During the progression of Huntington's disease (HD), changes in Ca2+ signaling cause neuronal cells to lose a range of functional properties. GABAergic medium spiny neurons (MSNs) are able to prevent Ca2+ imbalance in the early stages of the illness through a number of compensatory strategies. However, as people become older, their neuroprotective potential diminishes due to a decrease in metabolic activity and the generation of Ca2+-buffering proteins. Continuing Ca2+ regulation problems exhaust the cells' compensatory abilities, resulting in a continuous surge in cytosolic Ca2+ and neuronal degeneration.The sigma 1 receptor (S1R) is a potential therapeutic target for the treatment of HD because it regulates a number of cytosolic Ca2+-dependent signaling cascades. S1R activation by selective agonists protects neurons from glutamate excitotoxicity, reduces store-operated Ca2+ entry (SOCE) hyperactivation, and maintains the structural integrity of mitochondria-associated endoplasmic reticulum membranes (MAMs), which is required for synchronizing mitochondrial and endoplasmic reticulum (ER) activity to maintain cell bioenergetics balance. Because of the stability of Ca2+ signaling in neurons, pridopidine, a highly selective S1R agonist, has been demonstrated to protect neurons in cellular and animal models of HD.The synaptoprotective effect of pridopidine is very important since it is found in both cortical and striatal neurons, indicating that pridopidine has a systemic influence on HD therapy. Because synaptic dysfunctions are one of the earliest markers of neuropathology at the cellular level, normalization of Ca2+ balance by pridopidine may prevent disease development at the molecular level at the earliest stages. In this regard, the most significant therapeutic advantage of pridopidine will almost certainly be in preventative treatment, even before the start of the first clinical indications, which will improve neuronal cell compensatory abilities and significantly reduce the progression of HD.
Connecting Neuronal Cell Protective Pathways and Drug Combinations in a Huntington’s Disease Model through the Application of Quantitative Systems Pharmacology
