Effects of intranasal guanosine administration on brain function in a rat model of ischemic stroke

Abstract

Ischemic stroke is a major cause of morbidity and mortality worldwide and only few affected patients are able to receive treatment, especially in developing countries. Detailed pathophysiology of brain ischemia has been extensively studied in order to discover new treatments with a broad therapeutic window and that are accessible to patients worldwide. The nucleoside guanosine (Guo) has been shown to have neuroprotective effects in animal models of brain diseases, including ischemic stroke. In a rat model of focal permanent ischemia, systemic administration of Guo was effective only when administered immediately after stroke induction. In contrast, intranasal administration of Guo (In-Guo) was effective even when the first administration was 3 h after stroke induction. In order to validate the neuroprotective effect in this larger time window and to investigate In-Guo neuroprotection under global brain dysfunction induced by ischemia, we used the model of thermocoagulation of pial vessels in Wistar rats. In our study, we have found that In-Guo administered 3 h after stroke was capable of preventing ischemia-induced dysfunction, such as bilateral suppression and synchronicity of brain oscillations and ipsilateral cell death signaling, and increased permeability of the blood-brain barrier. In addition, In-Guo had a long-lasting effect on preventing ischemia-induced motor impairment. Our data reinforce In-Guo administration as a potential new treatment for brain ischemia with a more suitable therapeutic window. Keywords Stroke . Guanosine Intranasal administration . Neuroprotection . Quantitative electroencephalogram . Blood-brain barrier . Cell signaling Muller, G.C is a MD and Phd student in Biochemistry. His main work is focused on neuroprotective effects of nucleoside Guanosine in stroke models.

Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy

“…To our knowledge, no studies have reported any major side effects of exogenously administered Guo in in vivo models [74,163,165]. Guo administered i.p did not impair renal function.…”

“…In the rat ischemia model (thermocoagulation of pial vessels), IN administration of Guo was able to attenuate neurological deficits when administered as late as 3 h after ischemia onset. Contrarily, using the systemic route, Guo-elicited neuroprotection could only be observed when administered immediately after stroke induction [163].…”

“…Moreover, Guo modulates processes, including neuroinflammation and microglia activation, which can be detrimental to virtually all cells found in the brain [84,87,90]. Thus, together with evidence of Guo affecting remote areas from the ischemic lesion, it can be theorized that Guo-mediated neuroprotective effects are expressed globally throughout the CNS [163].…”

“…The intranasal administration of Guo was studied in models of permanent focal cerebral ischemia [161,163]. One of the major advantages of IN over the systemic administration route was the rapid penetration to the CNS (5 min post-ischemia), wide distribution in the CSF, decreased influence of systemic metabolism, and lower effective dose.…”

“…Notably, the authors have shown for the first time that Guo partially prevents the disruption in BBB integrity induced by stroke. The exact nature of the interaction between Guo and BBB is not fully understood but may include the modulation of the survival/apoptotic PI3k/Caspase 3 pathway [163].…”