Systemic administration of guanosine promotes functional and histological improvement following an ischemic stroke in rats

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

“…Our data are in agreement with our previous work, which reported a correlation between oxidative stress parameters in the penumbra area (but not infarct volume) and functional recovery of animals submitted to ischemia treated with systemic GUO [12]. However, the wide time window for therapy with GUO seems to be an outstanding outcome particular to the IN route, as systemic GUO injection was efficient only when administered before or immediately after ischemia onset [11][12][13][14][15]. In summary, we showed in the present work that the IN route is an efficient route to promptly deliver the neuroprotective nucleoside GUO to the CNS.…”

“…In order to increase the therapeutic time window, neuroprotection is an alternative or adjunct approach to thrombolysis, targeting the cerebral parenchyma in the acute ischemic phase [41]. The neuroprotective effects of the nucleoside GUO have been demonstrated after systemic administration in ischemia models by our and other groups [11][12][13][14][15]. We recently showed, using the same permanent focal cerebral ischemia model used in the present work, that systemic GUO treatment started immediately after ischemia induction improved functional recovery of behavioral impairment, simultaneously preventing brain oxidative stress, modulating glutamatergic parameters, attenuating changes in the inflammatory system, thus decreasing neuronal degeneration in the penumbra area [11,12].…”

“…As GLU is the main excitatory neurotransmitter in the CNS, and excessive GLU signaling (excitotoxicity) is involved with several brain diseases [5,6], the neuroprotective potential of GUO against excitotoxicity has been investigated. Accordingly, the exogenous administration of GUO has shown neuroprotective effects on CNS injury in several animal models linked to excitotoxicity events, including models of dementia [7], seizures [8,9], neuropathic pain [10], stroke [11][12][13][14][15], and hepatic encephalopathy [16].…”

“…Certainly, GUO effects seem to be directly mediated by action on the brain, as intracerebroventricular or intracortical GUO infusion in experimental models of excitotoxicity have demonstrated neuroprotection [8,13]. Nevertheless, most of the neuroprotective effects exerted by GUO were observed after its systemic (intraperitoneal [IP] or oral) administration [7,[9][10][11][12][13][14][15][16]. In this regard, systemic administration routes present important limitations for protocols with endogenous drugs that aim to reach the brain but can be metabolized in the systemic pathway, which is the case for GUO.…”

Gliopreventive effects of guanosine against glucose deprivation in vitro

“…Guanosine is released from astrocytes and confers neuroprotective effects in several in vivo and in vitro studies [3,[6][7][8][9][10][11]. Guanosine can effectively protect cells against hypoxia [12,13], cytotoxicity induced by the β-amyloid peptide [14], chronic cerebral hypoperfusion [15], ischemic insults [16][17][18], and other glutamatergic excitotoxic damage, such as seizures that are induced by quinolinic acid [3,9,19,20] and methylmercury-induced oxidative stress [21]. Although there is increasing evidence showing the neuroprotective effects of guanosine on models of neurotoxicity, its mechanisms are not fully understood.…”