Downregulation of Glial Scarring after Brain Injury: The Effect of Purine Nucleoside Analogue Ribavirin

Abstract

The weak regenerative capacity of self-repair after injury to the adult brain is caused by the formation of glial scar due to reactive astrogliosis. In the present study the beginning of reactive astrogliosis in the adult, as shown immunocytochemically by upregulation of glial fibrillary acidic protein (GFAP) and vimentin, was seen two days after the left sensorimotor cortex lesion, being maximal during the first two weeks and declining by 30 days after the lesion. This was accompanied by intensive glial scarring. Conversely, after the neonatal lesion a lack of gliotic scar was seen until 30 days postsurgery, although the pattern of GFAP and vimentin expression during recovery period was the same. The aim of the study was to define an appropriate therapeutic intervention that could modulate astrocyte proliferation and diminish glial scar formation after adult brain lesion. For this purpose the effects of an antiproliferative agent, the purine nucleoside analogue ribavirin was examined. It was shown that daily injection of ribavirin for 5 and 10 days considerably decreased the number of reactive astrocytes, while slight GFAP labeling was restricted to the lesion site. Obtained results show that ribavirin treatment downregulates the process of reactive astrogliosis after adult brain injury, and thus may be a useful approach for improving neurological recovery from brain damage.

The Effect of Ribavirin on Reactive Astrogliosis in Experimental Autoimmune Encephalomyelitis

“…In addition, it has been shown to arrest the cell cycle in the G0/ G1 phase and induce cell differentiation and growth suppression (16). These data are consistent with formerly published reports that ribavirin down-regulates process of reactive astrogliosis after brain injury (29).…”

“…IMPDH inhibition leads to depletion of the guanylate and ATP pools (14). Therefore, by depleting the intracellular content of guanosine nucleotides, ribavirin can act as a powerful proliferation inhibitor in proliferating cell types (16), including astrocytes (29). In addition, it has been shown to arrest the cell cycle in the G0/ G1 phase and induce cell differentiation and growth suppression (16).…”

Brain injury induces cholesterol 24-hydroxylase (Cyp46) expression in glial cells in a time-dependent manner

“…Surgical procedure Ablation of the rat sensorimotor cortex was performed as described previously (Pekovic et al 2005). Prior to the surgery animals were anesthetized with intraperitoneal injection of ZoletilÒ50 (Virbac, France) in the dose of 50 mg/kg body weight.…”

“…Recruitment and activation of all these cells limits neuronal degeneration and spreading of the lesion and ultimately results in a glial scar formation (Myer et al 2006). Previously, we have shown (Vasic et al 1998;Pekovic et al 2005; that after ablation of the sensorimotor cortex in neonatal rats, reactive astrocytes were concentrated around the wound, but did not make a glial scar at the lesion site until the 30th day post-lesion. In addition, functional recovery was better in neonates than in adults, where intensive reactive astrogliosis was followed by the appearance of a glial scar 2 weeks after the ablation.…”

“…Additionally, CNS damage can activate resident microglia, which undergoes morphological and functional changes and transforms into amoeboid brain macrophages. Astrocytes are also activated after the CNS injury (Wang and Bordey 2008;Pekovic et al 2005Pekovic et al , 2006. Recruitment and activation of all these cells limits neuronal degeneration and spreading of the lesion and ultimately results in a glial scar formation (Myer et al 2006).…”