A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo

Abstract

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.

Monoterpenoid Epoxidiol Ameliorates the Pathological Phenotypes of the Rotenone-Induced Parkinson’s Disease Model by Alleviating Mitochondrial Dysfunction

“…A promising class of compounds on the basis of which highly effective neuroprotective drugs for the treatment of Parkinson’s disease can be developed are monoterpenoids [ 13 , 14 , 15 , 16 ]. Previously, the antiparkinsonian potential of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-en-1,2-diol (diol (Prottremin), Figure 1 ) [ 17 , 18 ], which is currently in the first stage of clinical trials, was discovered.…”

3-N-Butylphthalide Attenuates the Neuroinflammation in Rotenone-Induced Parkinson’s Disease Models via the cGas/STING Pathway

“…In nerve cells,rotenone inhibits mitochondrial respiratory chain complex I, and subsequently induces reactive oxygen species(ROS) production and mitochondrial dysfunction,leading to the progressive damage of dopaminergic neurons in substantia nigra and stratium [14,15]. Janetzky B et al have found selective loss of respiratory chain complex I in the substantia nigra of PD patients [16].Improtantly,recent studies also found that pathological changes induced by rotenone is not limited to the dopaminergic neurons deterioration [17][18][19],but also includes overactivation of microgial adjacent to the neurons. Sherer TB et al proved that rotenone can activate microglia in rodent PD models before anatomical pathology appears of dopaminergic neurons loss [20].…”