CN102933092A - 控制和预防陪伴动物炎症及减轻陪伴动物炎性病况的方法 - Google Patents
控制和预防陪伴动物炎症及减轻陪伴动物炎性病况的方法 Download PDFInfo
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Abstract
本发明涉及控制和预防陪伴动物(例如狗或猫)的炎症及减轻陪伴动物(例如狗或猫)的炎性病况，特别是关节炎和关节痛的方法，其包括给予包含硫辛酸的饮食。
Description
发明领域
本发明涉及控制和预防陪伴动物(例如狗和猫)的炎症以及减轻陪伴动物(例如狗和猫)的炎性病况，特别是关节炎和关节痛的方法，其包括给予包含硫辛酸的饮食(diet)。
发明背景
硫辛酸(LA)为衍生自辛酸的有机硫化合物。LA包含两个通过二硫键连接的邻位硫原子(位于C6和C8)，因此认为其是氧化的(尽管任一硫原子均可存在于更高的氧化态下)。C6位的碳原子是手性的，该分子作为两种对映体R-(+)-硫辛酸(RLA)和S-(-)-硫辛酸(SLA)以及作为外消旋混合物R/S-硫辛酸(R/S-LA)存在。只有R-(+)-对映体天然存在，并且其为四个线粒体酶复合物的必需辅因子。RLA和R/S-LA两者均可作为非处方营养补充剂获得，自20世纪50年代以来已在营养和临床上用于多种疾病和病况。LA已经用于动物食物，例如Hill处方饮食犬b/d® (Hill’s Prescription Diet canine b/d®)，认为其提高警觉性和认知，特别是在年龄较大的狗中。
骨关节炎是由一个或多个关节的软骨、骨和软组织的进行性炎症和退化引起的慢性退行性关节病。类风湿性关节炎为引起炎症和关节损伤的自身免疫病况。二者均为慢性炎性病况，且普遍存在于年龄较大的狗和猫中。由于关节损伤为进行性的且在很大程度上不可逆，主动确定和处理炎性过程是合乎需要的。
发明概述
本发明提供控制和预防陪伴动物(例如狗和猫)的炎症以及减轻陪伴动物(例如狗和猫)的炎性病况，特别是关节炎和关节痛的方法，其包括给予包含硫辛酸的饮食例如至少两周的时间，例如，其中所述饮食包括含有10-10,000
ppm硫辛酸的食物，例如包含50-200 ppm硫辛酸的干燥食物。
在进一步的实施方案中，本发明提供控制和预防陪伴动物(例如狗和猫)的炎症以及减轻陪伴动物(例如狗和猫)的炎性病况，特别是关节炎和关节痛的方法，其包括测量炎症生物标志物的表达，和给予包含硫辛酸的饮食例如至少两周的时间，例如，其中所述饮食包括含有10-10,000
ppm硫辛酸的食物，例如包含50-200 ppm硫辛酸的干燥食物，以减少一个或多个炎症生物标志物的表达。
发明详述
本发明方法使用的饮食包括例如，包含至少500 IU/kg维生素E(例如500-2000 IU/kg)、至少约40 ppm维生素C(例如40-200 ppm)、至少50 ppm肉碱(例如50-300 ppm)和至少50 ppm硫辛酸(例如50-250 ppm)的犬科动物饮食，例如包含以下的犬科动物饮食：
所述硫辛酸为，例如，呈游离或营养上可接受的盐或酯形式，优选游离形式或钠盐形式的R-(+)-硫辛酸(RLA)和S-(-)-硫辛酸(SLA)或外消旋混合物R/S-硫辛酸(R/S-LA)，优选RLA或R/S-LA。
炎症生物标志物包括，例如，下列中的任何一种或多种：肿瘤坏死因子α、GM-集落刺激因子、单核细胞趋化蛋白-1、干扰素γ、白细胞介素-10、白细胞介素-15、白细胞介素-18、白细胞介素-2、白细胞介素-4、白细胞介素-6、白细胞介素-7、白细胞介素-8、干扰素γ诱导的蛋白-10、KC趋化因子。
实施例
1
：硫辛酸饮食对老年狗中炎性生物标志物的影响
进行研究以评估食物组合物对健康老年狗中炎性生物标志物和基因表达的影响。本研究包括29只老年比格犬(beagle dog)(初始体重为13.51
± 1.66 kg，年龄10.7 ± 2.33岁)。所有的狗用对照维持食物喂养28天，随后用试验食物喂养。试验食物包含升高水平的Ω3脂肪酸、硫辛酸、来自水果的抗氧化剂和蔬菜混合物、维生素C和E、以及L-肉碱。在控制食物的最后一天(第0天)和试验食物14天后收集血清和全血样品。测量炎性和激素生物标志物以及基因表达变化。根据PAXgene血液RNA试剂盒手册(Qiagen, Valencia, CA)提供的程序提取RNA。将RNA与Affymetrix基因芯片犬-2基因组阵列(Affymetrix GeneChip Canine-2
Genome Array)杂交，并使用稳健多阵列平均(Robust Multi-Array Average)标准化。认为P < 0.05 (在0.1的错误发现率调整值后)且倍数变化范围为至少1.3的转录物具有差异。消耗试验食物后，喂养试验食物的老年狗具有较低的IL-4、IL-6、IL-10、KC和总细胞因子。未检测到激素生物标志物的差异。喂养试验食物的老年狗还具有与第0天相比上调或下调的1123个基因。其中，β淀粉状蛋白斑形成相关基因下调，而β淀粉状蛋白斑清除相关基因上调。此外，当用试验食物喂养老年狗时，与对照的第0天相比，神经递质信号传导和细胞粘附相关基因显著上调。该研究提供基因表达证据，这支持先前所示在老年狗中观察到的试验食物对记忆和行为相关响应的益处。
通过工作和辨别测试(task and discrimination testing)测量，已表明试验食物将老年狗的记忆和认知改善至与年轻狗相似的水平。然而，尚未确定这些所观测到的改善的潜在机制。炎症在许多疾病过程包括一般性老化中起重要作用。此外，认知改善相关的生物化学量度例如基因表达仅在狗中有限使用。
本研究的目的是为了测定试验食物对老年狗中的炎性和激素生物标志物以及基因表达变化的影响。
确定29只阉割/切除卵巢的比格犬用于本研究，用试验食物喂养28天。通过身体检查和血清化学，认为狗是健康的。研究方案由公共机构动物护理和使用委员会(Institutional
Animal Care and Use Committee)审查和批准。所有的狗均针对犬瘟热、腺病毒、细小病毒、博德特氏菌和狂犬病进行免疫，且基于身体检查、全血计数测定、血清生化分析、尿分析和排泄物寄生虫检测的结果无一具有慢性全身性疾病。通过彼此间的互动、与看守人的日常互动和玩耍时间、每日户外奔跑和运动及获得玩具的机会，狗经历行为充实(behavioral enrichment)。在第0天收集样品前，用基础维持对照食物喂养所有的狗达28天。然后将狗的食物改为试验食物，14天后收集样品。抽血并收集入PAXgene管中，-80ºC保存直至进行评估。使用犬-2 Affymetrix基因芯片微列阵确定与第0天相比第14天的基因差异。
血浆生物标志物–采用SAS版本9.0，使用配对t检验分析测定炎性和激素生物标志物响应食物的变化。用所有的细胞因子计算总细胞因子。
基因–使用稳健多阵列平均，将基因表达标准化，并使用Partek分析工具测定差异。认为两组间P < 0.05 (在Q =
0.1的错误发现率调整值后)且倍数变化为至少1.25的基因具有差异。上调基因显示为正的倍数变化。下调基因显示为负的倍数变化。
表
1
：饮食内含物
表
2
：响应于试验食物的血浆中测量的炎性和激素生物标志物
(SE=
平均标准误差
):
表
3
：脑健康和功能相关基因：
| 基因名称 | 倍数变化 |
| 脑健康相关 | |
| 淀粉状蛋白β A4 | -1.3 |
| 共济失调蛋白7 | -1.3 |
| α2巨球蛋白 | 1.3 |
| 脑源性神经营养因子 | 1.3 |
| 其它脑疾病相关 | |
| 蜡样脂褐质沉积症神经元5 | -1.5 |
| 神经细胞粘附相关 | |
| 接触蛋白1 | 1.5 |
| 接触蛋白6 | 1.7 |
| 神经细胞粘附分子 | 1.4 |
| 神经细胞粘附分子2 | 1.5 |
| 神经细胞粘附分子短同工型 | 1.4 |
| 神经递质信号传导和转运蛋白相关 | |
| GABA受体A | 1.3 |
| GABA受体B | 1.3 |
| 谷氨酸受体5 | 1.3 |
| 谷氨酸受体6 | 1.3 |
| 谷氨酸受体8 | 1.3 |
| NMDA 2B | 1.4 |
| Neuritin 1 | 1.3 |
| 乙酰胆碱受体α 6 | 1.3 |
| SLC6A15 | 1.3 |
| SLC6A16 | 1.3 |
| SLC6A18 | 1.3 |
| 钙粘蛋白2 | 1.3 |
| 钠和氯依赖性神经递质转运蛋白NTT5 | 1.3 |
临床研究已表明用试验食物喂养老年狗可帮助恢复青年样能量，并将记忆/工作能力改善至与年轻成年狗相似的水平。在当前研究中，喂养维持对照食物后，将健康老年狗的食物改为试验食物，表现出炎性标志物IL-4、IL-10、IL-6、KC和总细胞因子的降低。另外，β淀粉状蛋白斑形成相关基因降低，而β-淀粉状蛋白清除或神经递质信号传导相关的其它基因增加。
本研究提示，喂养试验食物(通过降低炎性生物标志物和潜在地通过改变脑健康相关基因的表达)对老年狗的生活质量产生正面影响。
Claims (13)
1. 控制或预防陪伴动物的炎症和/或减轻陪伴动物的炎性病况的方法，其包括给予包含硫辛酸的饮食。
2. 权利要求1的方法，其中给予所述饮食至少两周的时间。
3. 权利要求1或2的方法，其中所述饮食包括含有10-10,000 ppm硫辛酸的食物。
4. 权利要求1或前述权利要求中任一项的方法，其中所述饮食包括含有50-200 ppm硫辛酸的干燥食物。
5. 权利要求1或前述权利要求中任一项的方法，其中待控制、预防或减轻的病况为关节炎。
6. 权利要求1或前述权利要求中任一项的方法，其中待治疗、控制、预防或减轻的病况为骨关节炎。
7. 权利要求1或前述权利要求中任一项的方法，其中所述陪伴动物为狗或猫。
8. 权利要求1或前述权利要求中任一项的方法，其中所述饮食包含至少500 IU/kg维生素E、至少200
ppm肉碱和至少50 ppm硫辛酸。
9. 权利要求1或前述权利要求中任一项的方法，其中所述硫辛酸为呈游离或营养上可接受的盐或酯形式的R-(+)-硫辛酸(RLA)或外消旋混合物R/S-硫辛酸(R/S-LA)。
10. 权利要求1或前述权利要求中任一项的方法，还包括测量炎症生物标志物的表达。
11. 权利要求10的方法，其中炎症生物标志物包括选自以下的一种或多种生物标志物：肿瘤坏死因子α、GM-集落刺激因子、单核细胞趋化蛋白-1、干扰素γ、白细胞介素-10、白细胞介素-15、白细胞介素-18、白细胞介素-2、白细胞介素-4、白细胞介素-6、白细胞介素-7、白细胞介素-8、干扰素γ诱导的蛋白-10和KC趋化因子。
12. 硫辛酸在制备用于前述权利要求中任一项方法的宠物食物中的用途。
13. 用于前述权利要求中任一项方法的硫辛酸。
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| US20090182032A1 (en) * | 2000-10-31 | 2009-07-16 | Hill's Pet Nutrition, Inc. | Companion animal compositions including lipoic acid and methods of use thereof |
| EP1635810A2 (en) * | 2003-06-23 | 2006-03-22 | Advanced Bionutrition (Europe) Limited | Inflammatory disease treatment |
| US20080069834A1 (en) * | 2004-11-09 | 2008-03-20 | Zicker Steven C | Use of Antioxidants for Gene Modulation |
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| ZA201208036B (en) | 2017-08-30 |
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