J Pharm Pharmacogn Res 2(Suppl. 1): S65, 2014
Special supplement with the abstract book of LATINFARMA 2013
C 022: THE GUANINE-BASED PURINERGIC SYSTEM AS A NEW TARGET FOR NEUROPROTECTION AGAINST GLUTAMATERGIC EXCYTOTOXICITY
Glutamate is the main excitatory neurotransmitter in mammalian CNS, essential for brain activities, as those involved in development, ageing, memory, and adaptation to the environment. However, hyper activation of the glutamatergic system may be potentially neurotoxic, involved in the pathogenesis of various acute and chronic brain injuries. The main process responsible by maintaining the extracellular glutamate levels below toxic levels, thus favoring the physiological glutamatergic tonus, is the glutamate uptake exerted by transporters located in neural cell membranes, mainly in astrocytes. Our group has given strong evidence that the guanine-based purinergic system is effectively neuroprotective against glutamate toxicity, in acute and chronic animal models, both in vitro and in vivo studies. Our results indicate that nucleoside guanosine (Guo) exerts neuroprotection. In vivo Guo i.c.v., i.p. or orally administered in rodents protects against brain injury caused by overstimulation of the glutamatergic system. In vitro studies, Guo protects cell death in brain slices caused by in vitro ischemia. Searching for mechanisms implicated in this neuroprotection, we demonstrated that: i) Guo stimulates the astrocytic glutamate uptake (in astrocyte cultures and brain slices), the main process involved in endogenous neuronal protection; ii) brain induced-injuries decrease glutamate uptake by brain slices and this decrease is reversed by Guo only when it acts as anticonvulsant; iii) brain oxidative stress caused by glutamate toxicity in experimental brain injury models is reversed by Guo administration. Thus we propose that the stimulatory effect on glutamate uptake and/or its antioxidant activity are involved in the neuroprotective actions of Guo. These results encourage further studies aiming at the therapeutic use in humans of Guo in acute (hypoxia, ischemia, brain traumatism) and chronic (neurodegenerative diseases) brain injuries involving glutamate excytotoxicity.