New neuroprotective and neuroregenerative compounds for Parkinson`s disease – ANTIPARK

Around 150.000 people in France are affected by Parkinson’s disease (PD) and 10.000 new cases are diagnosed every year. This is the 2nd motor handicap after cerebral vascular breakdown. PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. PD is determined at the clinical level by severe motor symptoms. Except in a few cases where PD is from familial origin, PD is sporadic and due to several factors: mitochondrial dysfunction, oxidative stress or proteasome deficiency are among other postulated causes to rationalize at molecular level the Parkinson symptoms. These symptoms can be partially improved by therapeutical agents that replace or modify the deficient neurotransmitter catabolism, dopamine. However the treatments are unable to slow down the disease progression and often induce undesired secondary effects in a long term. New therapies are thus necessary to preserve dopaminergic neurons and to stimulate their activity and to slow down or stopp the progression of PD. Several neurotrophines playing a role in the development and the survival of neurons have shown a protective effect against cellular death in different in vitro and in vivo models of PD. Even though a beneficial effect of neurotrophines administration has been observed their use is limited due to their high molecular weights and their protein nature that are responsible for their short half-life and low ability to cross the brain-blood-barrier (BBB) implying repeated intra-cranial administration.
We propose to develop small molecules possessing similar effects than neurotrophines without showing pharmacological drawbacks facilitating their administration and biodisponibility. We shall study on animal models of PD the therapeutical activity of synthetic compounds that have been designed and prepared in our laboratories and that already showed neuroprotective and neuroregenerative in vitro activities on dopaminergic neurons in mesencephal rats embryos. We’ll study in vitro their mechanisms of action by checking their mitochondrial activity and the inhibition of monoamine oxydases. The in vivo study of our 3 leads will be performed after intra-peritoneal or oral administration on MPTP lesioned mice. We shall check first the BBB permeation of our compounds by detecting by mass spectrometry the active compound in the brain tissues after treatment of mice by the active compounds as a function of the administration route. The methode that will be used is based on HPLC-MS/MS, which is sensitive and specific since we will focus only the ion mass of the compound.
The 2nd step of the project is to evaluate the presence of the active compound and its influence on the messengers expression in different parts of the brain of non-lesioned mice after sacrifice, by mass spectrometry imagery via 2 complementary techniques : MALDI-TOF (Matrix-Assisted Laser Desorption Ionization Time-of-Flight) imagery and TOF-SIMS (Time of Flight-Secondary Ion Mass Spectrometry) imagery that are today making a break through in imagery due to their specificity, sensitivity and well adapted to a wide range of molecular weights compounds.
The 3d step of our project concerns the PET imagery (positons emission tomography) in small animals of our active compounds, using 6-hydroxydopamine lesioned rats. Indeed, PET imagery allows the quantification at a molecular level the in vivo biochemical modifications in a very specific and sensitive manner. Its use in living animals, and in particular rats en mice, is in a very active development.