RESUMO
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.
Assuntos
Intoxicação por MPTP , Fármacos Neuroprotetores , Doença de Parkinson , Animais , Camundongos , Humanos , Neurônios Dopaminérgicos , Intoxicação por MPTP/tratamento farmacológico , Monoterpenos/farmacologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Haloperidol/farmacologia , Substância NegraRESUMO
The methods for quantification of highly potent analgesic agent (2R,4aR,7R,8aR)-4,7-dimethyl-2-(thiophen-2-yl)octahydro-2H-chromen-4-ol in rat whole blood and plasma were developed and validated using dried matrix spots (DMS) or fabric phase sorptive extraction (FPSE) techniques in combination with LC-MS/MS. 2-Adamantylamine hydrochloride was used as an internal standard (IS). Chromatographic separation was carried out on a reversed-phase column (2.0×75â¯mm, 5⯵m) using water containing 0.1% formic acid and methanol containing 0.1% formic acid as mobile phases in gradient mode at a flow rate of 200⯵L/min. The mass spectrometric detection was performed using electrospray ionization (ESI) in positive ion mode. MRM transitions were m/z 284.5â¯ââ¯137.2/157.4 for the analgesic agent and m/z 152.3â¯ââ¯93.1/107.2 for IS. Calibration curves were linear within 20-5000â¯ng/mL in dried plasma spots (DPS) or dried blood spots (DBS) experiments. The linearity was obtained in the range of 20-5000â¯ng/mL and 50-5000â¯ng/mL for plasma-FPSE and blood-FPSE experiments, respectively. The intra- and inter-day accuracy and precision did not exceed acceptable limits. The mean extraction recovery (%) was 26 for DPS, 25 for DBS, 38 for plasma-FPSE, 31 for blood-FPSE.