Murugan Madhuvika, Boison Detlev
Adenosine is an endogenous anticonvulsant, which is inversely linked to the expression levels of adenosine kinase (ADK), a ribokinase that metabolizes adenosine into AMP. ADK exists as two distinct isoforms, with unique cellular compartmentalization and functions. The short isoform (ADK-S) is localized primarily in the cytoplasm of astrocytes, where it controls, in conjunction with equilibrative adenosine transporters, the extracellular levels of adenosine and hence adenosine receptor-mediated mechanisms. On the other hand, the long isoform of ADK (ADK-L) is localized in the nucleus of astrocytes and a subset of neurons, where it regulates adenosine receptor independent epigenetic mechanisms. Overexpression of ADK-S was sufficient to generate spontaneous electrographic seizures, whereas increased ADK-L has been associated with epileptogenesis. Hence, targeting specific ADK isoforms is a rational approach for the suppression of seizures and the development of epilepsy. Systemic adenosine augmentation therapies are effective in seizure suppression, although accompanied by widespread cardiovascular side effects. The refinement of therapeutic administration strategies, the development of isoform-specific ADK inhibitors, or a combination of the two, will enable the formulation of more selective therapies for epilepsy and its prevention. Therapeutic tools to achieve focal adenosine augmentation, such as engineered stem cells and silk-based polymers, demonstrate robust protection from induced and spontaneous seizures. Metabolic therapies such as the ketogenic diet therapy have also been indicated to prevent disease progression via epigenetic mechanisms mediated by ADK. Small-molecule, ADK isoform-specific inhibitors are now in development with the goal to translate ADK-based therapies into clinical applications.
腺苷是一种内源性抗惊厥剂，它与腺苷激酶（ADK）的表达水平呈负相关，ADK是一种将腺苷代谢为AMP的核糖激酶。ADK以两种不同的同工型存在，具有独特的细胞区室化和功能。短同工型（ADK-S）主要定位于星形胶质细胞的细胞质中，在那里它与平衡型腺苷转运体共同控制细胞外腺苷水平，从而控制腺苷受体介导的机制。另一方面，ADK的长同工型（ADK-L）定位于星形胶质细胞和一部分神经元的细胞核中，在那里它调节与腺苷受体无关的表观遗传机制。ADK-S的过表达足以引发自发性脑电图癫痫发作，而ADK-L的增加与癫痫发生有关。因此，靶向特定的ADK同工型是抑制癫痫发作和预防癫痫发展的合理方法。全身性腺苷增强疗法在抑制癫痫发作方面有效，尽管伴有广泛的心血管副作用。改进治疗给药策略、开发同工型特异性ADK抑制剂或两者结合，将能够制定更具选择性的癫痫治疗和预防方法。实现局部腺苷增强的治疗工具，如工程干细胞和丝基聚合物，对诱导性和自发性癫痫发作具有强大的保护作用。生酮饮食疗法等代谢疗法也已被证明可通过ADK介导的表观遗传机制预防疾病进展。目前正在开发小分子、ADK同工型特异性抑制剂，目标是将基于ADK的疗法转化为临床应用。
