Mamo J C L, Lam V, Giles C, Coulson S H, Fimognari N, Mooranian A, Al-Salami H, Takechi R
Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia.
School of Public Health, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.
Int J Obes (Lond). 2017 Jun;41(6):926-934. doi: 10.1038/ijo.2017.57. Epub 2017 Feb 27.
While vascular risk factors including Western-styled diet and obesity are reported to induce cognitive decline and increase dementia risk, recent reports consistently suggest that compromised integrity of cerebrovascular blood-brain barrier (BBB) may have an important role in neurodegeneration and cognitive deficits. A number of studies report that elevated blood pressure increases the permeability of BBB.
In this study, we investigated the effects of antihypertensive agents, candesartan or ursodeoxycholic acid (UDCA), on BBB dysfunction and cognitive decline in wild-type mice maintained on high fat and fructose (HFF) diet for 24 weeks.
In HFF-fed mice, significantly increased body weight with elevated blood pressure, plasma insulin and glucose compared with mice fed with low-fat control chow was observed. Concomitantly, significant disruption of BBB and cognitive decline were evident in the HFF-fed obese mice. Hypertension was completely prevented by the coprovision of candesartan or UDCA in mice maintained on HFF diet, while only candesartan significantly reduced the body weight compared with HFF-fed mice. Nevertheless, BBB dysfunction and cognitive decline remained unaffected by candesartan or UDCA.
These data conclusively indicate that modulation of blood pressure and/or body weight may not be directly associated with BBB dysfunction and cognitive deficits in Western diet-induced obese mice, and hence antihypertensive agents may not be effective in preventing BBB disruption and cognitive decline. The findings may provide important mechanistical insights to obesity-associated cognitive decline and its therapy.
虽然据报道包括西式饮食和肥胖在内的血管危险因素会导致认知能力下降并增加患痴呆症的风险，但最近的报道一致表明，脑血管血脑屏障（BBB）完整性受损可能在神经退行性变和认知缺陷中起重要作用。多项研究报告称，血压升高会增加血脑屏障的通透性。
在本研究中，我们调查了抗高血压药物坎地沙坦或熊去氧胆酸（UDCA）对维持24周高脂肪和果糖（HFF）饮食的野生型小鼠血脑屏障功能障碍和认知能力下降的影响。
与喂食低脂对照饲料的小鼠相比，喂食HFF的小鼠体重显著增加，血压、血浆胰岛素和葡萄糖升高。与此同时，喂食HFF的肥胖小鼠血脑屏障明显破坏，认知能力下降。在维持HFF饮食的小鼠中，联合使用坎地沙坦或UDCA可完全预防高血压，而与喂食HFF的小鼠相比，只有坎地沙坦显著降低了体重。然而，坎地沙坦或UDCA对血脑屏障功能障碍和认知能力下降仍无影响。
这些数据确凿地表明，在西方饮食诱导的肥胖小鼠中，血压和/或体重的调节可能与血脑屏障功能障碍和认知缺陷没有直接关联，因此抗高血压药物可能无法有效预防血脑屏障破坏和认知能力下降。这些发现可能为肥胖相关的认知能力下降及其治疗提供重要的机制性见解。
