Abstract
Background5′-deoxy-5′-methylthioadenosine (MTA) is an endogenous compound produced through the metabolism of polyamines. The therapeutic potential of MTA has been assayed mainly in liver diseases and, more recently, in animal models of multiple sclerosis. The aim of this study was to determine the neuroprotective effect of this molecule in vitro and to assess whether MTA can cross the blood brain barrier (BBB) in order to also analyze its potential neuroprotective efficacy in vivo.MethodsNeuroprotection was assessed in vitro using models of excitotoxicity in primary neurons, mixed astrocyte-neuron and primary oligodendrocyte cultures. The capacity of MTA to cross the BBB was measured in an artificial membrane assay and using an in vitro cell model. Finally, in vivo tests were performed in models of hypoxic brain damage, Parkinson's disease and epilepsy.ResultsMTA displays a wide array of neuroprotective activities against different insults in vitro. While the data from the two complementary approaches adopted indicate that MTA is likely to cross the BBB, the in vivo data showed that MTA may provide therapeutic benefits in specific circumstances. Whereas MTA reduced the neuronal cell death in pilocarpine-induced status epilepticus and the size of the lesion in global but not focal ischemic brain damage, it was ineffective in preserving dopaminergic neurons of the substantia nigra in the 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-mice model. However, in this model of Parkinson's disease the combined administration of MTA and an A2A adenosine receptor antagonist did produce significant neuroprotection in this brain region.ConclusionMTA may potentially offer therapeutic neuroprotection.
Highlights
The sulfur-containing nucleoside 59-deoxy-59-methylthioadenosine (MTA, CAS 2457-80-9) is produced from S-adenosylmethionine during the synthesis of the polyamines spermine and spermidine [1], and it acts as a potent inhibitor of polyamine biosynthesis
Models of focal and global ischemia in rat were supported by the project SK-VEGA 02/0092/12
When mixed cultures were pre- or co-treated with MTA, we found that caspase 3 activation induced by NMDA reverted to basal levels, an effect produced by the ionotropic glutamate receptor antagonist, MK-801 (Fig. 1c and 1d)
Summary
The sulfur-containing nucleoside 59-deoxy-59-methylthioadenosine (MTA, CAS 2457-80-9) is produced from S-adenosylmethionine during the synthesis of the polyamines spermine and spermidine [1], and it acts as a potent inhibitor of polyamine biosynthesis. MTA is metabolized by MTA-phosphorylase to yield 5-methylthioribose-1-phosphate and adenine, a crucial step in the methionine and purine salvage pathways, respectively. The potential of this natural compound as a therapeutic agent was first demonstrated in experimental models of acute and chronic liver damage, and liver carcinogenesis, for which high doses were used without producing any significant toxicity [2,3]. MTA was proved to have a remarkable immunomodulatory activity in animal models of neuroinflammation, such as experimental autoimmune encephalomyelitis (EAE) [4] In this model, when MTA was compared with other currently approved therapies for multiple sclerosis (MS), it was more effective and better suited for combination therapy [5]. MTA can block the NGF- but not the high K+-mediated decrease in phosphorylated p70, thereby showing that neural survival may involve distinct protein phosphorylation pathways, these may later converge [6]
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