Effects of amantadine treatment on in vitro production of interleukin-2 in de-novo patients with idiopathic Parkinson's disease

Abstract

An involvement of immunological events in the process of neurodegeneration has frequently been reported. We investigated the cytokine producing capacity for interleukin-2 (IL-2), interferon-γ (IFN-γ) and interleukin-10 (IL-10) in whole blood cultures of de-novo patients with idiopathic Parkinson's disease (PD) at the time of first diagnosis and after oral amantadine treatment. Before treatment, productions of IL-2 and IFN-γ were markedly decreased in PD patients compared to patients with major depressive disorder and healthy controls. After amantadine treatment, the in vitro IL-2 secretion defect was corrected to normal levels in half of the patients, and the increase in IL-2 production was correlated with an increase in IFN-γ secretion. Our findings suggest that immunological abnormalities occur in the course of PD and that a formerly unappreciated therapeutic potential of amantadine may arise from its immunomodulatory effects on altered T cell function in patients with PD.

Introduction

Amantadine, a drug originally licensed to treat influenza A infections (Dolin et al., 1982), has been used for decades in the treatment of Parkinsonism, and idiopathic Parkinson's disease (PD) in particular (Lang and Blair, 1989). Although most Parkinsonian patients experience symptomatic improvement upon treatment, the exact mechanism of action remains a point of speculation. Most recently, the amelioration of levodopa-induced motor complications in advanced PD has been linked to possible antagonistic effects at the N-methyl-d-aspartate (NMDA) receptor (Adler et al., 1997; Verhagen Metman et al., 1998). Apart from this, the prolonged survival observed in PD patients with long term amantadine treatment suggests that the drug might have other, as yet unappreciated, therapeutic potentials (Uitti et al., 1996).

There is increasing evidence for a possible involvement of immune mechanisms in the etiopathogenesis of PD. Both peripheral and central disturbances in cellular or humoral immune functions have been reported in PD patients (Fiszer et al., 1994; Kuhn and Müller, 1995; Mogi et al., 1996a). Recently, we described a defective production of interleukin-2 (IL-2) in peripheral blood mononuclear cells (PBMC) of PD patients (Klüter et al., 1995). Interestingly, in the patients examined, previous oral amantadine treatment correlated significantly with higher IL-2 secretion, suggesting an immunomodulatory potential for the drug. Cytokines are soluble polypeptide mediators that control the growth, differentiation and function of most cell types and play a particular role as mediators of the immune system. In the CNS, these molecules are involved both in the normal development of the brain as well as in pathophysiological processes following injury and neurodegeneration (Zhao and Schwartz, 1998). The role of IL-2 is of particular interest since it has been hypothesized to be a modulator of striatal dopaminergic functions and implicated in the pathogenesis of several neuropsychiatric disorders involving the dopamine system, e.g., schizophrenia and PD (McAllister et al., 1995: Petitto et al., 1997).

We undertook a prospective study in order to examine the lymphokine producing capacity for IL-2, interleukin-10 (IL-10) and interferon-γ (IFN-γ) in PBMC from a series of drug free, newly diagnosed patients with idiopathic PD and to determine the long-term effects of oral amantadine treatment on cytokine synthesis.