Nantwi Kwaku D, Goshgarian Harry G
Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, MI 48201, USA.
Neurol Res. 2005 Mar;27(2):195-205. doi: 10.1179/016164105X21977.
In adult rats, a latent respiratory motor pathway can be pharmacologically activated with 1,3-dimethylxanthine (theophylline) to restore respiratory-related activity to a hemidiaphragm paralysed by an ipsilateral upper cervical (C2) spinal cord hemisection. The purpose of this review is to describe mechanisms that underlie theophylline-induced recovery of respiratory-related function following C2 hemisection and to underscore the therapeutic potential of theophylline therapy in spinal cord injured patients with respiratory deficits.
Theophylline mediates recovery of respiratory-related activity via antagonism of central adenosine A(1) receptors. When administered chronically, the drug restores and maintains recovered function. Since theophylline is an adenosine receptor antagonist with affinity for both the adenosine A(1) and A(2) receptors, we assessed the relative contributions of each receptor to functional recovery. While A(1) receptor antagonism plays a predominant role, activation of the A(2) receptors by specific agonists subserves the A(1) receptor-mediated actions. That is, when an adenosine A(2) receptor agonist is administered first, it primes the system such that subsequent administration of the A(1) antagonist induces a greater degree of recovered respiratory activity than when the antagonist alone is administered.
Chronic oral administration of theophylline in C2 hemisected animals demonstrates that even when animals have been weaned from the drug, theophylline-induced recovered respiratory actions persist. This suggests that in clinical application, it may not be necessary to maintain patients on long-term theophylline. We have shown that recovery of respiratory-related activity in the ipsilateral phrenic nerve can occur spontaneously 3-4 months after C2 hemisection. Theophylline administration after this post-injury period obliterates/negates the recovery function. This indicates strongly that there is therapeutic window (more acutely after injury) for the initiation of theophylline therapy. We have also demonstrated that peripheral (carotid bodies) adenosine A(1) receptors can be selectively activated to modulate theophylline-induced CNS actions. Blocking central adenosine receptors while simultaneously activating peripheral adenosine receptors minimizes the potential of respiratory muscle fatigue with theophylline.
The significance of the current findings lies in the potential clinical application of theophylline therapy in spinal cord injured patients with respiratory deficits. The ultimate goal of theophylline therapy is to wean ventilator-dependent patients off ventilatory support. Thus far, our animal studies suggest that the onset of theophylline therapy must be soon after injury.
在成年大鼠中，可通过药理学方法用1,3 - 二甲基黄嘌呤（茶碱）激活一条潜在的呼吸运动通路，以使因同侧上颈段（C2）脊髓半横断而麻痹的半侧膈肌恢复与呼吸相关的活动。本综述的目的是描述C2半横断后茶碱诱导呼吸相关功能恢复的潜在机制，并强调茶碱疗法在有呼吸功能缺陷的脊髓损伤患者中的治疗潜力。
茶碱通过拮抗中枢腺苷A(1)受体介导呼吸相关活动的恢复。长期给药时，该药物可恢复并维持恢复的功能。由于茶碱是一种对腺苷A(1)和A(2)受体均有亲和力的腺苷受体拮抗剂，我们评估了每种受体对功能恢复的相对贡献。虽然A(1)受体拮抗起主要作用，但特定激动剂激活A(2)受体有助于A(1)受体介导的作用。也就是说，当先给予腺苷A(2)受体激动剂时，它会使系统致敏，使得随后给予A(1)拮抗剂时诱导的呼吸活动恢复程度比单独给予拮抗剂时更大。
在C2半横断动物中慢性口服茶碱表明，即使动物已停用该药物，茶碱诱导的呼吸活动恢复仍会持续。这表明在临床应用中，可能无需让患者长期服用茶碱。我们已表明，在C2半横断后3 - 4个月，同侧膈神经的呼吸相关活动可自发恢复。在此损伤后时期给予茶碱会消除/否定恢复功能。这强烈表明存在启动茶碱治疗的治疗窗（损伤后更急性期）。我们还证明，外周（颈动脉体）腺苷A(1)受体可被选择性激活以调节茶碱诱导的中枢神经系统作用。在阻断中枢腺苷受体的同时激活外周腺苷受体可将茶碱导致呼吸肌疲劳的可能性降至最低。
当前研究结果的意义在于茶碱疗法在有呼吸功能缺陷的脊髓损伤患者中的潜在临床应用。茶碱疗法的最终目标是使依赖呼吸机的患者脱离通气支持。迄今为止，我们的动物研究表明，茶碱治疗必须在损伤后不久开始。
