Parkinson's disease (PD) is a neurodegenerative and debilitating disease that affects 1% of elderly population. Patient's motor disability results in an extreme difficulty to deal with daily activities. Conventional treatment is limited to dopamine replacement therapy, which fails to delay disease's progression and is often associated with a number of adverse reactions. Recent progress in understanding the mechanisms involved in PD has revealed new molecular targets for therapeutic approaches. Among them, caffeine and xanthine derivatives are promising drug candidates, because of the possible symptomatic benefits in PD. In fact, consumption of coffee correlates with a reduced risk of PD. Over the last decades, a lot of efforts have been made to uncover the therapeutic potential of xanthine structures. The substituted xanthine molecule is used as a scaffold for the synthesis of new compounds with protective effects in neurodegenerative diseases, including PD, asthma, cancer, and others. The administration of the xanthines has been proposed as a non-dopaminergic strategy for neuroprotection in PD and the mechanisms of protection have been associated with antagonism of adenosine A2A receptors and monoamine oxidase type B (MAO-B) inhibition. The current review summarizes frequently suspected non-dopaminergic neuroprotective mechanisms and the possible beneficial effects of the xanthine derivatives in PD, along with some synthetic approaches to produce perspective xanthine derivatives as non-dopaminergic agents in PD treatment.
The effects of new derivatives of caffeine-8-thioglycolic acid (100 μM) on isolated rat brain synaptosomes, human neuroblastoma cell line SH-SY5Y and human recombinant MAOB enzyme (hMAOB) (1 μM) were evaluated. Most of the compounds, administered alone, didn't show statistically significant neurotoxic effects on SH-SY5Y, when compared to the control (non-treated cells). Of all studied structures JTA-2Ox, JTA-11, JTA-12 and JTA-13 decreased cell viability. In combination with 6-hydroxydopamine (6-OHDA) (100 μM), only JTA-1 and JTA-2 revealed neuroprotective effects, stronger than those of caffeine. All compounds administered alone revealed, neurotoxic effects on synaptosomes, as compared to nontreated synaptosomes. JTA-1, JTA-2 and JTA-3 showed lowest neurotoxic effects and were investigated in a model of 6-OHDA-induced oxidative stress. In this model of neurotoxicity, only JTA-1 and JTA-2 showed statistically significant neuroprotective effect, by preserving the synaptosomal viability and the level of reduced glutathione. Inhibition of hMAOB, was revealed by JTA-1 and JTA-2. They inhibited the enzyme by 23% and 25% respectively, thus approaching the selegiline activity, which was 42%. The possible mechanisms of neuroprotection of JTA-1 and JTA-2 might be a result from the inhibition of hMAOB, which catalyze the production of neurotoxic p-quinone from 6-OHDA.
Objective:
The syntheses and biological activities of 8-thiosubstituted-1,3,7-
trimethylxanthine derivatives bearing an aromatic hydrazide-hydrazone fragment in the side chain
at C8 are described.
Methods:
The chemical structures of the synthesized compounds 6a-m were confirmed based on
their MS, FTIR, 1H NMR and 13C NMR analyses.
Results:
The in vitro investigations of neuroprotective effects manifested on cellular (human neuroblastoma
cell line SH-SY5Y) and sub-cellular (isolated rat brain synaptosomes) levels show that
compounds 6g and 6i demonstrate statistically significant activity. The performed monoamine
oxidase B (MAO-B) inhibition study in vitro show that compounds 6g and 6i possess a significant
MAO-B inhibition activity close to L-deprenyl.
Conclusion:
These results suggest that such compounds may be utilized for the development of
new candidate MAO-B inhibitors for the treatment of Parkinson’s disease.
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