Plasminogen activation in multiple sclerosis and other neurological disorders

Recent studies have implicated tissue-type plasminogen activator (tPA) in n eurodegenerative conditions. A role in synaptic remodelling has been sugges ted for tPA, since elevated mRNA and protein levels were detected in the ne uronal cells of mice trained to negotiate a pegged runway. tPA has also bee n implicated in the failure of neuronal survival in the presence of excitot oxic challenge. Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) of largely unknown aetiology, affecting young and mid dle-aged adults. The myelin sheaths surrounding nerves in the brain and spi nal cord are damaged, which affects the function of the nerves involved. Th e disease affects different parts of the brain and spinal cord, resulting i n typically scattered symptoms. Elevated activities of cerebrospinal fluid (CSF) tPA have been found in neurological patients when compared with refer ence subjects: MS > leukaemia > encephalitis. The PAI-1 levels were the rev erse of tPA activities: leukaemia > encephalitis > MS. Samples with quantif iable CSF uPA levels also had high levels of PAI-1 in the same order: leuka emia > encephalitis > MS, both for uPA and PAI-1. Reduced plasminogen conce ntrations and plasmin-alpha(2)-antiplasmin (PAP) complexes have been found in the CSF of MS patients. In MS brain, an increased expression of tPA mRNA and protein in neurons, mononuclear cells within perivascular cuffs, and f oamy macrophages in demyelinating plaques, have been found. While normal tP A levels may be of physiological benefit to the brain and in selected condi tions even therapeutic, exaggerated levels may result in tissue damage. Thi s review covers current knowledge of MS, and plasminogen activation in MS a nd some neurological disorders such as encephalitis and leukaemia. (C) Harc ourt Publishers Ltd 2000.