Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment.
Peroxisomes are ubiquitous subcellular organelles and abnormality in their biogenesis and specific gene defects leads to fatal demyelinating disorders. We report that neuroinflammatory disease in brain of experimental autoimmune encephalomyelitis (EAE) rats decreased the peroxisomal functions. Degradation of very long chain fatty acids decreased by 47% and resulted in its accumulation (C26:0, 40%). Decreased activity (66% of control) of dihydroxyacetonephosphate acyltransferase (DHAP-AT), first enzyme in plasmalogens biosynthesis, resulted in decreased levels of plasmalogens (16-30%). Catalase activity, a peroxisomal enzyme, was also reduced (37%). Gene microarray analysis of EAE spinal cord showed significant decrease in transcripts encoding peroxisomal proteins including catalase (folds 3.2; p<0.001) and DHAP-AT (folds 2.6; p<0.001). These changes were confirmed by quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis, suggesting that decrease of peroxisomal functions in the central nervous system will have negative consequences for myelin integrity and repair because these lipids are major constituents of myelin. However, lovastatin (a cholesterol lowering and anti-inflammatory drug) administered during EAE induction provided protection against loss/down-regulation of peroxisomal functions. Attenuation of induction of neuroinflammatory mediators by statins in cultured brain cells [J. Clin. Invest. 100 (1997) 2671-2679], and in central nervous system of EAE animals and thus the EAE disease [J. Neurosci. Res. 66 (2001) 155-162] and the studies described here indicate that inflammatory mediators have a marked negative effect on peroxisomal functions and thus on myelin assembly and that these effects can be prevented by treatment with statins. These observations are of importance because statins are presently being tested as therapeutic agents against a number of neuroinflammatory demyelinating diseases.
Singh
Inderjit
I
Department of Pediatrics, Medical University of South Carolina, 171 Ashley Avenue, Charleston SC 29425, USA. singhi@musc.edu
Paintlia
Ajaib S
AS
Khan
Mushfiquddin
M
Stanislaus
Romesh
R
Paintlia
Manjeet K
MK
Haq
Ehtishamul
E
Singh
Avtar K
AK
Contreras
Miguel A
MA
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000074183:ATPases Associated with Diverse Cellular Activities; D042962:Acyl-CoA Oxidase / Q000235:genetics / Q000378:metabolism; D000217:Acyltransferases / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D002374:Catalase / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications / Q000517:prevention & control*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005620:Freund's Adjuvant; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control; D008148:Lovastatin / Q000627:therapeutic use*; D008565:Membrane Proteins / Q000378:metabolism; D046228:Microarray Analysis / Q000379:methods; D018901:Peroxisomal Disorders / Q000209:etiology / Q000517:prevention & control*; D020675:Peroxisomes / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D018528:ATP-Binding Cassette Transporters; C489272:Abcd3 protein, rat; D000924:Anticholesteremic Agents; D005227:Fatty Acids; D008565:Membrane Proteins; D012333:RNA, Messenger; D005620:Freund's Adjuvant; D008148:Lovastatin; D002374:Catalase; D042962:Acyl-CoA Oxidase; D000217:Acyltransferases; C020051:glycerone-phosphate O-acyltransferase; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C096998:Pex6 protein, rat