A purine antimetabolite attenuates toll-like receptor-2, -4, and subarachnoid hemorrhage-induced brain apoptosis

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• 作者：Chih-Zen Chang ; MD^a ; ^b ; ^c ; ^{changchihzen2002@yahoo.com.tw" class="auth_mail" title="E-mail the corresponding author} ; Shu-Chuan Wu ; Ms^b ; Aij-Lie Kwan ; MD ; PhD^a ; ^b
• 关键词：Cysteine requiring aspartate proteases ; Early brain injury ; 6-Mercaptopurine ; Subarachnoid hemorrhage ; Toll-like receptors
• 刊名：Journal of Surgical Research
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：199
• 期：2
• 页码：676-687
• 全文大小：1877 K

文摘

Upregulation of high-level toll-like receptors (TLRs) is observed in the serum of animals following experimental subarachnoid hemorrhage (SAH) and is highly related to SAH-induced early brain injury (EBI). The present study was of interest to examine the effect of 6-mercaptopurine (6-MP) on alternation of TLR-2, -3, and -4 in this model.

Methods

15">A rodent SAH model was used. Administration with 6-MP (0.5/1/2 mg/kg/d) was initiated 1 h after the induction of SAH via an osmotic minipump. Cerebral cortex was harvested to measure TLRs messenger RNA and protein (reverse transcription polymerase chain reaction [rt-PCR] and Western blot). Cerebral cortex was harvested for activated caspases (rt-PCR) measurement.

Results

Cellular evaluation revealed increased neuronal nuclei(+) neurons with vacuolated nuclear and glial fibrillary acidic protein(+) astrocytes in the SAH group, but absent in the 6-MP treatment and healthy controls. The TLR-3 levels were not significantly increased in animals subject to SAH, compared with the controls (no SAH). The levels of TLR-2 and -4 in the SAH only and SAH plus vehicle groups were significantly elevated (P < 0.01), and treatment with 6-MP reduced TLR-2, -3 (at 2 mg/kg), and -4 (dose-dependently) protein expression following SAH. Likewise, the TLR-4 messenger RNA levels were also significantly reduced in the 6-MP (at 1 mg/kg and 2 mg/kg) groups. Cleaved caspase-3 and caspase-9a were reduced at 2-mg/kg 6-MP treatment group.

Conclusions

These results show that 6-MP attenuates the expression of TLR-2, -4, especially TLR-4, which play an antiapoptotic effect on SAH-induced EBI. This finding supported that through modulating TLRs, 6-MP can attenuate SAH-induced EBI. Those results offer credit to the neuroprotective effect of 6-MP.