急性缺血性中風的抗氧化治療可能會延遲阿爾茨海默氏癡呆症的發作 Antioxidant treatment in acute ischemic stroke may delay the onset of Alzheimer’s dementia

News Release 17-Mar-2020

The article by Dr. Anamaria Jurcau and Dr. Aurel Simion is published in the journal, CNS & Neurological Disorders – Drug Targets

Bentham Science PublishersShare Print E-Mail

Currently we are facing a dementia epidemic, with estimations showing that by 2050 approximately 131 million people will be affected. Every 7 seconds a patient is diagnosed worldwide. Because the common forms of dementia occur in the elderly, delaying the onset or worsening of the cognitive impairment could translate into a significant reduction of the incidence of the disease. Estimations have shown that of the huge number of cases expected by 2050, roughly 23 million could be avoided if the onset of the disease could be delayed by 2 years. Despite the ambition to identify a disease modifying therapy or a cure for dementia by 2025 set by the G8 dementia summit in 2013, the findings so far are not very encouraging.

To date there is growing evidence of the association of vascular risk factors like hypertension, high cholesterol levels or diabetes mellitus with cognitive impairment and Alzheimer’s disease. Unfortunately, simply managing these risk factors had little effect in reducing the incidence of dementia. These factors, however, strongly increase the risk of a patient to suffer an ischemic stroke and incident stroke approximately doubles the risk of dementia. From the study of Saver published in 2006 we know that “each hour in which treatment fails to occur the brain loses as many neurons as it does in 3.6 years of normal aging”.

These neuronal losses occur through ischemic necrosis in the core of the infarction, but may be prolonged up to 2 weeks after the ischemic insult in the penumbral area surrounding the ischemic core through another type of cell loss, namely apoptosis. In initiating apoptosis oxidative species have a major role. Several authors have shown consistent increases in oxidative stress after an ischemic stroke. As the authors pointed out in a previous study, oxidative stress increases mainly after cardioembolic stroke, followed by lacunar stroke, with a less prolonged burst of generation of oxidative species following thrombotic stroke.

There is a considerable overlap between the oxidative stress-induced pathogenesis in ischemic stroke and Alzheimer’s disease including mitochondrial dysfunction (the mitochondria being the main generators of energy in the cells), calcium overload of the cells, activation of different destructive enzymes by the excess intracellular calcium, aberrant gene transcription and expression, induction of autophagy (a process by which cells degrade their own cytoplasmic proteins and organelles) and activation of inflammatory responses.

Despite promising results of antioxidant molecules in animal models of ischemic stroke, human clinical trials were disappointing possibly due to late administration and incorrect selection of patients. However, in a study published in 2019, edaravone (an antioxidant molecule) given within 48 hours after endovascular revascularization in acute ischemic stroke was associated with greater functional independence at hospital discharge, lower in-hospital mortality and reduced intracranial hemorrhage after admission in a study which enrolled over 10,000 patients. More recently in a report presented at the International Stroke Conference 2020, nerinetide or NA1, a molecule which reduces endogenous nitric oxide (also an oxidative species) generated inside the cell during ischemia, improved the outcome of ischemic stroke patients who underwent endovascular thrombectomy. Unfortunately, NA1 interacted with alteplase, limiting its efficiency in patients who were also thrombolysed.

Antioxidants have been evaluated also in patients suffering from degenerative diseases, Alzheimer’s disease included, with promising results in animal models but inconclusive results in clinical trials. Therapeutic strategies are hampered by the dual role of oxidative species in the organism. On one hand, increased ROS production contributes to age-related chronic conditions and on the other, oxidant species function as signaling molecules in pathways that are critical for cell survival. However, based on the compelling evidence of the implication of oxidative stress in AD pathogenesis and of the pivotal role of mitochondria, molecules acting as mitochondria-targeted antioxidants show promise in animal models of neurodegenerative diseases, improve mitochondrial function after coronary ischemia/reperfusion in rats, and some have already been developed into drugs used in clinical trials in type 2 diabetic patients.

In view of the implication of oxidative stress in the genesis of AD pathology, the authors hypothesize that with aging, in the presence of well-established vascular risk factors, and possibly with a genetic contribution, AD pathology develops slowly without clinically overt cognitive impairment. However, after a stroke there is a sudden burst in oxidative stress which accelerates the pathogenesis of dementia and leads to clinically obvious cognitive impairment. If this hypothesis would be proven the reason for reaching antioxidant treatment in acute ischemic stroke would be reinforced. Further studies in this direction with long follow-up periods would be needed. Nonetheless, in view of the high incidence and prevalence of the disease, the results could be rewarding.

###

For more information, please visit: http://www.eurekaselect.com/179898/article

急性缺血性中風的抗氧化治療可能會延遲阿爾茨海默氏癡呆症的發作

目前，我們正面臨癡呆症的流行，據估計，到2050年，將有大約1.31億人受到影響。全球每7秒就會診斷出一名患者。因為癡呆症的常見形式發生在老年人中，延遲認知障礙的發作或惡化可能轉化為疾病發病率的顯著降低。估計表明，到2050年，如果該疾病的發作可以推遲2年，則可以避免大約2300萬例病例。儘管有志於在2013年G8癡呆症峰會確定的2025年之前確定一種改善疾病的療法或治愈癡呆症的方法，但迄今為止的發現並不十分令人鼓舞。

迄今為止，越來越多的證據表明血管危險因素如高血壓，高膽固醇水平或糖尿病與認知障礙和阿爾茨海默氏病相關。不幸的是，僅管理這些危險因素對降低癡呆症的發生率幾乎沒有影響。但是，這些因素極大地增加了患者發生缺血性中風的風險，而突發性中風使癡呆的風險大約增加了一倍。根據2006年發表的Saver研究，我們知道“治療失敗的每一小時，大腦失去的神經元數量與正常衰老3.6年中的神經元數量一樣多”。

這些神經元損失是通過梗死核心的缺血性壞死發生的，但在缺血性損傷周圍缺血半身周圍的半影區通過另一種類型的細胞損失（即凋亡）可能會延長至2週。在啟動細胞凋亡中，氧化物質起主要作用。幾位作者顯示缺血性中風後氧化應激持續增加。正如作者在先前的研究中指出的那樣，氧化應激主要在心臟栓塞性卒中後，腔隙性卒中後增加，而血栓性卒中後氧化性物質的爆發時間延長則較少。

缺血性中風的氧化應激誘發的發病機制與阿爾茨海默氏病之間存在相當多的重疊，包括線粒體功能障礙（線粒體是細胞中主要的能量產生器），細胞鈣超載，細胞內過量的各種破壞性酶的激活鈣，異常的基因轉錄和表達，自噬的誘導（細胞降解其自身胞質蛋白和細胞器的過程）和炎症反應的激活。

儘管抗氧化劑分子在缺血性中風的動物模型中取得了令人鼓舞的結果，但人類臨床試驗還是令人失望的，這可能是由於給藥晚和患者選擇不正確所致。然而，在2019年發表的一項研究中，在急性缺血性卒中的血管內血運重建後48小時內給予依達拉奉（抗氧化劑分子）與出院時更大的功能獨立性，更低的院內死亡率和入院後顱內出血的減少相關招募了10,000多名患者。最近在2020年國際中風會議上發表的一份報告中，神經氨酸或NA1是一種減少缺血期間細胞內部產生的內源性一氧化氮（也是一種氧化性物質）的分子，可改善接受血管內血栓切除術的缺血性中風患者的預後。不幸的是，NA1與阿替普酶相互作用，從而限制了其在血栓溶解患者中的療效。

抗氧化劑也已經在患有退行性疾病（包括阿爾茨海默氏病）的患者中進行了評估，其在動物模型中的結果令人鼓舞，但在臨床試驗中卻沒有定論。氧化物種在生物體中的雙重作用阻礙了治療策略。一方面，ROS產生的增加導致了與年齡有關的慢性疾病，另一方面，氧化劑在細胞存活至關重要的途徑中充當信號分子。然而，基於氧化應激在AD發病機理中的意義以及線粒體的關鍵作用的令人信服的證據，充當線粒體靶向抗氧化劑的分子在神經退行性疾​​病的動物模型中顯示出希望，可改善大鼠冠狀動脈缺血/再灌注後的線粒體功能，其中一些已經開發成2型糖尿病患者用於臨床試驗的藥物。

考慮到氧化應激在AD病理學的發生中的作用，作者推測，隨著年齡的增長，在存在公認的血管危險因素的情況下，可能還有遺傳因素，AD病理學發展緩慢，而沒有臨床上明顯的認知障礙。 然而，中風後氧化應激突然爆發，這加速了癡呆的發病機理並導致臨床上明顯的認知障礙。 如果這一假設得到證實，那麼在急性缺血性卒中達到抗氧化劑治療的原因將得到加強。 在這個方向上需要長期隨訪的進一步研究。 儘管如此，鑑於該疾病的高發病率和流行，結果可能是有益的。