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

Abstract

Intraperitoneal administration of guanosine to rats with chronic spinal cord injury stimulates remyelination and functional recovery. If guanosine produced its effects in the nervous system, it should enter it and elevate endogenous concentrations. [(3)H]-guanosine (8 mg/kg) was administered intraperitoneally to rats and its distribution and concentration in different sites determined. Guanosine rapidly entered all tissues; its concentration peaked at about 15 minutes except in adipose tissue and CNS where it continued to rise for 30 minutes. Its chief metabolic product in all sites was guanine with over twice as much guanine as guanosine present in CNS after 30 minutes.

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

“…Together, these data reinforced the idea that the CSF may be a major source of distribution to the brain following IN administration while the purine levels after IP administration reflect blood levels. This hypothesis is reinforced by works of Jiang's group [19,20] that showed, using a mixture of unlabeled and labeled [ H] GUO than was used here), that GUO is promptly and markedly metabolic breakdown after systemic administration reflecting in an increase of GUO metabolites in the brain [25,26].…”

“…Blood plasma GUO and HYP levels were not possible to be detected due to its value not reaching the HPLC inferior detection limits (data not shown). This inability seems to be related specifically to the use of TFA 7 % in purines extraction protocol, as GUO plasma levels could be observed using different extraction compounds [7,16,25,26]. Notably, we chose TFA 7 % based on a pilot experiment which we tested different chemicals to homogenize brain tissue and blood samples to obtain the highest radioactivity extraction derived from [ 3 H] GUO (TCA 10 %, TFA 7 %, ACN, methanol, perchloric acid; data not shown).…”

“…Moreover, the interconversion among guanine-and adenine-based purines, such as ADO and its derivatives inosine (INO) and hypoxanthine (HYPO), plays an important role in maintaining purine homeostasis [23,24]. Therefore, a long systemic pathway could decrease the amount of GUO that reaches the brain by metabolization and/or uptake, consequently decreasing the effectiveness of the administered dose [25,26].…”

Guanosine and its role in neuropathologies

“…Within this context, it was observed that the plasmatic levels of guanosine increase in a dose-and timedependent manner following systemic administration [69]. Indeed, the basal plasmatic concentration of guanosine can double 90 min after intraperitoneal injection of this nucleoside, with maximum plasmatic levels of its metabolites (guanine, xanthine, and uric acid) being detected as soon as 15-30 min after administration [70]. Since the levels of these metabolites remain constant for up to 3 h after treatment, it is likely that this nucleoside has a prolonged half-life in the extracellular medium [29].…”

“…Given the rapid metabolism of purines, various studies sought to determine whether the neuroprotective properties of guanosine were indeed due to this nucleoside and not to the stimulation of an unknown humoral effector or metabolite of this nucleoside [69][70][71][72]. Within this context, it was observed that the plasmatic levels of guanosine increase in a dose-and timedependent manner following systemic administration [69].…”