The Neuroprotective Effects of Simvastatin on High Cholesterol Following Traumatic Brain Injury in Rats.

Abstract

BACKGROUND:

High cholesterol has been correlated with a greater risk of cerebrovascular diseases. Whether pre-existing high cholesterol exacerbates traumatic brain injury (TBI), and whether treatment with the cholesterol-lowering agent simvastatin has neuroprotective effects, especially anti-neuroinflammatory effects, after TBI are not well investigated.

METHODS:

Five-week-old male Sprague-Dawley rats were fed a high-fat diet for 8 weeks to induce hypercholesterolemia. Anesthetized male Sprague-Dawley rats were divided into 5 groups, including the sham-operated control, TBI control, and TBI with simvastatin treatment (4 mg/kg, 10 mg/kg, or 20 mg/kg) groups. Simvastatin was intraperitoneally injected at 0, 24, and 48 hours after TBI. Motor function was measured using an inclined plane. Neuronal apoptosis (maker Neu-N, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling), tumor necrosis factor-α expression in microglia (marker OX42) and astrocytes (marker glial fibrillary acidic protein), and Tumor necrosis factor-alpha receptor (TNFR) 1 and TNFR2 expression in neurons in the ischemic cortex were investigated using an immunofluorescence assay. All of the parameters were measured on the third day after TBI.

RESULTS:

TBI significantly increased the serum levels of cholesterol. The TBI-induced motor deficit was significantly attenuated by 4, 10, and 20 mg/kg simvastatin therapy on the third day after TBI. TBI-induced neuronal TNFR1 activation and apoptosis, as well as tumor necrosis factor-α expression in astrocytes in the ischemic cortex, were significantly attenuated by simvastatin, particularly when 20 mg/kg was administered. Simultaneously, the serum cholesterol remained high despite simvastatin treatment.

CONCLUSIONS:

The neuroprotection effects of simvastatin on the pre-existing hypercholesterolemia during TBI in rats may be related to its anti-neuroinflammatory effects but not to its cholesterol-lowing effects.

• Authors: Arng Jack Chong, Sher-Wei Lim, Yao-Lin Lee, Chung-Ching Chio, Chin-Hung Chang, Jinn-Rung Kuo, Che-Chuan Wang
• Journal: World neurosurgery (World Neurosurg) Vol. 132 Pg. e99-e108 (Dec 2019) ISSN: 1878-8769 [Electronic] United States
• PMID: 31518751 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Anticholesteremic Agents
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Neuroprotective Agents
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha
• Cholesterol
• Simvastatin

Topics

• Animals
• Anticholesteremic Agents (therapeutic use)
• Brain Injuries, Traumatic (complications, psychology)
• Cholesterol (blood)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Hypercholesterolemia (drug therapy, etiology)
• Macrophage Activation (drug effects)
• Male
• Neuroprotective Agents (therapeutic use)
• Psychomotor Performance (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Tumor Necrosis Factor (biosynthesis)
• Simvastatin (therapeutic use)
• Tumor Necrosis Factor-alpha (blood)