Guanosine Prevents Thermal Hyperalgesia in a Rat Model of Peripheral Mononeuropathy
ABSTRACT It is well known that adenine-based purines exert multiple effects on pain transmission. Less attention has been given, however, to the antinociceptive effects of guanine-based purines. The aim of this study was to investigate the effects of intraperitoneal administration of guanosine on a rat model of peripheral mononeuropathy. Additionally, investigation of the mechanism of action of guanosine, its general toxicity and measurements of central nervous system purine levels were performed. Rats received an intraperitoneal administration of vehicle (0.1 mM NaOH) or guanosine (up to 120 mg.kg(-1)) in an acute or chronic regimen. Guanosine significantly reduced thermal hyperalgesia on the ipsilateral side of the sciatic nerve ligation. Additionally, guanosine prevented locomotor deficits and body weight loss induced by the mononeuropathy. Acute systemic administration of guanosine caused an approximately 11-fold increase on central nervous system guanosine levels, but this effect was not observed after chronic treatment. Chronic guanosine administration prevented the increase on cortical glutamate uptake but not the decrease in spinal cord glutamate uptake induced by the mononeuropathy. No significant general toxicity was observed after chronic exposure to guanosine. This study provides new evidence on the mechanism of action of guanine-based purines, with guanosine presenting antinociceptive effects against a chronic pain model. PERSPECTIVE: This study provides a new role for guanosine: chronic pain modulation. Guanosine presents as a new target for future drug development and might be useful for treatment of neuropathic pain.
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- "Guo and Urd. Our results imply that Guo, Urd and their analogs may be useful, effective and safe antiepileptic drugs (Lara et al., 2001; Kimura et al., 2001b; Kova´cs and Dobolyi, 2013; Kova´cs et al., 2014) in the treatment of human absence epilepsy because Guo and Urd are well tolerated drugs with only minor toxic potential as demonstrated previously (Lara et al., 2001; Vinadeét al., 2003; Zhao et al., 2008; Schmidt et al., 2010). "
ABSTRACT: Adenosine (Ado) and non-adenosine (non-Ado) nucleosides such as inosine (Ino), guanosine (Guo) and uridine (Urd) may have regionally different roles in the regulation of physiological and pathophysiological processes in the central nervous system (CNS) such as epilepsy. It was demonstrated previously that Ino and Guo decreased quinolinic acid (QA)-induced seizures and Urd reduced penicillin-, bicuculline- and pentylenetetrazole (PTZ) -induced seizures. It has also been demonstrated that Ino and Urd may exert their effects through GABAergic system by altering the function of GABAA receptors whereas Guo decreases glutamate-induced excitability through glutamatergic system, which systems (GABAergic and glutamatergic) are involved in pathomechanisms of absence epilepsy. Thus, we hypothesized that Ino and Guo, similarly to the previously described effect of Urd, might also decrease absence epileptic activity. We investigated in the present study whether intraperitoneal (i.p.) application of Ino (500 and 1000 mg/kg), Guo (20 and 50 mg/kg), Urd (500 and 1000 mg/kg), GABAA receptor agonist muscimol (1 and 3 mg/kg), GABAA receptor antagonist bicuculline (2 and 4 mg/kg), non-selective Ado receptor antagonist theophylline (5 and 10 mg/kg) and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine maleate (MK-801, 0.0625 and 0.1250 mg/kg) alone and in combination have modulatory effects on absence epileptic activity in Wistar Albino Glaxo Rijswijk (WAG/Rij) rats. We found that Guo decreased the number of spike-wave discharges (SWDs) whereas Ino increased it dose-dependently. We strengthened that Urd can decrease absence epileptic activity. Our results suggest that Guo, Urd and their analogues could be potentially effective drugs for treatment of human absence epilepsy. Copyright © 2015. Published by Elsevier Ltd.Neuroscience 05/2015; 300. DOI:10.1016/j.neuroscience.2015.05.054 · 3.33 Impact Factor
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ABSTRACT: Guanine-based purines have been traditionally studied as modulators of intracellular processes, mainly G-protein activity. However, more recently, several studies have shown that they exert a variety of extracellular effects not related to G-proteins, including trophic effects on neural cells, modulation of glutamatergic activity, behavioral effects and anticonvulsant activity. In this article, the putative effects of the guanine-based purines against seizures and neurotox-icity are reviewed. Current evidence suggests that guanine-based purines, especially guanosine, seem to be endogenous anticonvulsant substances, perhaps in a similar way to the adenine-based purines. Although studies addressing the mecha-nism of action of guanine-based purines are still lacking, their anticonvulsant activity is probably related to the modula-tion of several glutamatergic parameters, especially the astrocytic glutamate uptake. These findings point to the guanine-based purines as potential new targets for the development of novel drugs for neuroprotection and management of epi-lepsy.The Open Neuroscience Journal 01/2010; 4(1). DOI:10.2174/1874082001004010102
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ABSTRACT: The role of adenosine-5'-triphosphate (ATP) and of the ligand-gated P2X3 receptor in neuronal dorsal root ganglia (DRG) pain transmission is relatively well established. Much less is known about the purinergic system in trigeminal ganglia (TG), which are involved in certain types of untreatable neuropathic and inflammatory pain, as well as in migraine. Emerging data suggest that purinergic metabotropic P2Y receptors on both neurons and satellite glial cells (SGCs) may also participate in both physiological and pathological pain development. Here, we provide an updated literature review on the role of purinergic signaling in sensory ganglia, with special emphasis on P2Y receptors on SGCs. We also provide new original data showing a time-dependent downregulation of P2Y2 and P2Y4 receptor expression and function in purified SGCs cultures from TG, in comparison with primary mixed neuron-SGCs cultures. These data highlight the importance of the neuron-glia cross-talk in determining the SGCs phenotype. Finally, we show that, in mixed TG cultures, both adenine and guanosine induce intracellular calcium transients in neurons but not in SGCs, suggesting that also these purinergic-related molecules can participate in pain signaling. These findings may have relevant implications for the development of new therapeutic strategies for chronic pain treatment.Neuron Glia Biology 02/2010; 6(1):31-42. DOI:10.1017/S1740925X10000086 · 6.64 Impact Factor