caveolin-1, a scaffolding protein in caveolae that reviewed by international expert reviewers. physically interacts with membrane-associated signaling molecules. RSG dose and time-dependently increases caveo- lin-1 mRNA and protein levels by activating PPAR-γ and/or Bernal C, Araya C, Palma V, Bronfman M (2015) PPARβ/δ and PPARγ epidermal growth factor receptor (Burgermeister et al., 2003; maintain undifferentiated phenotypes of mouse adult neural precur- Llaverias et al., 2004; Seda et al., 2008; Tencer et al., 2008). sor cells from the subventricular zone. Front Cell Neurosci 9:78-86.
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