Queensland Health, Gold Coast Population Health Unit, Southport, Gold Coast, Queensland, Australia.
Neuropsychiatr Dis Treat. 2009;5:81-9. Epub 2009 Apr 8.
Neuropsychiatric symptoms occur in a number of neurological fatigue-related conditions including multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and chronic fatigue syndrome (CFS). These conditions have been attributed variably to neuroinflammatory and neurodegenerative processes. While autoimmune pathology, at least in part, has long been suspected in these conditions proof has been elusive. Autoimmune pathomechanisms affecting the blood-brain barrier (BBB) or blood-spinal barrier (BSB) may predispose the BBB/BSB to 'leakiness' and be a precursor to additional autoimmune events resulting in neuroinflammatory or neurodegenerative processes. The aim of the paper is to postulate immunopathology of the cerebrospinal perivascular compartment involving certain vasoactive neuropeptides, specifically pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), in the etiology of certain neuropsychiatric fatigue-related conditions such as MS, ALS, PD, and CFS. Vasoactive neuropeptides (VNs) such as PACAP and VIP have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, and immune and nociception modulators. PACAP and VIP are widely distributed in the central nervous system (CNS) and have key roles in CNS blood vessels including maintaining functional integrity of the BBB and BSB. Autoimmunity affecting these VNs would likely have a detrimental effect on BBB and BSB functioning arguably predisposing to further pathological processes. Virchow-Robin spaces (VRS) are perivascular compartments surrounding small vessels within the CNS which contribute to the BBB and BSB integrity and contain PACAP and VIP receptors. Autoimmunity of these receptors would likely affect BBB and VRS function and therefore may contribute to the etiology of these conditions by affecting CNS and immunological homeostasis, including promoting neuropsychological symptomatology. PACAP and VIP, as potent activators of adenylate cyclase (AC), have a key role in cyclic adenosine monophosphate (cAMP) production affecting regulatory T cell (Treg) and other immune functions. Phosphodiesterase enzymes (PDEs) catalyze cAMP and PDE inhibitors (PDEIs) maintain cAMP levels and have proven and well known therapeutic benefit in animal models such as experimental allergic encephalomyelitis (EAE). Therefore PDEIs may have a role in therapy for certain neuropsychiatric fatigue-related conditions.
神经精神症状发生在许多与神经疲劳相关的疾病中，包括多发性硬化症（MS）、帕金森病（PD）、肌萎缩侧索硬化症（ALS）和慢性疲劳综合征（CFS）。这些疾病的发病机制各不相同，包括神经炎症和神经退行性过程。虽然自身免疫病理学在这些疾病中至少部分存在已经有很长时间了，但一直难以证实。影响血脑屏障（BBB）或血脊髓屏障（BSB）的自身免疫机制可能使 BBB/BSB 易于“渗漏”，并成为导致神经炎症或神经退行性过程的其他自身免疫事件的前兆。本文的目的是推测涉及某些血管活性神经肽的脑脊液血管周围间隙的免疫病理学，特别是垂体腺苷酸环化酶激活多肽（PACAP）和血管活性肠肽（VIP），在某些与神经疲劳相关的疾病（如 MS、ALS、PD 和 CFS）的发病机制中的作用。血管活性神经肽（VNs），如 PACAP 和 VIP，作为神经递质、血管扩张剂（包括灌注和缺氧调节剂）以及免疫和伤害感受调节剂发挥着关键作用。PACAP 和 VIP 在中枢神经系统（CNS）中广泛分布，在 CNS 血管中发挥关键作用，包括维持 BBB 和 BSB 的功能完整性。影响这些 VNs 的自身免疫可能对 BBB 和 BSB 的功能产生不利影响，从而可能导致进一步的病理过程。Virchow-Robin 空间（VRS）是 CNS 中小血管周围的血管周围间隙，有助于 BBB 和 BSB 的完整性，并包含 PACAP 和 VIP 受体。这些受体的自身免疫可能会影响 BBB 和 VRS 的功能，因此可能通过影响 CNS 和免疫稳态，包括促进神经心理学症状，从而有助于这些疾病的发病机制。PACAP 和 VIP 作为腺苷酸环化酶（AC）的有效激活剂，在环磷酸腺苷（cAMP）的产生中发挥关键作用，影响调节性 T 细胞（Treg）和其他免疫功能。磷酸二酯酶酶（PDEs）催化 cAMP，而 PDE 抑制剂（PDEIs）维持 cAMP 水平，并在实验性变态反应性脑脊髓炎（EAE）等动物模型中证明具有良好的治疗益处。因此，PDEIs 可能在某些与神经疲劳相关的疾病的治疗中发挥作用。
