Roles of Adenosine Receptor (subtypes A 1 and A 2A ) in Cuprizone-Induced Hippocampal Demyelination.

Hippocampal demyelination in multiple sclerosis (MS) has been linked with cognitive deficits, however, patients could benefit from treatment that induces oligodendroglial cell function and promotes remyelination. We investigated the role of A 1 and A 2A adenosine receptors (AR) in regulating oligodendrocyte precursor cells (OPCs) and myelinating oligodendrocyte (OL) in the demyelinated hippocampus using the cuprizone model of MS. Spatial learning and memory were assessed in wild type C57BL/6 mice (WT) or C57BL/6 mice with global deletion of A 1 (A 1 AR-/-) or A 2A AR (A 2A AR-/-) fed standard or cuprizone diet (CD) for four weeks. Histology, immunofluorescence, Western blot and TUNEL assays were performed to evaluate the extent of demyelination and apoptosis in the hippocampus. Deletion of A 1 and A 2A AR alters spatial learning and memory. In A 1 AR-/- mice, cuprizone feeding led to severe hippocampal demyelination, A 2A AR-/- mice had a significant increase in myelin whereas WT mice had intermediate demyelination. The A 1 AR-/- CD-fed mice displayed significant astrocytosis and decreased expression of NeuN and MBP, whereas these proteins were increased in the A 2A AR-/- CD mice. Furthermore, Olig2 was upregulated in A 1 AR-/- CD-fed mice compared to WT mice fed the standard diet. TUNEL staining of brain sections revealed a fivefold increase in the hippocampus of A 1 AR-/- CD-fed mice. Also, WT mice fed CD showed a significant decrease expression of A 1 AR. A 1 and A 2A AR are involved in OPC/OL functions with opposing roles in myelin regulation in the hippocampus. Thus, the neuropathological findings seen in MS may be connected to the depletion of A 1 AR.