Simvastatin Attenuates Microglial Cells and Astrocyte Activation and Decreases Interleukin-1b Level After Traumatic Brain Injury

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 three groups: sham, saline control group and simvastatin treatment group. Simvastatin was administered orally starting at day 1 after TBI until sacrifice. Animals were sacrificed at 1, 3, 7, 14, and 35 days after treatment. Functional outcome was measured using modified neurological severity scores (mNSS). ELISA and immunohistochemical staining were employed to measure the expression of IL-1β, IL-6 and TNF-α, and to identify activated microglia 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-treated rats and saline-treated rats compared to the sham group, peaking at day 3. Simvastatin only reduced the level of IL-1 β but not IL-6 and TNF-α compared with the saline group. Also, simvastatin reduced significantly the number of activated microglia and astrocytes compared to the saline control animals. There was also a trend towards improvement of mNSS score, reaching statistical significance (P=0.003) towards the end of the trial.Conclusion-Our data demonstrate that TBI causes inflammatory reaction, including increased levels of IL-1β, IL-6 and TNF-α, as well as activated microglia. Simvastatin selectively reduces IL-1β expression and inhibits the activation of microglia and astrocytes after TBI, which may be one of the mechanisms underlying the therapeutic benefits of simvastatin treatment of TBI.

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

“…TBI in rodents also increases levels of activated glial cells and proinflammatory cytokines, [34][35][36][37][38] and administration of these cytokines increases anxiety-like behaviors. [29][30][31][32] The aim of the present study was therefore to determine whether neuroinflammation is associated with the long-term maintenance of post-traumatic anxiety in an animal model.…”

“…Peri-injury and immediate postinjury immunosuppression have been found to be neuroprotective after TBI in rodents, resulting in increased structural preservation and improved functional outcomes. 104 Early administration of the immunosuppressant drugs, minocycline, statins, cyclosporin A, and FK506, have been shown to exert anti-inflammatory effects through suppression of micro-and astroglial production of IL-1b, TNF-a, and IL-6, resulting in reduced functional deficits, cerebral edema, and brain lesion volumes, [35][36][37][38]66 improving mitochondrial preservation, reducing dendritic spine loss, and improving cognitive performance and functional motor recovery. 105,106 Our previous investigation found that peri-injury Ibudilast treatment attenuated glial cell activation at the time of injury, resulting in reduced anxiety-like behaviors and immunological impairments after LFPI.…”

Statins and Brain Dysfunction

“…Their actions favor a switch toward antiinfl ammatory phenotypes that may contribute to neuronal healing rather than damage ( Fig 2 ), a process observed in studies of animal models and cultured mouse microglial cells. Li et al 35 reported that mice treated with simvastatin had signifi cantly…”

Targeting Microglia to Prevent Post-Traumatic Epilepsy

“…Glial activation is normally neuroprotective (26,32); however, the chronic inflammatory responses and exaggerated proinflammatory cytokine levels observed following injury initiate neurotoxic processes resulting in secondary tissue damage (20,(33)(34)(35), neuronal death (29,(36)(37)(38), secondary injury cascades (39)(40)(41)(42)(43) and neuronal hyperexcitability (28, 34, 38, 44). There is substantial support for chronic inflammation following TBI.…”

“…Several studies have reported increased anxiety-like behavior in rodent TBI models, [29][30][31][32] including increased conditioned 33 and unconditioned 34 fear responses to both learned and novel stimuli. TBI in rodents also increases levels of activated glial cells and proinflammatory cytokines, [34][35][36][37][38] and administration of these cytokines increases anxiety-like behaviors. [29][30][31][32] The aim of the present study was therefore to determine whether neuroinflammation is associated with the long-term maintenance of post-traumatic anxiety in an animal model.…”