Low dosage of rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism.
BACKGROUND
The anti-Parkinson monoamine oxidase B inhibitor rasagiline appears to be the first neuroprotective disease-modifying therapy in early-stage Parkinson's disease (PD).


OBJECTIVE
Using a polypharmacy paradigm, we tested whether the distinct neuroprotective pharmacological profile of rasagiline would complement that of (-)-epigallocatechin-3-gallate (EGCG), the main antioxidant/iron chelator polyphenol constituent of green tea, and restore the neuronal loss and molecular targets damaged in animal parkinsonism.


RESULTS
We show by high-performance liquid chromatography, immunohistochemistry and Western blot analyses that the combination of rasagiline and EGCG, at subliminal doses which have no profound protective effect, acts synergistically to restore the nigrostriatal axis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. A detailed analysis revealed a complementary action of these drugs, differentially acting at MPTP-injured molecules/targets in the substantia nigra (SN): induction of brain-derived neurotrophic factor by rasagiline, increased membranal levels of the protein kinase C alpha-isoform by EGCG and a synergistic replenishment of their downstream effector, the serine/threonine kinase Akt/protein kinase B, suggesting that this kinase might represent one point of convergence of the distinct mechanisms of action of the drug cocktail.


CONCLUSIONS
These results provide molecular evidence that activation of multiple brain targets by the combination of rasagiline and EGCG may synergistically contribute to the rescue of the dopamine neurons in the SN and replenishment of striatal dopamine. This may have important implications for rasagiline-treated PD patients who could further benefit from an adjunct administration of EGCG.
Reznichenko
Lydia
L
Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
Kalfon
Limor
L
Amit
Tamar
T
Youdim
Moussa B H
MB
Mandel
Silvia A
SA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome
D000975:Antioxidants; D004338:Drug Combinations; D007189:Indans; D018696:Neuroprotective Agents; C031967:rasagiline; D002392:Catechin; C045651:epigallocatechin gallate