Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson’s disease

Abstract

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.

Complementary opposing D2-MSNs and D1-MSNs dynamics during interval timing

“…Computational modeling predicted that disrupting either D2-MSNs or D1-MSNs increased selfreported estimates of time, which was supported by both optogenetic and pharmacological experiments. Notably, these disruptions are distinct from increased timing variability reported with administrations of amphetamine, ventral tegmental area dopamine neuron lesions, and rodent models of neurodegenerative disease (Balci et al, 2008;Gür et al, 2020Gür et al, , 2019Larson et al, 2022;Weber et al, 2023). \Furthermore, our current data demonstrate that disrupting either D2-MSN or D1-MSN activity shifted MSN dynamics and degraded temporal encoding, supporting prior work (De Corte et al, 2019;Drew et al, 2007Drew et al, , 2003Stutt et al, 2023).…”

“…We focus on the time that mice depart the first nosepoke as the switch 'response'. Departing the first nosepoke is guided by temporal control of action because no external cue indicates when to switch from the first to the second nosepoke (Balci et al, 2008;Bruce et al, 2021;Tosun et al, 2016;Weber et al, 2023).…”

X‐Linked Levodopa‐Responsive Parkinsonism‐Epilepsy Syndrome: A Novel PGK1 Mutation and Literature Review

“…38 The analysis of the human PD patient database suggests that terazosin is associated with slowed motor symptom progression and even protection against developing PD. 38,39 Interestingly, PGK1's chromosomic location, Xq21.1, lies inside the susceptibility locus for classical PD associated with PARK12, Xq21-q25, which has no identified gene yet. 35 Finally, our report describes 3 cases of X-linked L-dopa-responsive parkinsonism epilepsy due to PGK1 mutation, the oldest in the literature, as well as a novel likely pathogenic variant in PGK1: p.(Gly317Asp).…”

Sex similarities and dopaminergic differences in interval timing.

“…We adapted an interval timing switch task used previously in rodents and humans (Balci et al, 2009; Larson et al, 2022; Weber et al, 2023). This task required participants to estimate when a short interval (2 s) had elapsed by switching response keys before the end of a longer interval (3 s; Figure 1A).…”

“…We trained mice on an interval timing switch task that assessed their ability to guide their behavior based on their internal representation of time (Figure 1D; Balci et al, 2008; Larson et al, 2022; Weber et al, 2023). Training occurred in operant chambers placed in sound attenuating cabinets (MedAssociates, St. Albans, VT).…”