Comorbidities in Neurology: Is adenosine the common link?
Comorbidities in Neurology: Is adenosine the common link?
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DOI：
10.1016/j.neuropharm.2015.04.031
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发表时间：
2015-10
影响因子：
4.7
通讯作者：
Aronica E
中科院分区：
文献类型：
--
作者：
Boison D;Aronica E
神经病学的共病是一个主要的概念和治疗挑战。例如，颞叶癫痫（TLE）是由癫痫发作和共病症状（包括记忆和精神损害、抑郁和睡眠功能障碍）组成的综合征。类似地，阿尔茨海默病（AD）、帕金森病（PD）和肌萎缩侧索硬化症（ALS）伴随有不同程度的记忆功能障碍。AD患者癫痫发作的可能性增加，而所有四种疾病都具有精神病，抑郁症和睡眠功能障碍的某些方面。这种显著的重叠表明共同的病理生理机制，其中包括突触功能障碍和突触毒性，以及胶质细胞活化和星形胶质细胞增生。星形胶质细胞增生通过三重突触与突触功能相关，但星形胶质细胞也控制胶质递质和腺苷的可用性。在这里，我们将特别关注'腺苷假说的合并症'，这意味着星形胶质细胞激活，通过腺苷激酶（ADK）的过度表达，诱导腺苷的稳态紧张度的不足。我们从患者来源的样本中提供证据，显示星形胶质细胞增生和ADK过度表达是癫痫、AD、PD和ALS的常见病理标志。我们讨论了一个转基因的“共病模型”，其中ADK的全脑过度表达和由此产生的腺苷缺乏症产生共病谱癫痫发作，多巴胺能功能改变，注意力障碍，认知领域和睡眠调节的赤字。我们的结论是腺苷信号传导功能障碍是常见的神经系统疾病，腺苷功能障碍可以解释共病表型，治疗性腺苷增强可能是有效的治疗多种神经系统疾病的共病症状。
Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the ‘adenosine hypothesis of comorbidities’ implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic ‘comorbidity model’, in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain comorbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.