De Keyser Jacques, Zeinstra Esther, Mostert Jop, Wilczak Nadine
Department of Neurology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Trends Pharmacol Sci. 2004 Feb;25(2):67-71. doi: 10.1016/j.tips.2003.12.002.
Relapses of multiple sclerosis (MS) are considered to be the clinical expression of acute T-cell-mediated inflammatory demyelinating lesions disseminated in the CNS, whereas disease progression seems to result from widespread axonal degeneration. The pathophysiology of both disease components is incompletely understood. Astrocytes in MS lack beta(2)-adrenoceptors, which via cAMP-mediated processes inhibit the expression of major histocompatibility (MHC) class II molecules and stimulate glycogenolysis in normal conditions. In a pro-inflammatory CNS environment this beta(2)-adrenoceptor defect might allow astrocytes to transform into facultative antigen-presenting cells that can initiate the inflammatory cascade. The same receptor defect might impair astrocytic glycogenolysis, which normally generates lactate that is transported to axons as an energy source. Failure of axonal energy metabolism might result in axonal degeneration through mechanisms that involve intra-axonal accumulation of Ca(2+) ions and mitochondrial dysfunction. If this hypothesis is correct, therapies designed to elevate cAMP levels in astrocytes should reduce or prevent both relapses and progression of MS.
多发性硬化症（MS）的复发被认为是中枢神经系统中急性T细胞介导的炎症性脱髓鞘病变的临床表现，而疾病进展似乎是由广泛的轴突变性引起的。这两种疾病成分的病理生理学尚未完全了解。MS中的星形胶质细胞缺乏β(2)-肾上腺素能受体，在正常情况下，该受体通过cAMP介导的过程抑制主要组织相容性（MHC）II类分子的表达并刺激糖原分解。在促炎性中枢神经系统环境中，这种β(2)-肾上腺素能受体缺陷可能使星形胶质细胞转变为兼性抗原呈递细胞，从而引发炎症级联反应。相同的受体缺陷可能会损害星形胶质细胞的糖原分解，而糖原分解通常会产生乳酸，并作为能量来源转运至轴突。轴突能量代谢的失败可能通过涉及轴突内Ca(2+)离子积累和线粒体功能障碍的机制导致轴突变性。如果这一假设正确，那么旨在提高星形胶质细胞中cAMP水平的疗法应能减少或预防MS的复发和进展。
