Daniel Offen

Antibodies from ALS patients inhibit dopamine release mediated by L-type calcium channels

Objective: To examine the presence of anti-L-type calcium channel antibodies in the serum of ALS patients. Background: Autoimmunity has been hypothesized as one of the mechanisms underlying the pathogenesis of sporadic ALS. Previous studies reported that sera from patients with sporadic ALS contain antibodies against voltagegated calcium channels (L-type and P-type), but others do not support these findings. Methods: Regulated secretion of tritiated dopamine ([3H]DA) in PC12 cells in mediated exclusively by calcium entry through L-type calcium channels. To examine whether purified ALS immunoglobulin G (IgG) inhibits [3H]DA release by interfering with calcium entry through L-type calcium channels, evoked release in PC12 cells was determined in the presence of ALS IgG. This functional assay provides a sensitive way to examine L-type calcium channel interaction with IgG from ALS patients. Results: A significant inhibition of depolarization-evoked [3H]DA release (32 ± 4%) was observed by purified IgG from ALS patients compared with control subjects (11 ± 2%; p < 0.01). Significant inhibition by IgG occurred in 79% (15/19) of the ALS patients compared with only 29% (5/17) in the control group (p < 0.01). The level of calcium channel inhibition by ALS IgG correlated positively with disease duration (r = 0.68; p < 0.01) and correlated negatively with age (r = -0.48; p < 0.05). Conclusions: These results confirm the presence of antibodies against the L-type calcium channel in the majority of sera from ALS patients, supporting their role in the pathogenesis of ALS.

Chapter 13 – The Role of Oxidative Stress in the Pathogenesis of Multiple Sclerosis: Current State

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS), often beginning in late adolescence and early adult life. The etiology of MS has not yet been fully elucidated, and it is attributed to both genetic and environmental causes. Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of MS. Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of demyelination and axonal damage in both MS and its animal model: experimental autoimmune encephalomyelitis (EAE). ROS cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids, thereby resulting in cell death. Weakened cellular antioxidant defense systems in the CNS of MS patients resulting in increased vulnerability to ROS effects may increase CNS damage. This chapter reviews the current knowledge on OS in MS and possible antioxidant treatments.