Terazosin is an α1-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson’s disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α1-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.
Terazosin is an α1-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson's disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function and produced a non-statistically significant trend towards protected VTA tyrosine hydroxylase levels. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α1-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.
Striatal pathways control motivation and movement; however, their role in cognition is unclear. We studied dorsomedial striatal cognitive processing during interval timing, an elementary cognitive task that requires mice to estimate intervals of several seconds. Interval timing involves working memory for temporal rules and attention to the passage of time. We discovered that both pharmacological and optogenetic disruptions of D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) or D1-dopamine receptor-expressing MSNs (D1-MSNs) delayed timing. Disrupting D2-MSNs or D1-MSNs did not affect task-specific movements. Furthermore, pharmacological blockade of D2-dopamine receptors or D1-dopamine receptors degraded dorsomedial MSN temporal encoding. We compared the timing-related firing of optogenetically-tagged D2-MSNs and D1-MSNs. Strikingly, we found that D2-MSNs and D1-MSNs exhibited opposite dynamics over temporal intervals despite similar effects of D2-MSN and D1-MSN disruptions. MSN dynamics helped construct and constrain a four-parameter drift-diffusion computational model that captured interval timing behavior and D2-MSN and D1-MSN perturbations. Despite opposing dynamics, disrupting either D2-MSNs or D1-MSNs slowed timing, implying that D2-MSNs and D1-MSNs make complementary contributions to interval timing. These data provide novel insight into basal ganglia cognitive operations beyond movement. Our findings carry implications for a broad range of human striatal diseases and for therapies targeting striatal pathways.
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