Guanosine reduces apoptosis and inflammation associated with restoration of function in rats with acute spinal cord injury

Abstract

Spinal cord injury results in progressive waves of secondary injuries, cascades of noxious pathological mechanisms that substantially exacerbate the primary injury and the resultant permanent functional deficits. Secondary injuries are associated with inflammation, excessive cytokine release, and cell apoptosis. The purine nucleoside guanosine has significant trophic effects and is neuroprotective, antiapoptotic in vitro, and stimulates nerve regeneration. Therefore, we determined whether systemic administration of guanosine could protect rats from some of the secondary effects of spinal cord injury, thereby reducing neurological deficits. Systemic administration of guanosine (8 mg/kg per day, i.p.) for 14 consecutive days, starting 4 h after moderate spinal cord injury in rats, significantly improved not only motor and sensory functions, but also recovery of bladder function. These improvements were associated with reduction in the inflammatory response to injury, reduction of apoptotic cell death, increased sparing of axons, and preservation of myelin. Our data indicate that the therapeutic action of guanosine probably results from reducing inflammation resulting in the protection of axons, oligodendrocytes, and neurons and from inhibiting apoptotic cell death. These data raise the intriguing possibility that guanosine may also be able to reduce secondary pathological events and thus improve functional outcome after traumatic spinal cord injury in humans.

Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway

“…Guanosine has been studied in a variety of experimental neuropathological contexts, including brain trauma [49], glucose deprivation, [29] pathological events involved in spinal cord injury [50], and seizures [14,27]; however, the precise mechanism of guanosine's neuroprotective effects is not completely understood. Some data support the existence of specific receptor-like binding sites for guanosine [17,51,52], and data also indicate that the extracellular effects of guanosine may involve the activation of intracellular signaling pathways, including the involvement of G proteins, MAPK, PI3K, and HO-1 [17,30,51,53,54].…”

Guanosine and its role in neuropathologies

“…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.…”

“…Taking into account that, in addition to its wellestablished neuroprotective activities, guanosine also stimulates regenerative processes in the CNS [15], various studies sought to investigate the potential of this nucleoside as a therapeutic intervention for the treatment of SCI. 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].…”

The Hydrolysis of Striatal Adenine- and Guanine-Based Purines in a 6-Hydroxydopamine Rat Model of Parkinson’s Disease

“…There is growing evidence to indicate that guanosine has a neuroprotective role in neurodegenerative processes due to anti-apoptotic, anti-inflamatory and neurotrophic effects, and also to its ability to prevent glutamate excitotoxicity by stimulating astrocytic glutamate uptake [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]55]. More importantly, it has already been shown that, in two different models of PD, the administration of guanosine can promote neuroprotection or, at least, reduce motor symptoms [24,26].…”