Chronic oral administration of minocycline to sheep with ovine CLN6 neuronal ceroid lipofuscinosis maintains pharmacological concentrations in the brain but does not suppress neuroinflammation or disease progression
Chronic oral administration of minocycline to sheep with ovine CLN6 neuronal ceroid lipofuscinosis maintains pharmacological concentrations in the brain but does not suppress neuroinflammation or disease progression
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DOI：
10.1186/1742-2094-10-97
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发表时间：
2013-07-30
影响因子：
9.3
通讯作者：
Palmer, David N.
中科院分区：
文献类型：
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作者：
Kay, Graham W.;Palmer, David N.
背景：神经性蜡样脂褐素增多症(NCLS；或巴顿病)是一种致命的遗传性人类神经退行性疾病，全世界估计有1：12,500名活产儿受到影响。它们是由至少11个不同基因的突变引起的。目前，还没有有效的治疗方法。了解发病机制和可能的治疗方法的进展取决于对动物模型的研究。研究最多的动物是南汉普郡的CLN6绵羊，其神经病理过程与受影响儿童的神经病理过程密切相关。神经退行性变是这种疾病的一个标志，它与神经炎症有关，并由此导致。星形胶质细胞和小胶质细胞的激活在产前就开始了，从与进行性皮质萎缩和临床症状(包括枕叶皮质和失明)的发展相关的特定病灶开始。神经退行性变和神经炎都是泛发性的，随着年龄的增长和临床严重程度的增加而变得更加严重。本研究的目的是为了确定从幼年起长期服用抗炎药物米诺环素是否能阻止或逆转疾病的发展。方法：米诺环素是一种具有抗神经炎症活性的四环素家族抗生素，在临床症状明显的3个月至14个月龄时，通过长期口服米诺环素25 mg/kg/d给患CLN6 NCL的症状前羔羊进行试验，以确定这是否能抑制神经炎症或疾病的进展。结果：米诺环素在没有明显的瘤胃生物转化的情况下被吸收，以维持血浆中1MU M和脑脊液中400 NM的药理浓度，结论：口服给药是大动物中枢神经系统给药的一种有效途径，在动物体内的模型研究应先于人类的高度推测性操作。米诺环素不能抑制这种形式的巴顿病神经炎性级联反应中的关键步骤。识别神经退行性疾病中神经炎性级联反应的关键步骤，并针对它们进行特定的药物治疗，将极大地增加成功的可能性。
Background: The neuronal ceroid lipofuscinoses (NCLs; or Batten disease) are fatal inherited human neurodegenerative diseases affecting an estimated 1:12,500 live births worldwide. They are caused by mutations in at least 11 different genes. Currently, there are no effective treatments. Progress into understanding pathogenesis and possible therapies depends on studying animal models. The most studied animals are the CLN6 South Hampshire sheep, in which the course of neuropathology closely follows that in affected children. Neurodegeneration, a hallmark of the disease, has been linked to neuroinflammation and is consequent to it. Activation of astrocytes and microglia begins prenatally, starting from specific foci associated with the later development of progressive cortical atrophy and the development of clinical symptoms, including the occipital cortex and blindness. Both neurodegeneration and neuroinflammation generalize and become more severe with increasing age and increasing clinical severity. The purpose of this study was to determine if chronic administration of an anti-inflammatory drug, minocycline, from an early age would halt or reverse the development of disease.Method: Minocycline, a tetracycline family antibiotic with activity against neuroinflammation, was tested by chronic oral administration of 25 mg minocycline/kg/day to presymptomatic lambs affected with CLN6 NCL at 3 months of age to 14 months of age, when clinical symptoms are obvious, to determine if this would suppress neuroinflammation or disease progression.Results: Minocycline was absorbed without significant rumen biotransformation to maintain pharmacological concentrations of 1 mu M in plasma and 400 nM in cerebrospinal fluid, but these did not result in inhibition of microglial activation or astrocytosis and did not change the neuronal loss or clinical course of the disease.Conclusion: Oral administration is an effective route for drug delivery to the central nervous system in large animals, and model studies in these animals should precede highly speculative procedures in humans. Minocycline does not inhibit a critical step in the neuroinflammatory cascade in this form of Batten disease. Identification of the critical steps in the neuroinflammatory cascade in neurodegenerative diseases, and targeting of specific drugs to them, will greatly increase the likelihood of success.