CNS delivery of L-dopa by a new hybrid glutathione-methionine peptidomimetic prodrug.
Amino Acids
; 42(1): 261-9, 2012 Jan.
Article
in En
| MEDLINE
| ID: mdl-21080012
ABSTRACT
Parkinson's disease (PD) is a neurodegenerative disorder associated primarily with loss of dopamine (DA) neurons in the nigrostriatal system. With the aim of increasing the bioavailability of L -dopa (LD) after oral administration and of overcoming the pro-oxidant effect associated with LD therapy, we designed a peptidomimetic LD prodrug (1) able to release the active agent by enzyme catalyzed hydrolysis. The physicochemical properties, as well as the chemical and enzymatic stabilities of the new compound, were evaluated in order to check both its stability in aqueous medium and its sensitivity towards enzymatic cleavage, providing the parent LD drug, in rat and human plasma. The radical scavenging activities of prodrug 1 was tested by using both the DPPH-HPLC and the DMSO competition methods. The results indicate that the replacement of cysteine GSH portion by methionine confers resistance to oxidative degradation in gastric fluid. Prodrug 1 demonstrated to induce sustained delivery of DA in rat striatal tissue with respect to equimolar LD dosages. These results are of significance for prospective therapeutic application of prodrug 1 in pathological events associated with free radical damage and decreasing DA concentration in the brain.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptides
/
Prodrugs
/
Levodopa
/
Central Nervous System
/
Glutathione
/
Methionine
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Amino Acids
Journal subject:
BIOQUIMICA
Year:
2012
Document type:
Article
Affiliation country:
Italy