Parkinson’s Disease (PD) is a neurological disorder currently affecting more than 1.5 million Americans, characterized by chronic and progressive degeneration of the dopaminergic (DA) neurons in the
Substantia Nigra
and by the formation of Lewy bodies (Qu et al., 2007). The molecular basis of DA neuronal degeneration in PD are not clearly understood, although some gene candidates have been identified (Belin and Westerlund, 2008) and a role for astrocytes and microglia in the disease has been suggested (Mallajosyula et al., 2008). Importantly, the current pharmacological treatment for the pathology is mainly symptomatic, as it partly restores the dopaminergic transmission but does not act on neurodegeneration. The main challenge therefore remains the identification of new drugs slowing or preventing neuronal death in PD.
The goal of the present project is to develop a miniaturized biodevice (engineered device + cells) for the screening of neuroprotective factors for the treatment of PD.
The biodevice will enable the screening, at submicroliter level, of drugs designed to prevent neurodegeneration in PD, acting directly on neurons, or indirectly, through astrocytes and/or microglia. To validate this innovative micro-biodevice, we will take advantage of the well characterized neurodegenerative effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Burns et al., 1985 and Langston et al., 1983), whose active metabolite MPP+ (1-methyl-4-phenylpyridinium) is potently neurotoxic and induces specific loss of DAergic neurons in the CNS.
Estrogenic drugs (estrogens, progesterone, dehydroepiandrosterone, the estrogen receptor agonist, PPT, and the selective estrogen receptor modulator raloxifene) will be used as well-established neuroprotective agents acting on the DA system against the MPP+ challenge (Tripanichkul 2008, Morrisette et al., 2008, Mani 2006). The neurotoxic effect of MPP+ and the neuroprotective effect of estrogens on MPP+-induced damage will allow to validate the device, opening to its application for neuroprotective drug screening. Since it is well known that non-neuronal cells (astrocytes and microglia) release factors involved in neuroprotection (reviewed in Dhandapani et al., 2007), drugs will be applied either directly to cavities containing neurons or to cavities containing astrocytes and/or microglia, maintained in communication with neurons. This approach will allow to pick up even those drugs which exert a neuroprotective effect by inducing the release of neuroprotective factors from glial cells, thus facilitating the development of drugs specifically acting on different brain cell populations. The proposed approach will be faster than conventional methods, conservative in its use of samples and reagents, capable of screening analytes in parallel, and highly sensitive.