Effect of cytosine arabinofuranoside (AraC) on reactive gliosis in vivo. An immunohistochemical and morphometric study

Abstract

Glial reactivity is believed to contribute to the lack of functional recovery after injury to the mammalian central nervous system. The role of glial mitosis in the progression of events associated with reactive gliosis has received little attention. In the present study, the expression of reactive gliosis distal to the site of crush in rat optic nerves was assessed in the presence and absence of a chronically administered mitotic inhibitor, cytosine arabinofuranoside (AraC). Right optic nerves were crushed and animals sacrificed 1, 2 or 3 weeks later. Parameters assessed were (1) glial hypertrophy, (2) degradation of myelin sheaths and (3) ability of tissue to stain with antisera raised against glial filament protein (GFA), actin and vimentin. In saline treated animals, greater than 90% of the myelin sheaths distal to the site of axonal injury had degraded within 7 days post-operatively. Glial hypertrophy was evident by the second week after after crush and increased progressively. The number of GFA-positive profiles (i.e., cells) increased between 1 and 3 weeks postoperatively. Vimentin staining increased 4-fold between 1 and 2 weeks after injury and subsequently showed no change. Actin staining rose 3-fold between 1 and 2 weeks after injury, but decreased by the third postoperative week. In AraC treated animals, almost 50% of the myelin sheaths distal to the injury site were preserved a week after surgery. A delay in myelin degradation continued until the second postoperative week. Glial hypertrophy was evident at the 2 and 3 week time points. However, the extent of hypertrophy was substantially lower in drug (vs saline) treated animals. Vimentin staining never rose above minimal levels in AraC treated animals. Actin staining in AraC rats at 2 weeks postoperatively was equivalent to that in saline injected animals, but in contrast to the results in the latter group, increased (3-fold) between 2 and 3 weeks after crush. Results indicate a delay in the expression of reactive gliosis with chronic administration of AraC. It is proposed that this might be due to a delay in the appearance of ‘signals’ (e.g., myelin debris) which initiate the process of reactive gliosis.