Statin-induced T-lymphocyte modulation and neuroprotection following experimental subarachnoid hemorrhage.
BACKGROUND
Statins influence immune system activities through mechanisms independent of their lipid-lowering properties. T cells can be subdivided based on cytokine secretion patterns into two subsets: T-helper cells type 1 (Th1) and type 2 (Th2). Independent laboratory studies have shown statins to be potent inducers of a Th2 switch in immune cell response and be neuroprotective in several models of central nervous system (CNS) disease. This study was the first to evaluate the immune modulating effects of statins in subarachnoid hemorrhage (SAH).


METHODS
Simvastatin was administered to rats intraperitoneally in two dosages (1 and 20 mg/kg) 30 min after the induction of SAH using endovascular perforation. Neurological scores were assessed 24 h later. Animals were then sacrificed, and samples of cortex and brain stem were tested for expression of the T-regulatory cell cytokine transforming growth factor (TGF) β1, as well as interleukin (IL) 1β, a proinflammatory cytokine associated with Th1 immune responses. The presence of TGF-β1 secreting T cells was evaluated with the use of brain slices.


RESULTS
SAH significantly impaired neurological function in all SAH groups (treated and untreated) versus sham. Animals treated with high-dose simvastatin had less neurological impairment than both untreated and low-dose groups. Cortical and brain-stem levels of TGF-β1 were significantly elevated following SAH in the high-dose group. IL-1β was significantly elevated following the induction of SAH but was inhibited by high-dose simvastatin. Double-labeled fluorescent immunohistochemical data demonstrated the presence of lymphocytes in the subarachnoid and perivascular spaces following SAH. Expression of TGF-β1 by lymphocytes was markedly increased following treatment with high-dose simvastatin.


CONCLUSIONS
The present study elucidated the potential role of a Th2 immune switch in statin provided neuroprotection following SAH.
Department of Neurosurgery, Loma Linda University Medical Center, Loma Linda, CA, USA.
Robert E
RE
Ayer
Robert P
RP
Ostrowski
Takashi
T
Sugawara
Qingy
Q
Ma
Nazanin
N
Jafarian
Jiping
J
Tang
John H
JH
Zhang
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D016212:Transforming Growth Factor beta