雄性素受體於小鼠之脊髓損傷中扮演的角色

嚴重的脊髓損傷常常導致在脊髓受傷部位以下的肌肉癱瘓無力以及感覺功能喪失，雖然甲基去氫氧化可體松（methylprednisolone，MP）是目前美國藥物食品檢驗局所核可治療急性脊髓損傷的藥物，然而其療效卻相當有限且有不少副作用。因此，發展出比MP更有效治療脊髓損傷的方法，是目前治療脊髓損傷的最重要課題。過去的研究報告指出在脊髓損傷發生後，男性患者的恢復情形比女性患者為佳。此外，研究也顯示雄性素具有保護受傷神經的作用。因為雄性素的作用一般被認為經由活化雄性素受體所達成。上述的研究結果引導我們提出雄性素受體 (androgen receptor) 在脊髓損傷上扮演著重要角色的假說。在本論文中，我們使用剔除雄性素受體（androgen receptor knockout, ARKO）的雄性小鼠以及同胎的正常雄性小鼠來檢驗上述的假說，我們於小鼠四個月大時為其施行脊髓損傷的手術，並觀察牠們在手術後後肢行動能力恢復的情形。我們的研究結果顯示，去除雄性素受體的雄性小鼠在脊髓損傷後，其後肢行動能力的恢復比起同胎具有雄性素受體的對照組雄性小鼠來的差。而剔除雄性素受體的雄性小鼠在脊髓損傷後顯示較大面積的脊髓損傷範圍及保留較少的軸突。我們的結果強烈支持，雄性素受體對脊髓損傷具有保護作用的論述。

關鍵字

脊髓損傷；雄性素受體；基因轉殖鼠

並列摘要

Severe spinal cord injuries (SCI) often cause loss of motor and sensory functions below the lesion site. Up to now, methylprednisolone (MP) is the only FDA-approved therapeutic agent for treating acute SCI, however, MP has only limited therapeutic effect accompanied by adverse side effects. Thus, it is imperative to develop or invent a better therapeutic agent or strategy to treat SCI. Some studies have reported that male SCI patients show a better recovery outcome than female SCI patients. Evidence also shows that androgen has a neuroprotective effect on injured neurons. It is widely accepted that androgen exerts its effects on cells via binding to androgen receptor. Based on the above findings, we propose the hypothesis that androgen receptor plays an important role in spinal cord injury. In this study, we employed transgenic mice with androgen receptor knockout (ARKO) in all cells ad their male littermates (4 months old) to test the effect of on the functional recovery of SCI. Spinal cord injury was induced by a force of 60 K dynes delivered by IH Impactor. The locomotor activity of mice was evaluated before and 1, 4, 7, 10, 14, 21, 28, and 35days after SCI. Moreover, the spinal lesion and the amount of remaining axons at the lesion site were assessed after sacrifice of SCI mice. Our results showed that male ARKO mice exhibited a worse functional recovery than the male wild-type littermates after SCI. In addition, SCI mice with ARKO showed a lager spinal lesion and had fewer preserved axons at the lesion site. These findings strongly suggest that androgen receptor exerts a beneficial effect on SCI.

並列關鍵字

spinal cord injury ； androgen receptor ； transgenic mice

參考文獻

Anderberg L, Aldskogius H, Holtz A (2007) Spinal cord injury--scientific challenges for the unknown future. Ups J Med Sci 112:259-288.

Barker RN, Kendall MD, Amsters DI, Pershouse KJ, Haines TP, Kuipers P (2008) The relationship between quality of life and disability across the lifespan for people with spinal cord injury. Spinal Cord.

Boden BP, Jarvis CG (2008) Spinal injuries in sports. Neurol Clin 26:63-78; viii.

Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, Eisenberg HM, Flamm E, Leo-Summers L, Maroon J, et al. (1990) A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 322:1405-1411.

Brinkmann AO (2001) Molecular basis of androgen insensitivity. Mol Cell Endocrinol 179:105-109.

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雄性素受體於小鼠之脊髓損傷中扮演的角色

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