Expression of the heparin-binding growth factor midkine in the cerebrospinal fluid of patients with neurological disorders

Objective This study was to clarify the roles of midkine (MK) in the brain. Methods We determined cerebrospinal fluid MK levels in patients with neurological disorders by enzymelinked immunoassay and immunostained autopsied brain samples in patients with meningitis. Results MK levels were 0.37 +/- 0.21 ng/ml in controls (n=46, mean +/- S. D.), 0.67 +/- 0.19 ng/ml in patients with cerebral infarction (n=8), 1.78 +/- 1.32 ng/ml in patients with meningitis (n=25; ANOVA and post-hoc Fisher's PLSD test, p < 0.0001), 0.31 +/- 0.25 ng/ml in patients with human T-lymphotrophic virus type I-associated myelopathy/tropical spastic paraparesis (n=29), and 0.42 +/- 0.17 ng/ml in patients with amyotrophic lateral sclerosis (n=8). The regression equations were Y=0.005X+0.498 (Y, CSF MK level; X, cell number) and Y=0.007X+0.326 (Y, MK level; X, protein level) for all CSF samples. Autopsy brain samples from patients with meningitis expressed MK weakly in mononuclear cells on immunohistochemical examination. Western blot and polymerase chain reaction analyses showed that leukocytes were MK positive. CSF MK levels were not high in patients with cerebral infarction but were increased in patients with meningitis. CSF MK levels were high in normal controls, compared to those of other cytokines. MK was expressed in choroid plexus of normal brain and released there. Conclusion Our findings suggested that MK may maintain normal adult brain as a neurotrophic factor, and that MK may be released from leucocytes in brain of patients with meningitis as an immunological mediator.