RESUMEN
Parkinson's disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured näive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood-brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug.
Asunto(s)
Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , Humanos , Neuronas Dopaminérgicas , Intoxicación por MPTP/tratamiento farmacológico , Monoterpenos/farmacología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Haloperidol/farmacología , Sustancia NegraRESUMEN
Biodegradable poly(l-lactide)/calcium phosphate composites are promising materials for fabrication of bone fixation implants with improved properties. Multistage compounding was proposed as an efficient method for the preparation of biodegradable poly(l-lactide)/calcium phosphate composites with submicron filler dispersion and mechanical characteristics similar to native bone. The improvement of the characteristics is caused both by the filler itself and by the increase of polymer crystallinity due to the nucleation effect. The technique allows to fabricate biodegradable composites with controlled properties by varying concentration and type of the filler as well as degree of PLLA matrix crystallinity. Animal studies revealed that all the composites were biocompatible and non-toxic.
Asunto(s)
Materiales Biocompatibles/química , Durapatita/química , Poliésteres/química , Animales , Materiales Biocompatibles/metabolismo , Materiales Biocompatibles/uso terapéutico , Cristalización , Módulo de Elasticidad , Masculino , Peso Molecular , Músculo Esquelético/patología , Prótesis e Implantes , Ratas , Ratas Wistar , Resistencia a la TracciónRESUMEN
We previously showed that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 alleviates motor manifestations of Parkinson's disease in animal models. In the present study, we designed and synthesized monoepoxides of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 and evaluated their biological activity in the MPTP mouse model of Parkinson's disease. We also assessed the ability of these compounds to penetrate the blood-brain barrier (BBB). According to these data, we chose epoxide 4, which potently restored the locomotor activity in MPTP-treated mice and efficiently penetrated the BBB, to further explore its potential mechanism of action. Epoxide 4 was found to robustly promote the survival of cultured dopamine neurons, protect dopamine neurons against toxin-induced degeneration, and trigger the mitogen-activated protein kinase (MAPK) signaling cascade in cells of neuronal origin. Meanwhile, neither the survival-promoting effect nor MAPK activation was observed in non-neuronal cells treated with epoxide 4. In the MPTP mouse model of Parkinson's disease, compound 4 increased the density of dopamine neuron fibers in the striatum, which can highlight its potential to stimulate striatal reinnervation and thus halt disease progression. Taken together, these data indicate that epoxide 4 can be a promising compound for further development, not only as a symptomatic but also as a neuroprotective and neurorestorative drug for Parkinson's disease.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Intoxicación por MPTP/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Animales , Células Cultivadas , Cuerpo Estriado/metabolismo , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/metabolismo , Intoxicación por MPTP/metabolismo , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Actividad Motora/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Transducción de Señal/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Earlier it was found, that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (1) possess high antiparkinsonian activity. The N-, O-, S- and C-derivatives at the C-9 position of diol 1 were synthesized in this work. The antiparkinsonian activity of these compounds was studied in MPTP mice models. As a rule, the introduction of substituents containing nitrogen atoms at the C-9 position led to a considerable decrease or loss of antiparkinsonian activity. A derivative of 2-aminoadamantane 8 significantly decreased the locomotor activity time, thus enhancing the symptoms of the parkinsonian syndrome. However the introduction of butyl or propylthio substituents at the C-9 position of diol 1 did not diminish the antiparkinsonian activity comparing to parent compound. This information is important when choosing a route for immobilization of compound 1 to find possible targets.
Asunto(s)
Antiparkinsonianos/química , Ciclohexanoles/química , Animales , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Ciclohexanoles/farmacología , Ciclohexanoles/uso terapéutico , Modelos Animales de Enfermedad , Intoxicación por MPTP/inducido químicamente , Intoxicación por MPTP/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , EstereoisomerismoRESUMEN
Compounds with different sets of three of the four functional groups of (1R,2R,6S)-3-methyl-6-(prop-1-en-2- yl)cyclohex-3-ene-1,2-diol 1 possessing high antiparkinsonian activity were synthesized. The synthesized compounds were tested for the antiparkinsonian activity in vivo on a mouse model with MPTP neurotoxin. A pronounced antiparkinsonian effect of 1 can only be achieved if it contains all the four functional groups (two hydroxy groups and two double bonds). The 2-hydroxy group or the 3,4-double bond is not required for stimulating the exploratory activity of the animals.
Asunto(s)
Antiparkinsonianos/química , Antiparkinsonianos/farmacología , Ciclohexanoles/farmacología , Ciclohexanoles/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Antiparkinsonianos/síntesis química , Antiparkinsonianos/uso terapéutico , Ciclohexanoles/síntesis química , Ciclohexanoles/química , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Conformación MolecularRESUMEN
(1R,2R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 possesses potent antiparkinsonian activity in both MPTP and haloperidol animal models. The use of compound 1 resulted in nearly full recovery of the locomotor and exploratory activities and was as effective as the comparator agent (levodopa). All eight stereoisomers of compound 1 have been synthesized and the influence of the absolute configuration on the antiparkinsonian activity of compound 1 was shown.