Discorvery of novel neuroprotective drugable targets and repurposed drugs to treat incurable neurodegenerative disorders

Neuroinflammation and neurodegeneration are cardinal elements in the pathogenesis of most neurological diseases. In some of them, such as Alzheimer disease (AD), Amyotrophic Lateral Sclerosis (ALS), Parkinson disease (PD), epilepsy, Huntington's disease (HD), inflammation is a reactive process to neuronal damage, while in others - multiple sclerosis (MS), spinal cord injury, brain trauma, brain ischemia - inflammation is a key element that leads to neurodegeneration. Which is the contribution of one versus the other pathogenic event is not yet fully understood but whatever the primary cause, axonal damage and neuronal loss lead to the irreversible neurological deficit. There are no current treatments to prevent or slowdown disease progression as well as to halt neuronal loss in still orphan diseases like ALS. Also, for ischemic stroke, one of the most burdensome neurological diseases, there are currently, besides acute recanalizing strategies, no available neuroprotective treatments aimed to ameliorate clinical outcomes.
Thus, it is still of paramount importance to develop neuroprotective treatments able to rescue neuronal damage.
A rational approach to develop safe therapies is the selection of repurposed drugs with strong biological links and rationale for treating such disorders. Through a combined in silico and in vitro approach, we have previously identified a few registered molecules that rescue murine neuronal integrity upon excitotoxic stress. Among them, Bifeprunox, a dopamine DRD2 receptor partial agonist, has been selected as a potential lead based on its promising neuroprotective profile, as it has been demonstrated to rescue neuronal integrity upon excitotoxic stress, in various murine cellular assays. The registered drug Bifeprunox also displays good pharmacokinetic and safety data, as well as blood-brain-barrier permeability. Our objective is to validate the neuroprotective properties of Bifeprunox using human iPSC-derived motor neurons and more sophisticated 3D models, upon oxidative or excitotoxic stress, or with pro-inflammatory cues mimicking neuroinflammatory conditions. We will also evaluate the 4D expression (in time and space) of the DRD2 receptor in experimental stroke and in human stroke at various timepoints after injury.
The study of Bifeprunox mechanism of action is intended to pave the way to a drug optimization program using in silico and in wet lab approaches. The final goal of the project is to provide a small set of optimized compounds to be tested in the available cellular models. Selected candidate/s will receive in vivo validation using mouse models of two neurodegenerative diseases: 1) transgenic mice expressing a G93A mutant form of the human SOD1 gene (SOD1G93A), which recapitulate familiar ALS; 2) experimental transient middle cerebral artery occlusion (MCAo) mice that closely mimic human brain ischemia patients to thrombectomy treatment.
Our findings will advance the development of neuroprotective agents aimed at reducing central nervous system damage so to reduce the neurological deficit.