Remyelination after chronic spinal cord injury is associated with proliferation of endogenous adult progenitor cells after systemic administration of guanosine

Abstract

Axonal demyelination is a consistent pathological sequel to chronic brain and spinal cord injuries and disorders that slows or disrupts impulse conduction, causing further functional loss. Since oligodendroglial progenitors are present in the demyelinated areas, failure of remyelination may be due to lack of sufficient proliferation and differentiation of oligodendroglial progenitors. Guanosine stimulates proliferation and differentiation of many types of cells in vitro and exerts neuroprotective effects in the central nervous system (CNS). Five weeks after chronic traumatic spinal cord injury (SCI), when there is no ongoing recovery of function, intraperitoneal administration of guanosine daily for 2 weeks enhanced functional improvement correlated with the increase in myelination in the injured cord. Emphasis was placed on analysis of oligodendrocytes and NG2-positive (NG2+) cells, an endogenous cell population that may be involved in oligodendrocyte replacement. There was an increase in cell proliferation (measured by bromodeoxyuridine staining) that was attributable to an intensification in progenitor cells (NG2+ cells) associated with an increase in mature oligodendrocytes (determined by Rip+ staining). The numbers of astroglia increased at all test times after administration of guanosine whereas microglia only increased in the later stages (14 days). Injected guanosine and its breakdown product guanine accumulated in the spinal cords; there was more guanine than guanosine detected. We conclude that functional improvement and remyelination after systemic administration of guanosine is due to the effect of guanosine/ guanine on the proliferation of adult progenitor cells and their maturation into myelin-forming cells. This raises the possibility that administration of guanosine may be useful in the treatment of spinal cord injury or demyelinating diseases such as multiple sclerosis where quiescent oligodendroglial progenitors exist in demyelinated plaques.

Guanosine and its role in neuropathologies

“…Within this scenario, one study has demonstrated that repeated systemic administration of guanosine for a period of 2 weeks following SCI in rats (beginning 4 h post-injury) results in an improvement of sensory and motor function as well as a reduction in inflammation and apoptotic cell death, an effect probably attributable to its neuroprotective properties [107]. Importantly, in support of the idea that guanosine also stimulates regenerative processes [15], it has been shown that this nucleoside is able to induce functional recovery even when administered 5 weeks after SCI, an effect that is accompanied by the activation of endogenous cells from the oligodendrocyte lineage and remyelination of the surviving nerve fibers [108,168].…”

“…1), it is not surprising that this nucleoside was shown to be neuroprotective both in vitro and in vivo against a plethora of different insults, including excitotoxins [95,96], apoptosis induced by staurosporine [86], stress-induced oxidative damage [97], sepsis-induced cognitive impairment [98], hepatic encephalopathy [99], azide-induced oxidative damage [100], lipopolysaccharide (LPS)-induced inflammation [94], ischemic damage [63,101,102], toxicity induced by amyloid β peptide (Aβ) [91,103] as well as 1-methyl-4-phenylpyridinium (MPP + ) and 6-hydroxydopamine (6-OHDA) [36,[104][105][106], and spinal cord injury (SCI) [107,108]. Based on these studies, the modulation of the purinergic system has emerged as a therapeutic approach for the treatment of various neurological conditions, and guanosine in particular may be a therapeutic target for several of these neuropathologies.…”

Roles of NG2 glial cells in diseases of the central nervous system

“…On the one hand, lovastatin (HMG-CoA reductase inhibitor) [40] , glamorgan acetate [41] , guanosine or guanine [42] , ciliary neurotrophic factor [43] , thymosin β4 [44] , and endogenous leukemia inhibitory factor [45] , through different cascades of signal transduction, increase the numbers of NG2 cells and oligodendrocytes, and put an end to the demyelination process. The expression of platelet-derived growth factor α receptors (PDGFαRs) increases during the proliferation of NG2 cells, and NG2 proteoglycan expression disappears as NG2 cells differentiate into mature oligodendrocytes [46] .…”

Metabolism and Distribution of Guanosine Given Intraperitoneally: Implications for Spinal Cord Injury

“…This correlates with remyelination of denuded axons [9] due to proliferation of endogenous adult progenitor cells. [10] Since systemically administered purines are actively metabolized, [11,12] we questioned whether GUO acts peripherally by stimulating an unknown humoral effector that indirectly acts on the central nervous system (CNS), or whether GUO or a metabolic product crosses the blood-brain barrier and acts directly on cells in the CNS. Thus, we measured the distribution and metabolism of GUO after intraperitoneal (i.p.)…”