Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta level after traumatic brain injury - PubMed (original) (raw)

Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta level after traumatic brain injury

Bo Li et al. Neurosurgery. 2009 Jul.

Abstract

Objective: Our previous studies demonstrated that simvastatin promotes neurological functional recovery after traumatic brain injury (TBI) in rat; however, the underlying mechanisms remain poorly understood. The purpose of this study was to investigate the anti-inflammatory effect of simvastatin by measuring the level of cytokines and activation of glial cells.

Methods: Controlled cortical impact injury was performed in adult male Wistar rats. The rats were randomly divided into 3 groups: sham, saline control group, and simvastatin treatment group. Simvastatin was administered orally starting at day 1 after TBI until animals were killed at days 1, 3, 7, 14, and 35 after treatment. Functional outcome was measured using modified neurological severity scores. Enzyme-linked immunosorbent assay and immunohistochemical staining were used to measure the expression of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha and to identify activated microglial cells and astrocytes.

Results: At days 1 and 3 after simvastatin or saline treatment, cytokine levels in the lesion boundary zone were significantly higher in the simvastatin- and saline-treated rats compared with the sham group, peaking at day 3. Simvastatin only reduced the level of IL-1beta but not IL-6 and tumor necrosis factor-alpha, compared with the saline group. Also, simvastatin significantly reduced the number of activated microglial cells and astrocytes compared with the saline control animals. There was also a trend toward improvement of modified neurological severity score, reaching statistical significance (P = 0.003) toward the end of the trial.

Conclusion: Our data demonstrate that TBI causes inflammatory reaction, including increased levels of IL-1beta, IL-6, and tumor necrosis factor-alpha, as well as activated microglial cells. Simvastatin selectively reduces IL-1beta expression and inhibits the activation of microglial cells and astrocytes after TBI, which might be one of the mechanisms underlying the therapeutic benefits of simvastatin treatment of TBI.

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Figures

Figure 1

Figure 1

Plot shows the temporal profile of the modified neurological severity score in sham, saline- or simvastatin-treated rats post TBI. The score was significantly lower in the simvastatin-treated group compared with the saline-treated group at 35 days after treatment. Data are represented as mean ± SD. * P =0.0028 versus the saline-treated group, n = 8.

Figure 2

Figure 2

Plots show the temporal profiles of ELISA of IL-1β (a), TNF (b), and IL-6(c) in the lesion boundary zone of rats treated with saline after TBI. These cytokines increase on day 1 and peak on day 3 after treatment. Data are represented as mean ± SD. * P < 0.05 versus sham group.

Figure 3

Figure 3

Bar graphs show the level of IL-1β (a), TNF (b), and IL-6(c) in the lesion boundary zone of rats at day 3 after treatment with simvastatin or saline. Data are represented as mean ± SD. *P < 0.05 versus sham group, # P = 0.040 versus the saline group. IL-1β expression was decreased at day 3 after simvastatin treatment compared to the saline-treated group. However, simvastatin did not suppress the expression of IL-6 and TNF compared to the saline-treated group.

Figure 4

Figure 4

Immunohistochemical staining for CD68 at day 3 in the lesion boundary zone of the sham group (a, d), saline-treated group (b, e) and simvastatin-treated group (c, f). CD68 positive cells are stained brown. *P < 0.05 versus sham group, # P =0.001 versus saline-treated group. Scale bar = 100 μm (a, b, c), 50 μm (d, e, f). Simvastatin significantly reduces the number of CD68-positive cells after TBI.

Figure 5

Figure 5

Immunohistochemical staining of GFAP for the detection of reactive astrocytes on day 3 at the lesion boundary zone. This image shows a representative section of the sham group (a, d), saline-treated group (b, e) and simvastatin-treated group (c, f). The bar graph shows the statistic analysis of the number of GFAP positive cells between the saline control group and the simvastatin-treated group (g). *P < 0.05 versus sham group, # P = 0.001 versus saline group. Scale bar = 100μm (a, b, c), 50 μm (d, e, f). The GFAP positive cells (brown) were significantly decreased after treatment with simvastatin post TBI.

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