Role of Regulatory T cells in Atorvastatin Induced Absorption of Chronic Subdural Hematoma in Rats

Wei Quan; Zhifei Zhang; Pan Li; Qilong Tian; Jinhao Huang; Yu Qian; Chuang Gao; Wanqiang Su; Zengguang Wang; Jianning Zhang; Alex Zacharek; Poornima Venkat; Jieli Chen; Rongcai Jiang

doi:10.14336/AD.2018.0926

Role of Regulatory T cells in Atorvastatin Induced Absorption of Chronic Subdural Hematoma in Rats

Aging Dis. 2019 Oct 1;10(5):992-1002. doi: 10.14336/AD.2018.0926. eCollection 2019 Oct.

Authors

Wei Quan^{1

2}, Zhifei Zhang^{1

2

3}, Pan Li⁴, Qilong Tian⁵, Jinhao Huang^{1

2}, Yu Qian^{1

2}, Chuang Gao^{1

2}, Wanqiang Su⁶, Zengguang Wang^{1

2}, Jianning Zhang^{1

2}, Alex Zacharek⁷, Poornima Venkat⁷, Jieli Chen⁷, Rongcai Jiang¹

Affiliations

¹ 1Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin, China.
² 2Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Tianjin, China.
³ 3Department of Neurosurgery, The First Central Hospital of Tianjin, Tianjin, China.
⁴ 4Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China.
⁵ 5Department of Neurology, Tangdu Hospital, Baqiao, Shanxi, China.
⁶ 6Department of Neurosurgery, The First Central Hospital of Baoding City, Lianchi, Baoding, China.
⁷ 7Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.

Abstract

Chronic subdural hematoma (CSDH) is a neurological disorder with a substantial recurrence rate. Atorvastatin is an effective drug for treating hyperlipidemia and known to improve neurological outcome after intracerebral hemorrhage. Previous studies have reported that atorvastatin treatment promotes hematoma absorption in CSDH, while the underlying mechanisms remain unclear. In this study, we investigated whether the anti-inflammatory effects of atorvastatin mediate absorption of CSDH. 144 male, Wistar rats (6 months old) were randomly divided into the following groups: 1) sham surgery control, 2) treatment: CSDH + atorvastatin, and 3) vehicle control: CSDH + saline. Atorvastatin or saline was orally administered daily for 19 days after CSDH procedure. A T2WI MRI was used to evaluate CSDH volume changes during the time course of the study. Flow cytometry and immunohistochemical staining were used to measure the number of regulatory T cells (Treg). ELISA was used to measure cytokine level in the hematoma border. Neurological function and cognitive outcome were evaluated using Foot-Fault test and Morris Water Maze test, respectively. When compared to saline treatment, atorvastatin treatment accelerated the absorption of CSDH as indicated by decreased hematoma volume in T2WI MRI data on 14^th and 21^st day after CSDH (P<0.05). Atorvastatin treatment significantly increased the number of Treg in circulation and hematoma border from 3^rd to 21^st day after CSDH. Atorvastatin treatment significantly decreased the levels of interleukins (IL-6 and IL-8) and tumor necrosis factor-α (TNF-α), but increased IL-10 level in the hematoma border. Atorvastatin treatment also improved neurological function and cognitive outcome compared to vehicle treated group. Atorvastatin induced anti-inflammatory responses and increased Treg in circulation and brain which may contribute to the accelerated CSDH absorption in rats.

Keywords: atorvastatin; chronic subdural hematoma; cytokines; inflammation; regulatory T cell.