Abstract
Hyperhomocysteinemia plays a crucial role in the pathogenesis of many diseases of the central nervous system (CNS). The nervous system is particularly sensitive to high homocysteine (Hcy) level mainly due to its prooxidative and cytotoxic effects. Cladribine, a drug recently registered for the treatment of multiple sclerosis (MS), possesses additionally neuroprotective effects which are independent of its peripheral immunosuppressant action. Accumulating evidence suggests that oxidative stress and homocysteine thiolactone-mediated protein homocysteinylation play a causal role in MS. Both of these processes may be attenuated by paraoxonase 1 (PON1). Therefore, in the present study, we aimed to examine whether the beneficial effects of the drug in MS patients with a secondary progressive (SP) clinical course, treated with cladribine subcutaneously (s.c.), may be related to its ability to modify serum PON1 activity, Hcy concentration, and protein homocysteinylation, as well as to correct total antioxidant status. A total of 118 subjects were enrolled into the study: (1) patients with a SP type of MS, SP-MS (n = 40); (2) patients with a relapsing-remitting (RR) type of MS, RR-MS (n = 30); and (3) healthy people (n = 48). Patients with SP-MS were treated with cladribine. The drug was given in SP-SM patients s.c. six times every 6 weeks up to a total mean cumulative dose of 1.8 mg/kg. PON1 activity was assessed spectrophotometrically. The level of Hcy, homocysteine thiolactone (HTL) attached to plasma proteins (N-Hcy-protein), and antibodies against homocysteinylated proteins was assessed with an enzyme immunoassay. The total antioxidant activity of the serum was assessed with the ferric-reducing activity of plasma (FRAP) method. Basically, there was no difference in PON1 activity between untreated SP-MS, RR-MS, and control subjects. Serum Hcy was significantly higher in RR-MS patients (p < 0.001) and in SP-MS patients (p < 0.01) compared to the control group. The N-Hcy protein level was higher in RR-MS patients (p < 0.05) in comparison to the control group. Moreover, the elevated level of antibodies against homocysteinylated proteins was observed in the serum of patients with SP-MS. The total antioxidant capacity of serum was lower in MS patients vs. the control group (p < 0.001). After cladribine treatment, the activity of PON1 did not change in SP-MS patients, whereas cladribine treatment decreased the level of total Hcy (p < 0.05). Treatment with cladribine increased the total serum antioxidant activity in SP-MS patients (p < 0.01). The Expanded Disability Status Scale (EDSS) score did not change in SP-MS patients. Cladribine treatment in the SP-MS group attenuates hyperhomocysteinemia-induced protein homocysteinylation (n.s.). It also stabilises the neurological condition of SP-MS patients. The stabilisation of a neurological condition observed in SP-MS patients after cladribine treatment may be partially related to its ability to reduce elevated Hcy level and to improve serum antioxidant potential.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that affects predominantly young people
As cladribine may increase the level of oxidative stress, we studied the activity of paraoxonase 1 (PON1) in patients treated with cladribine
Serum PON1 activity toward paraoxon was not significantly different between groups; only a tendency to higher PON1 activity was observed in relapsing-remitting type of MS (RR-MS) patients than in secondary progressive (SP)-MS patients
Summary
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that affects predominantly young people It is associated with the development of disability and shortening of mean lifetime by about 10 years. A new drug, cladribine, has been launched in an oral form to the pharmaceutical market It has been registered by both FDA (Food and Drug Administration) and EMA (European Medicines Agency) for the treatment of a relapsing-remitting type of MS (RR-MS) on the basis of CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study [2] and by FDA for the treatment of an active secondary progressive type of MS (SP-MS) (https://www .fda.gov). Cladribine was used with good results in a parenteral form in phase II trials in progressive MS patients [3] It is a purine analogue, 2-chloro-2′-deoxyadenosine, 2Cda (C10H12CIN5O3), that was synthesized in the early 1980s and originally licensed as a chemotherapeutic agent to treat hairy cell leukaemia; it is used in B cell chronic lymphocytic leukaemia. In its subcutaneous (s.c.) form, it is bioavailable in 100% comparing to 42% of oral drug [4, 5]
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