Anticonvulsant Effects of Oral Guanosine: Implied Neuroprotective and Dopaminergic Effects

There's a series of articles showing that orally administered guanosine or guanosine 5'-monophosphate (GMP) have anticonvulsant effects. One of those effects is to oppose the decreases in glutamate uptake produced by quinolinic acid. Here are some of the articles on the effects of oral or intraperitoneal (i.p.) guanosine or GMP (usually 7.5-8 mg/kg bw) on glutamatergic transmission or other brain functions (remyelination, etc.):

http://www.ncbi.nlm.nih.gov/pubmed/15262204 (de Oliveira et al., 2004)

http://www.ncbi.nlm.nih.gov/pubmed/14990233 (Vinade et al., 2004)

http://www.ncbi.nlm.nih.gov/pubmed/15558762 (Vinade et al., 2005)

http://scholar.google.com/scholar?num=100&hl=en&lr=&cluster=10342337793122389314(Vinade et al., 2003)

i.p. or other route of administration, in vivo, for guanosine or GMP:

http://www.ncbi.nlm.nih.gov/pubmed/16076013

http://www.ncbi.nlm.nih.gov/pubmed/15044076 (Soares et al., 2004)

http://www.ncbi.nlm.nih.gov/pubmed/14663211 (Jiang et al., 2003)

http://www.ncbi.nlm.nih.gov/pubmed/17682941 (Tavares et al., 2008)

http://www.ncbi.nlm.nih.gov/pubmed/15313029 (Tort et al., 2004)

http://www.ncbi.nlm.nih.gov/pubmed/18404454 (Jiang et al., 2007)

This effect of guanosine on maintaining glutamate uptake, in the face of factors that elevate extracellular glutamate, would be expected to help preserve ATP levels and mitochondrial functioning, more broadly, during the excessive glutamatergic transmission that accompanies most neurodegenerative diseases. I know the authors of some of the articles that discuss the guanosine-induced antiapoptotic effects in cultured astrocytes talk about the cell energy issue, but seizures induce elevations of the lactate/pyruvate ratio and can cause mitochondrial toxicity. But there's lots of research showing that the inhibition of glutamate uptake, such as is produced by quinolinic acid, impairs mitochondrial functioning and produces, as the authors (Rothstein et al., 1993) of this article state, "slow neurotoxicity":

http://www.pnas.org/content/90/14/6591.abstract (pubmed: http://www.ncbi.nlm.nih.gov/pubmed/8393571?dopt=Abstract)

I know the authors of this article discussed these implications, to the treatment or understanding of Lesch-Nyhan syndrome, of these effects of guanosine:

http://www.ncbi.nlm.nih.gov/pubmed/15711436

And that effect on glutamate uptake [(which incidentally doesn't occur in response to guanosine by itself but does occur in response to guanosine + quinolinic acid: http://www.ncbi.nlm.nih.gov/pubmed/17682941 (Tavares et al., 2008)] would be expected to increase dopaminergic activity in the context of the increases in glutamatergic input to the striatum, such as occur in Parkinsonism or in the Parkinsonism that occurs in about a third of people who have Alzheimer's. This article shows, much as other articles examining the neurotoxic effects of reductions in glutamate uptake have shown, that the Abeta peptides, polypeptides that are derived from the cleavage of soluble amyloid precursor protein (sAPP) and that are likely to mediate some of the neuronal loss in Alzheimer's disease, can produce lipid peroxidation and mitochondrial toxicity by inhibiting glucose and glutamate uptake across the synaptosomal membranes of neurons from rat cerebral cortices:

http://www.ncbi.nlm.nih.gov/pubmed/9202320

The broader message by the authors of that last review article I cited (http://www.ncbi.nlm.nih.gov/pubmed/15711436) is that guanosine nucleotides might increase or maintain dopamine release in something like Parkinson's disease (especially after a couple of years of treatment with dopaminergic drugs), in which there's excessive calcium influx, due to NMDA receptor activation and other mechanisms, into dopaminergic neurons. This article shows that inhibition of glutamate uptake reduces dopamine release in the nucleus accumbens, which is in the ventral striatum (in the basal ganglia). It's worth noting that kynurenic acid blocked the effect of the glutamate uptake inhibitor, and kynurenic acid also blocks the glutamate uptake inhibition produced by quinolinic acid (in some of the guanosine studies). The authors (Taber et al., 1996) noted that the increased levels of extracellular glutamate were reducing dopamine release by some polysynaptic pathways and were not acting directly on the terminals of dopaminergic neurons in the nucleus accumbens:

http://www.ncbi.nlm.nih.gov/pubmed/8890458

Even though excitatory, glutamatergic inputs and some level of calcium influx, in response to NMDA receptor activation, for example, are required for dopamine release in the short term, prolonged dopaminergic stimulation tends to lead to excessive calcium influx and neurotoxicity. Here's an article (Donzanti et al., 1993) that shows that the extracellular glutamate levels, in the striatum, tend to be increased as the rats age and that the D2 dopamine receptor-agonist-mediated decreases in extracellular glutamate become blunted as the rats age:

http://www3.interscience.wiley.com/journal/109703041/abstract (pubmed: http://www.ncbi.nlm.nih.gov/pubmed/8097598)

That article shows that aberrant increases in the firing rates or excitabilities of dopaminergic neurons can, in a "reciprocal" sense, such as in response to an age-associated decrease in D2-dopamine-receptor responsiveness, contribute to an excessive level of extracellular (i.e. synaptic in this context) glutamate. The increase in extracellular glutamate then could produce feed-forward increases in calcium influx into dopaminergic neurons, an effect that would further exacerbate mitochondrial dysfunction in dopaminergic neurons. Memantine and other low-level NMDA receptor antagonists have been used to ameliorate this type of thing, and guanosine may have similar effects.