Pridopidine exerts neuroprotective effects via activation of the Sigma-1 receptor

Michal Geva1, Chiara Scaramuzzino2, Noga Gershoni-Emek1, Frédéric Saudou2 and Michael R. Hayden1,3

1 Prilenia Therapeutics
2 Grenoble Institut Neuroscience, Univ. Grenoble Alpes, Inserm, U 1216, CHU GrenobleAlpes F-38000 Grenoble, France
3 CMMT, University of British Columbia, Vancouver, Canada 

Pridopidine is a selective and potent Sigma-1 receptor (S1R) agonist in clinical development for Huntington Disease (HD).
The S1R is located at the mitochondria-associated membrane (MAM) of the Endoplasmic Reticulum (ER). The S1R modulates diverse cellular processes which are commonly impaired in various neurodegenerative disorders, such as calcium signaling, BDNF secretion, mitochondrial function and oxidative stress. Activation of the S1R exerts neuroprotective effects, acting to stimulate brain repair and plasticity. The S1R is highly expressed in the basal ganglia and cortex, areas especially relevant for HD.

Pridopidine demonstrates S1R-mediated neuroprotective effects in several preclinical models of HD. In HD neurons, pridopidine increases spine density and rescues the aberrant calcium signaling, enhances mitochondrial function including ATP production and respiration and mitigates mHtt-induced ER and oxidative stress, all known features of HD. Pridopidine shows a robust neuroprotective effect against mutant huntingtin-(mHTT)-induced cell death in human HD induced pluripotent stem cells (iPSCs), and mouse HD cortical neurons. When the S1R is deleted or an antagonist is used, these effetcs are completely eliminated, indicating pridopidine’s effects are exquisitely mediated via the S1R.
We assessed the effects of pridopidine on HD corticostriatal networks, including presynaptic dynamics, synaptic transmission, postsynaptic trafficking and signaling, using primary neurons from HTTCAG140/+ HD mice.

BDNF trafficking is significantly diminished in HD neurons, with decreased velocity, number of motile vesicles and global flow. Pridopidine rescues the number and velocity of secreted BDNF vesicles, restoring BDNF presynaptic flow. Pridopidine rescues impaired glutamate release from HD neurons, improving cortical synaptic function. Finally, pridopidine increases phospho-ERK in the post-synaptic striatal compartment, which is downstream to BDNF signaling and propagates survival signals. Importantly, pridopidine’s effect is completely abolished by the S1R antagonist NE-100, indicating that it acts exclusively via the S1R.

Thus, pridopidine restores pre- and post-synaptic functions in an HD cellular model. The neuroprotective effects of pridopidine are exclusively mediated by S1R activation.
The efficacy of pridopidine for treating HD is currently being evaluated in the global phase 3 PROOF-HD trial. Primary endpoint is the effect of pridopidine on maintenance of Total Functional Capacity in early HD patients at 65 weeks.