Glatiramer acetate induces pro-apoptotic mechanisms involving Bcl-2, Bax and Cyt-c in peripheral lymphocytes from multiple sclerosis patients.

Abstract

Apoptotic deletion of autoreactive T-cells is defective in patients with multiple sclerosis (MS). Glatiramer acetate (GA) treatment seems to restore apoptosis of detrimental T-cells. We analyzed the mitochondria membrane pro- (Bax) and anti-apoptotic (Bcl- 2) and cytosolic pro-apoptotic (Cyt-c, APAF-1) proteins expression in peripheral lymphocytes from relapsing-remitting (RR) MS patients during GA treatment. Blood samples were collected from 8 healthy controls (HCs) and from 8 RR MS patients prior to and every three months during the 9 months of GA treatment. Peripheral blood mononuclear cells (PBMNCs) Bcl-2, Bax, Cyt-c and APAF-1 were quantified by western blot followed by densitometric scanning and Bax/Bcl-2, cytosolic Cyt-c/Bcl-2 and APAF-1/Bcl-2 ratios were calculated. T-cells were in vitro tested for oxygen consumption by a respirometric analysis. Bax/Bcl-2, cytosolic Cyt-c/Bcl-2 and APAF-1/Bcl-2 ratios in untreated MS patients were significantly (p < 0.05) lower than in HCs. Bax/Bcl-2 ratio increased (p = 0.03) and Cyt-c/Bcl-2 ratio showed a trend to increase during the 9 months of GA treatment in MS patients. A reduction of 58% and 59% in oxygen consumption by PBMNCs was evident after GA treatment in vitro or when GA treated patients' cells were compared with those from HCs, respectively. Our findings suggest that GA exerts a regulatory effect on peripheral T lymphocytes through pro-apoptosis mechanisms involving mitochondria and cytosolic proteins.

• Authors: M Ruggieri, C Avolio, S Scacco, C Pica, A Lia, G B Zimatore, S Papa, P Livrea, M Trojano
• Journal: Journal of neurology (J Neurol) Vol. 253 Issue 2 Pg. 231-6 (Feb 2006) ISSN: 0340-5354 [Print] Germany
• PMID: 16184340 (Publication Type: Comparative Study, Journal Article)

Chemical References

• APAF1 protein, human
• Apoptosis Regulatory Proteins
• Apoptotic Protease-Activating Factor 1
• Immunosuppressive Agents
• Intracellular Signaling Peptides and Proteins
• Peptides
• Proteins
• Proto-Oncogene Proteins c-bcl-2
• Uncoupling Agents
• bcl-2-Associated X Protein
• Rotenone
• Carbonyl Cyanide m-Chlorophenyl Hydrazone
• Glatiramer Acetate
• Cytochromes c

Topics

• Adult
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Apoptotic Protease-Activating Factor 1
• Blotting, Western (methods)
• Carbonyl Cyanide m-Chlorophenyl Hydrazone (pharmacology)
• Case-Control Studies
• Cytochromes c (metabolism)
• Female
• Glatiramer Acetate
• Humans
• Immunosuppressive Agents (administration & dosage)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Lymphocytes (drug effects, pathology)
• Male
• Middle Aged
• Multiple Sclerosis (drug therapy, pathology)
• Oxygen Consumption (drug effects)
• Peptides (administration & dosage)
• Proteins (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rotenone (pharmacology)
• Statistics, Nonparametric
• Time Factors
• Uncoupling Agents (pharmacology)
• bcl-2-Associated X Protein (metabolism)