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 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.

Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily spread to cortical and subcortical structures and lead to isolated behavioral symptoms

“…We also quantified tyrosine hydroxylase positive (TH+) fluorescence levels in the PFC, striatum, ventral tegmental area, and substantia nigra (Fig. 2G), similar to prior methods established in the lab (Weber et al, 2022). We found no significant change in TH+ fluorescent levels in PFF-injected mice compared with controls in any of the four regions: PFC ( t (14) = 0.38; p = 0.71), striatum ( t (14) = 0.07; p = 0.99), ventral tegmental area ( t (14) = 0.57; p = 0.58), and substantia nigra ( t (14) = 0.10; p = 0.92).…”

“…The data presented here, and our prior report demonstrate that PFC PFFs are not sufficient to affect interval timing. This may because midbrain dopaminergic cell loss, which is absent in this model, may be necessary for interval timing deficits (Kim et al, 2017; Weber et al, 2022).…”

“…Interval Timing Switch Task: All mice were trained to perform an interval timing switch task described in detail previously (Balci et al, 2008;Bruce et al, 2021;Larson et al, 2022;Weber et al, (which was not certified by peer review) is the author/funder. All rights reserved.…”

“…Interval Timing Switch Task: All mice were trained to perform an interval timing switch task described in detail previously (Balci et al, 2008;Bruce et al, 2021;Larson et al, 2022;Weber et al, 2022). Interval timing behavior was assessed on two occasions: 1) 12 mpi; 2) 20 mpi.…”

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

“…It is known that impaired energy metabolism is a critical factor in PD, and preclinical studies have found that terazosin, a glycolysis‐enhancing agent, increases energy metabolism and protects against motor degeneration in the MPTP mouse model, 6‐OHDA rat model, and synuclein‐overexpressing mice 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 …”