The Neuroprotective Disease-Modifying Potential of Psychotropics in Parkinson's Disease

Figure 1

Factors affecting the viability of dopamine neurons. Relations terminating in an arrowhead indicate facilitation, those with double arrowheads indicate mutual facilitation, and dashed lines terminating in a bulb indicate inhibition. Though still being settled, recent data suggest that alpha-synuclein (αSyn) is neuroprotective whereas monoubiquitylated αSyn, aggregated αSyn, and other pathogenic proteins promote neurodegeneration. H3 histone deacetylase inhibition (HDACI) increases αSyn, brain derived neurotrophic factor (BDNF), and glial derived neurotrophic factor (GDNF), supporting neuronal synapses (αSyn) and providing trophic support for neurons and promoting neurogenesis (BDNF and GDNF). Neurotrophism appears to be facilitated by D3 dopamine receptor stimulation. HDACI also inhibits inflammation. Aggregated proteins inhibit the proteasome, promote reactive oxygen species (ROS), mitochondrial dysfunction, inflammation, and apoptosis, and impair neuronal viability. Inhibition of the proteasome results in reduced elimination of obsolete proteins, increases in aggregated protein species, facilitates apoptosis, and impairs neuronal viability. N-methyl-D-aspartate (NMDA) receptor activation by glutamate promotes neurotoxicity and apoptosis. Generation of peroxide radicals by MAOB promotes ROS. ROS and inflammation mutually promote each other, and each can induce apoptosis. Mitochondrial dysfunction and ROS also mutually promote each other. Impaired mitochondrial respiration through inhibition of respiratory chain complexes (I-IV) can produce mitochondrial dysfunction. Mitochondrial dysfunction leads to the loss of the mitochondrial membrane potential, opening of the mitochondrial permeability transition pore, and the release of cytochrome c and apoptosis inhibiting factor (AIF). Cytochrome c and AIF each independently trigger apoptosis. Protective factors against neurodegeneration include GBA, DRD3, CALB1, and other gene products. Thus, neurodegenerative processes include pathogenic proteins, proteasomal dysfunction, glutamate and other toxic molecules, NMDA receptor activation, ROS, mitochondrial dysfunction, apoptotic pathway activation, and subsequent neuroinflammation, in turn potentially inducing further ROS and apoptosis. Neuroprotective factors include GBA, MCCC1, CCDC62, HIP1R, DRD3, CALB1, αSyn, HDACI, BDNF, and GDNF. Neuroprotective factors promote while neurodegenerative processes impair the viability of the dopamine neuron. Nigral dopamine neurons promote normal motor functioning by release of dopamine on striatal D2 receptors, transcribed from the DRD2 gene, and reduced D2 stimulation is associated with Parkinson motor features.