Increased cerebrospinal fluid adenosine 5'-triphosphate in patients with amyotrophic lateral sclerosis

Abstract

Background Extracellular adenosine 5'-triphosphate (ATP) has been suggested to cause neuroinflammation and motor neuron degeneration by activating microglia and astrocytes in amyotrophic lateral sclerosis (ALS). Since we have developed a highly sensitive ATP assay system, we examined cerebrospinal fluid (CSF) ATP levels in patients with ALS whether it can be a useful biomarker in ALS. Methods Forty-eight CSF samples from 44 patients with ALS were assayed for ATP with a newly established, highly sensitive assay system using luciferase luminous reaction. CSF samples from patients with idiopathic normal pressure hydrocephalus (iNPH) were assayed as a control. Patients were divided into two groups depending on their disease severity, as evaluated using the Medical Research Council (MRC) sum score. Correlations between the CSF ATP levels and other factors, including clinical data and serum creatinine levels, were evaluated. Results CSF ATP levels were significantly higher in patients with ALS than in the iNPH (716 ± 411 vs. 3635 ± 5465 pmol/L, p < 0.01). CSF ATP levels were significantly higher in the more severe group than in the iNPH group (6860 ± 8312 vs. 716 ± 411 pmol/L, p < 0.05) and mild group (6860 ± 8312 vs. 2676 ± 3959 pmol/L, p < 0.05) respectively. ALS functional rating scale-revised (ALSFRS-R) (37.9 ± 5.7 vs. 42.4 ± 2.8, p < 0.01) and serum creatinine levels (0.51 ± 0.13 vs. 0.68 ± 0.23 mg/dL, p < 0.05) were significantly lower in the severe group than in the mild group respectively. A negative correlation of CSF ATP levels with MRC sum score was demonstrated in the correlation analysis adjusted for age and sex (r = -0.3, p = 0.08). Conclusions Extracellular ATP is particularly increased in the CSF of patients with advanced ALS. CSF ATP levels may be a useful biomarker for evaluating disease severity in patients with ALS.

Purinergic P2X7 Receptor: A Therapeutic Target in Amyotrophic Lateral Sclerosis

“…In advanced ALS patients, there is a significant increase in extracellular ATP in CSF samples compared to non-ALS controls . In conjunction, the P2X 7 R is upregulated on activated microglial cells from post-mortem ALS spinal cord specimens, presumably representing the end stage of disease .…”

Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders

“…On the other hand, increased ATP levels in ALS patients CSF were measured [ 129 ]. Importantly, Apolloni et al demonstrated that the antagonism of P2X7 receptor in a SOD1-G93A mouse model of ALS ameliorates the early symptomatic phase of the disease by reducing microglia-related pro-inflammatory markers and autophagy [ 130 ].…”

Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders

“…On the other hand, increased ATP levels in ALS patients CSF were measured [125]. Importantly, Apolloni et al demonstrated that the antagonism of P2X7 receptor in a SOD1-G93A mouse model of ALS ameliorates the early symptomatic phase of the disease by reducing microglia-related pro-inflammatory markers and autophagy [126].…”