Reduced levels of alpha-1-antitrypsin in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a novel approach for a potential treatment
Background
Amyotrophic lateral sclerosis (ALS) is an incurable, neurodegenerative motor neuron disease with devastating impact that relentlessly causes injury and death of the lower motor neurons in the brainstem and spinal cord and of the upper motor neurons in the motor cortex [1]. Patients experience signs and symptoms of progressive muscle atrophy and weakness, fatigue and dysphagia, and typically succumb to respiratory failure [2, 3]. The median survival period from the clinical onset to the fatal outcome ranges from 20 to 48 months. However, a relatively small group (10–20 %) of the patients survives more than 10 years [4]. ALS is most commonly a sporadic disease while 10–15 % of cases are familial [5]. The worldwide incidence of ALS is approximately 2–3 per 100,000 individuals [1], except for a few high-incidence foci, such as the Kii Peninsula and Guam [6].
Accumulating data support the notion that inflammatory processes are involved in ALS pathophysiology. Activation of microglia and astrocytes was demonstrated in both animal model and humans. Brain infiltration of both CD4+ and CD8+ T lymphocytes was shown in ALS patients [7]. Regulatory T lymphocytes number was found to be a prognostic factor both in animal models of ALS and in human patients affected by the disease [8]. Alterations in pro- and anti-inflammatory cytokines and growth factors such as IL-6, IL-10, GM-CSF, G-CSF, IL-2, IL-4, IL-8, IL12, IL-15, IL-17, IL-18, basic FGF, VEGF, and IFN-gamma were observed in CSF of ALS patients [9–12].
Apart from cytokines and growth factors, proteinase inhibitors play a central role in controlling inflammation. For instance, the serine proteinase inhibitor (serpin) alpha-1-antitrypsin (AAT) blocks neutrophil elastase and prevents pathological tissue disruption. Thus, its absence may lead to certain lung pathologies such as pulmonary emphysema, cystic fibrosis, and chronic obstructive lung disease [13]. In addition, the immuno-modulatory activities of AAT is expressed by controlling proinflammatory cytokine release [14], binding to complement C3 [15] and neutrophil functions [16]. Due to its anti-inflammatory properties, AAT is a drug candidate for various disorders including panniculitis, diabetes mellitus, rheumatoid arthritis, vasculitis, and fibromyalgia [13]. In view of the key function of AAT in controlling immunological response and inflammation, this study was aimed to quantitatively determine the levels of this protein and for comparing the pro-inflammatory cytokine IL-23, in CSF specimens of ALS patients and control group.