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1.
Curr Top Med Chem ; 16(17): 1906-9, 2016.
Article in English | MEDLINE | ID: mdl-26845550

ABSTRACT

Parkinson's disease is a motor dysfunction that has been widely studied but many of the reports on commercial drugs for the treatment of this disease have afforded some undesirable side effects that generate an extensive and unviable treatment by economic costs and due to the bioavailability of the assayed compounds. At present, some molecules are used as L-DOPA agonists or can change the dopamine concentrations in the CNS. Thus, the use of aporphine-type alkaloids has given a real alternative due to the diverse natural sources where can be isolated or to obtain them by means of conventional syntheses. Isoquinoline alkaloids as liriodenine, phenanthrene-type alkaloids, alkoxy-hydroxyaporphine, aminothiazole-aporphine or lipoic ester aporphine derivatives are some of the examples to be considered in this mini-review, wherein the applied pharmacological effects to reduce the motor disorders and the possible medical properties of these alkaloids on the dopaminergic receptors are analyzed.


Subject(s)
Alkaloids/therapeutic use , Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Humans , Levodopa/agonists , Molecular Structure , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology
2.
J Pineal Res ; 55(3): 304-12, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23952687

ABSTRACT

The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is the preferred drug for Parkinson's disease, but long-term treatment results in the drug-induced dyskinesias and other side effects. This study was undertaken to examine whether melatonin could potentiate low dose L-DOPA effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental parkinsonism. Mice were treated with the parkinsonian neurotoxin, MPTP, and different doses of melatonin and low doses of L-DOPA. Behavior, striatal histology, and dopamine metabolism were evaluated on the 7th day. MPTP-induced striatal dopamine loss was not modified by melatonin administration (10-30 mg/kg; i.p. at 10-hr intervals, 6 times; or at 2-hr intervals, by day). However, low doses of L-DOPA (5 mg/kg, by oral gavage) administered alone or along with melatonin (10 mg/kg, i.p.) twice everyday for 2 days, 10 hr apart, after two doses of MPTP significantly attenuated striatal dopamine loss and provided improvements in both catalepsy and akinesia. Additionally, Golgi-impregnated striatal sections showed preservation of the medium spiny neurons, which have been damaged in MPTP-treated mouse. The results demonstrated that melatonin, but not L-DOPA, restored spine density and spine morphology of medium spiny neurons in the striatum and suggest that melatonin could be an ideal adjuvant to L-DOPA therapy in Parkinson's disease, and by the use of this neurohormone, it is possible to bring down the therapeutic doses of L-DOPA.


Subject(s)
Antiparkinson Agents/pharmacology , Central Nervous System Depressants/pharmacology , Corpus Striatum/metabolism , Dendrites/metabolism , Levodopa/pharmacology , Melatonin/pharmacology , Parkinson Disease, Secondary/drug therapy , Animals , Antiparkinson Agents/agonists , Central Nervous System Depressants/agonists , Corpus Striatum/pathology , Dendrites/pathology , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Synergism , Levodopa/agonists , MPTP Poisoning/drug therapy , MPTP Poisoning/metabolism , MPTP Poisoning/pathology , Melatonin/agonists , Mice , Mice, Inbred BALB C , Parkinson Disease, Secondary/metabolism , Parkinson Disease, Secondary/pathology
3.
Behav Pharmacol ; 23(2): 126-33, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22236652

ABSTRACT

Peripheral aromatic amino acid decarboxylase (AADC) inhibitors, such as benserazide, are routinely used to potentiate the effects of L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease (PD) and in experimental models of PD. However, there is little information available on the optimal dose or the timing of administration relative to L-DOPA treatment. We now assess the effect of dose, timing, and supplemental administration of benserazide on the rotational response induced by L-DOPA in unilateral 6-hydroxydopamine-lesioned rats. L-DOPA (12.5 mg/kg, p.o.) concomitant with benserazide (3.125-15 mg/kg, p.o.) produced a dose-dependent increase in contraversive rotation compared with the effects of L-DOPA alone. The optimal L-DOPA response was achieved with 10 mg/kg of benserazide and this dose was used in subsequent experiments. When L-DOPA treatment was delayed for 1, 2, or 3 h after benserazide, the rotational response declined suggesting loss of AADC inhibition. Unexpectedly, there was also a progressive decline in response when benserazide and L-DOPA were given together but at increasingly later time points of 08.00, 09.00, 10.00, and 11.00 h. To assess supplemental administration of benserazide, an additional dose was given 2 h after the initial benserazide/L-DOPA treatment. This produced a further increase in the number of contralateral rotations indicating that the effect of benserazide declines while plasma levels of L-DOPA are maintained. Therefore, optimization of the dose and timing of benserazide administration is essential to achieve a consistent L-DOPA response in 6-hydroxydopamine-lesioned rats. These findings may have implications for the way in which peripheral AADC inhibitors are used in the treatment of PD.


Subject(s)
Benserazide/pharmacology , Dose-Response Relationship, Drug , Drug Administration Schedule , Levodopa/agonists , Motor Activity/drug effects , Animals , Aromatic Amino Acid Decarboxylase Inhibitors , Benserazide/administration & dosage , Enzyme Inhibitors/pharmacology , Levodopa/administration & dosage , Male , Microinjections , Oxidopamine/administration & dosage , Rats , Rats, Wistar , Time Factors
4.
Bioorg Med Chem Lett ; 9(19): 2815-8, 1999 Oct 04.
Article in English | MEDLINE | ID: mdl-10522697

ABSTRACT

4-Benzyl-1-[4-(1H-imidazol-4-yl)but-3-ynyl]piperidine (8) has been identified as a potent antagonist of the NR1A/2B subtype of the NMDA receptor. When dosed orally, this compound potentiates the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease.


Subject(s)
Imidazoles/chemical synthesis , Imidazoles/pharmacology , Piperidines/chemical synthesis , Pyrazoles/pharmacology , Pyrroles/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Disease Models, Animal , Levodopa/agonists , Levodopa/pharmacology , Ligands , Molecular Structure , Oxidopamine , Parkinsonian Disorders/metabolism , Piperidines/pharmacology , Pyrazoles/chemical synthesis , Pyrroles/chemical synthesis , Rats
5.
J Neural Transm Gen Sect ; 98(1): 57-67, 1994.
Article in English | MEDLINE | ID: mdl-7710739

ABSTRACT

Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and alpha-methyl-p-tyrosine. In the present study memantine (2.5, 5.0 mg/kg), amantadine (10, 20 mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0 mg/kg) and L-dopa (50, 100 mg/kg, +benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10 mg/kg) and L-dopa (100, 200 mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-dopa produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.


Subject(s)
Amantadine/pharmacology , Levodopa/agonists , Memantine/pharmacology , Selegiline/pharmacology , Animals , Bromocriptine/pharmacology , Dopamine/deficiency , Drug Synergism , Male , Motor Activity/drug effects , N-Methylaspartate/antagonists & inhibitors , Parkinson Disease/drug therapy , Rats , Rats, Wistar
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