New Hope For Mechanism Based Treatment Of Parkinson’s Disease
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Researchers have discovered that rifampicin, an antibiotic used to treat tuberculosis and leprosy, inhibit the formation of alpha synuclein fibrils that have already formed.
Because the aggregation of alpha synuclein in dopaminergic neuron is critical steps in pathogenesis of Parkinson’s disease (PD). Rifampicin or a related compound could provide a new approach to the treatment of PD. 1
Alpha-Synuclein And Parkinsons Disease
PD is a common neurodegenerative disease disorder caused by the progressive loss of dopaminergic neurons in the substantia nigra.Current treatment is symptomatic- patients are usually given levodopa to improve motor symptoms.
Recent discoveries indicate that PD pathogenesis involves the conversion of solouble alpha synuclein into abnormal filamentous alpha synuclein. Researcher reported that is mutated in a familial form of PD. The discovery of an alpha- synuclein mutation thus encouraged Goedert to examine Lewy bodies and neuritis, the defining neuropathological lesion of PD, for the presence of alpha –synuclein. Both types of lesion stained strongly for alpha- synuclein, and it is now clear that this protein is the major components of the filaments of these lesions.
Two further missence mutation and triplication and duplication of the alpha synuclein gene, all of which cause the protein to aggregate, have since discovered in inherited forms of PD. Although it is not known why alpha synuclein aggregate in sporadic disease, notes alpha- synuclein is clearly a good target for mechanism based treatment of PD.
The Rifampicin Connection
While some researchers are concentrating on enhancing cellular defense against aggregated alpha-synuclein (example by increasing cellular chaperone activity), researcher are looking for molecules that inhibit fibril formation of alpha-synuclein in vitro. Compounds that can do this have a common molecular structure, namely a benzene ring with two hydroxyl groups. This structure, which is found in flavonoids, readily undergoes to form quinone. This interacts with the side chains of alpha-synuclein which then forms make stable oligomers rather than large aggregate.2
In june 2004 reseacher reported that the flavonoids baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils. However it is reported that rifampicin has similar effects on alpha-synuclein.1
This in vitro data is an intriguing but early step in the development of new therapy for PD commonly Andrew who works on the genetics basis of neurodegenerative disease. However we don’t know whether fibrillar alpha-synuclein or soluble alpha synuclein oligomers are the toxic species in PD so rifampicin could exacerbate rather than treat the disease.
Rifampicin is certainly worth checking out since it is also inhibit the aggregation of other proteins involved in neurodegenerative disease; patients treated with rifampicin for leprosy have lower risk of developing senile dementia that patients do not given the drug.
Furthermore, a recent clinical study provides some evidence that rifampicin in combination with doxycycline might slow mental deterioration in patients with mild to moderate Alzheimer’s disease.3
References:
(1) Li, J. et. al. (2004) Rifampicin inhibit alpha-synuclein fibrillation and disaggregates. Chem. Bio, 11 1513- 1521
(2) Zhu, M. et. al. (2004) the flavonoids baicalein inhibits fibrillation of alpha-synuclein and dissagregates, existing fibrils. J.Biol.Chem, 25 26846-26857
(3) Loeb.M.b.etal (2004) A randomized, controlled trail of soc 52, 381-387. Doxycycline and rifampicin for patients with Alzheimer’s disease J. Am. Geriatr,
About Authors:
Talha jawaid, M.pharm
Faculty of pharmacy, Integral university, Lucknow
Mehnaz Kamal
Faculty of pharmacy, Integral university, Lucknow