ABSTRACT
Inositol monophosphatase (IMPase), a cytoplasmic enzyme that hydrolyses inositol monophosphates to produce inositol is also found in the cerebrospinal fluid (CSF). Since levels of inositol have been previously reported to be elevated in Down syndrome (DS) CSF, IMPase activity was measured in CSF of DS subjects to establish whether altered inositol levels may be related to changes in IMPase activity. In addition, and to better understand the regulation of IMPase expression in the CSF, enzyme activity was measured in normal aging, patients with Alzheimer-type or multi-infarct dementia (DAT and MID, respectively) and in CSF obtained by repeat lumbar puncture or from sequential aliquots of CSF from along the rostro-caudal axis. IMPase activity was relatively constant in CSF obtained from repeated lumbar puncture and there was no significant rostro-caudal gradient of activity in either normal or DS subjects, indicating that the enzyme originates from both brain and spinal cord. Compared to respective age-matched normal subjects, CSF IMPase activity was unaltered in DS, DAT and MID. However, in normal volunteers there was a significant positive correlation between age and CSF IMPase activity. Furthermore, there were significant correlations between CSF IMPase activity and acetylcholinesterase and butyrylcholinesterase activities and total protein, suggesting co-regulation of these parameters within the CSF.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/enzymology , Down Syndrome/cerebrospinal fluid , Down Syndrome/enzymology , Phosphoric Monoester Hydrolases/cerebrospinal fluid , Acetylcholinesterase/cerebrospinal fluid , Adult , Age Factors , Aged , Aged, 80 and over , Analysis of Variance , Butyrylcholinesterase/cerebrospinal fluid , Enzyme Activation , Female , Humans , Male , Middle Aged , Observer Variation , Prospective Studies , Regression Analysis , Spinal Puncture/statistics & numerical data , Time FactorsABSTRACT
BACKGROUND: Inositol monophosphatase (IMPase) is a key enzyme in the regulation of the activity of the phosphatidyl inositol (PI) signaling pathway. This enzyme is also found in the cerebrospinal fluid (CSF), where it may prove useful as a marker of dysfunctional PI signal transduction. METHODS: IMPase activity was measured in lumbar CSF of depressed and neuroleptic-treated schizophrenic patients. In addition, and to gain an insight into the factors that influence the levels of CSF IMPase, enzyme activity was measured in subgroups of schizophrenic patients treated for 3-7 days with lithium or 7 days with inositol. RESULTS: CSF IMPase activity was significantly increased by 88% in depressed and by 172% in schizophrenic patients relative to control subjects. Lithium produced a marked increase in CSF IMPase activity in the group as a whole, and this group effect could be more specifically attributed to 3 of the 8 individuals in whom enzyme activity increased by over 300%. On the other hand, inositol had no effect on CSF IMPase activity. CONCLUSIONS: In the absence of a clear relationship between CSF IMPase activity and neuronal PI signaling pathways it is not possible to correlate these changes with altered neuronal function. Nevertheless, increased CSF IMPase activity in depression and schizophrenia may be a marker of the pathophysiological processes underlying these disorders. Moreover, the large lithium-induced increase in IMPase activity seen in a subgroup of schizophrenic subjects suggests a differential regulation of CSF enzyme activity in these patients.
Subject(s)
Antipsychotic Agents/therapeutic use , Depressive Disorder/enzymology , Lithium/therapeutic use , Phosphoric Monoester Hydrolases/cerebrospinal fluid , Schizophrenia/enzymology , Depressive Disorder/cerebrospinal fluid , Female , Humans , Male , Middle Aged , Schizophrenia/cerebrospinal fluid , Schizophrenia/drug therapy , Signal Transduction/physiologyABSTRACT
Inositol monophosphatase (IMPase) has been identified and characterized in human lumbar cerebrospinal fluid (CSF). The CSF enzyme has a Km for inositol 1-phosphate (Ins(1)P; 0.12 mM), a magnesium dependence (optimum concentration 10 mM) and a sensitivity to inhibition by either the bisphosphonate inhibitor 1-(4-hydroxyphenyloxy)ethane-1,1-bisphosphonic acid (L-690,330) or LiCl (IC50's: 1.3 microM and 1.6 mM, respectively) similar to native human brain and human recombinant enzymes. In CSF, antiserum raised against purified bovine brain IMPase recognised a protein of 30 kDa, identical to that seen in human brain homogenate. It remains to be determined whether CSF IMPase activity may be a useful in vivo marker of CNS phosphatidyl inositol cycle activity in disorders where this signalling pathway may be altered (e.g. manic depression).
