Effect of Cladribine on Neuronal Apoptosis: New Insight of In Vitro Study in Multiple Sclerosis Therapy

Abstract

Background: Cladribine (2-CdA) can cross the blood–brain barrier, resulting in inhibition of DNA synthesis and repair and disruption of cellular proliferation in actively dividing lymphocytes. No data on effect on neurons are available. Aim: To study “in vitro” 2-CdA apoptotic effects on neurons in healthy donor and multiple sclerosis patient lymphocytes. Methods: Neuroblastoma cells were co-cultured with lymphocytes, with and without 2-CdA. Results: Apoptosis increased in lymphocytes with 2-CdA; increase was also observed when lymphocytes were cultured with neuronal cells. However, neurons were not affected by 2-CdA for apoptosis. Conclusions: 2-CdA causes peripheral and central lymphocyte death preserving neurons, with a reasonable impact on inflammation and neuroprotection.

Real-Life Experience of the Effects of Cladribine Tablets on Lymphocyte Subsets and Serum Neurofilament Light Chain Levels in Relapsing Multiple Sclerosis Patients

“…Information regarding the CLAD effects on neuronal cells is scarce, though. In an Italian in vitro study [ 23 ], CLAD induced apoptosis in the lymphocytes of healthy donors and MS patients, but neuron vitality did not seem compromised either during acute or prolonged (72 h) exposure to the drug.…”

Cladribine treatment improves cortical network functionality in a mouse model of autoimmune encephalomyelitis

“…Ruggieri et al . [ 12 ] recently showed that neuronal apoptosis was not affected by cladribine treatment in vitro. However, they did not analyze the susceptibility of neurons to cladribine conditioned by their expression of DCK.…”

“…In addition, treatment with cladribine in patients with RMS is associated with a more pronounced preservation of brain tissue than would be expected from its effect on the immune system alone, raising the hypothesis that this drug also exhibits direct neuroprotective effects [11]. Indeed, data from the literature indicate that cladribine is widely active on CNS resident cells [12][13][14]. In this context, cladribine has been described to modify functional properties of activated microglia [14].…”

“…In vitro stimulation of these cells with cladribine did not affect cell viability, while it amplified the gene expression of both anti- and pro-inflammatory molecules [ 14 ]. Accordingly, cladribine did not affect the apoptosis rate in a human neuronal cell line [ 12 ]. Intrathecally administrated cladribine was further able to reverse EAE-associated synaptic alterations, also pointing towards a direct neuroprotective effect of this drug in MS [ 13 ].…”

Cladribine Tablets for Relapsing–Remitting Multiple Sclerosis: A Clinician’s Review

“…It is thought that B cells are one of the predominant drivers of immune responses within the CNS, with pathogenic B cells possessing the ability to act both centrally and peripherally [ 27 ]. Studies have indicated that cladribine has the potential to penetrate the CNS and achieve a concentration in the cerebrospinal fluid of up to 25% of its concentration in plasma [ 28 – 30 ], which raises the possibility that cladribine tablets may be able to reduce lymphocyte numbers within the CNS as well as those circulating in the periphery [ 31 , 32 ]. However, a need exists to better understand if the potential for direct effects of cladribine within the CNS are clinically significant in terms of additional benefits over and above treatment effects on peripheral immune cells [ 33 ].…”