Plasminogen activation in multiple sclerosis and other neurological disorders

Abstract Recent studies have implicated tissue-type plasminogen activator (tPA) in neurodegenerative conditions. A role in synaptic remodelling has been suggested for tPA, since elevated mRNA and protein levels were detected in the neuronal cells of mice trained to negotiate a pegged runway. tPA has also been implicated in the failure of neuronal survival in the presence of excitotoxic challenge. Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) of largely unknown aetiology, affecting young and middle-aged adults. The myelin sheaths surrounding nerves in the brain and spinal cord are damaged, which affects the function of the nerves involved. The disease affects different parts of the brain and spinal cord, resulting in typically scattered symptoms. Elevated activities of cerebrospinal fluid (CSF) tPA have been found in neurological patients when compared with reference subjects: MS > leukaemia > encephalitis. The PAI-1 levels were the reverse of tPA activities: leukaemia > encephalitis > MS. Samples with quantifiable CSF uPA levels also had high levels of PAI-1 in the same order: leukaemia > encephalitis > MS, both for uPA and PAI-1. Reduced plasminogen concentrations and plasmin-α2-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 foamy macrophages in demyelinating plaques, have been found. While normal tPA levels may be of physiological benefit to the brain and in selected conditions even therapeutic, exaggerated levels may result in tissue damage. This review covers current knowledge of MS, and plasminogen activation in MS and some neurological disorders such as encephalitis and leukaemia.