Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury.
Traumatic brain injury (TBI) triggers a complex sequence of inflammatory responses that contribute to secondary injury. Statins have demonstrated neuroprotective effects against brain injury, but the underlying mechanisms remain unclear. This study evaluated the effects of lovastatin on a rat model of controlled cortical impact (CCI) injury. Our two hypotheses were that pre-administration of lovastatin would reduce functional deficits and extent of anatomical brain damage and that lovastatin would attenuate levels of pro-inflammatory cytokines. Rats were injected with lovastatin (4 mg/kg) or vehicle for 5 days and subjected to CCI. Neurological status was evaluated using rotarod and adhesive removal tests. Contusion volume and neuronal degeneration were examined using cresyl violet and FluoroJade B (FJB) histochemistry. Levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA and protein were assessed by real-time quantitative reverse transcriptase polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry. Lovastatin significantly improved performance on both the rotarod and adhesive removal tests before post-injury day 7. Lovastatin also significantly reduced contusion volume (20%) and number of FJB-positive degenerating neurons (35%) at 4 days. These changes were associated with a significant decrease in levels of TNF-alpha and IL-1beta mRNA and protein at the contusion site at 6 h and 4 days, respectively. Our results show that pre-administration of lovastatin improved functional outcomes and reduced extent of brain damage, with a concomitant decrease in tissue levels of TNF-alpha and IL-1beta mRNA and protein. These findings suggest that lovastatin's protective mechanisms may be partly attributed to a dampening of the inflammatory response.
Chen
Szu-Fu
SF
Department of Physical Medicine & Rehabilitation, Cheng Hsin General Hospital, Taiwan.
Hung
Tai-Ho
TH
Chen
Chien-Cheng
CC
Lin
Kuei-Han
KH
Huang
Ya-Ni
YN
Tsai
Hung-Chih
HC
Wang
Jia-Yi
JY
D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045442:Rotarod Performance Test; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D008148:Lovastatin