The Neuroprotective Disease-Modifying Potential of Psychotropics in Parkinson’s Disease
Results indicate that, from a PD pathobiology perspective, the safest drugs (i.e., drugs least likely to promote cellular neurodegenerative mechanisms balanced against their likelihood of promoting neuroprotective mechanisms) include pramipexole, valproate, lithium, desipramine, escitalopram, and dextromethorphan. Fluoxetine favorably affects transcription of multiple genes (e.g., MAPT, GBA, CCDC62, HIP1R), although it and desipramine reduced MPTP mouse survival. Haloperidol is best avoided.
In MPTP mice, dextromethorphan protected dopamine neurons [87, 88], dopamine concentrations [87], and locomotor activity [87] and reduced glutamatergic excitotoxicity on dopamine neurons [89]. A previous study had not demonstrated protection of dopamine concentrations in this model [89]. Dextromethorphan also protected dopamine concentrations in mice treated with both MPTP and diethyldithiocarbamate [89]. In the methamphetamine mouse model of PD, dextromethorphan protected dopamine neurons and prevented microglial activation [90]. Finally, in the mouse neuroinflammatory LPS model of PD, dextromethorphan protected dopamine neurons, dopamine concentrations, and locomotor activity [87].
Drugs with multiple actions that may confer disease-modifying neuroprotection include dextromethorphan, valproate, lithium, and pramipexole. These drugs have neuroprotective effects on αSyn, except that the HDACI dextromethorphan lacked direct data for this protein, and lithium had neuroprotective effects on both αSyn and tau protein. One potential therapeutic strategy that might be tested in animal models and humans is the combination of valproate with dextromethorphan in attempting to therapeutically modulate H3 HDAC, GSK-3, αSyn, ROS, apoptosis, and trophic factors.
ncbi.nlm.nih.gov/pmc/articles/PMC3255316/