TY - JOUR
T1 - 1,4-dihydroxy-2-naphthoic acid prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced motor function deficits
AU - Madison, Caitlin A.
AU - Debler, Roanna A.
AU - Gallegos, Paula L.
AU - Hillbrick, Lauren
AU - Chapkin, Robert S.
AU - Safe, Stephen
AU - Eitan, Shoshana
N1 - Publisher Copyright:
Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2024/12/12
Y1 - 2024/12/12
N2 - Parkinson’s disease (PD), characterized by death of dopaminergic neurons in the substantia nigra, is the second most prevalent progressive neurodegenerative disease. However, the etiology of PD is largely elusive. This study employed the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model to examine the effectiveness of 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA), an aryl hydrocarbon receptor (AhR) active gut bacteria-derived metabolite, in mitigating MPTP’s motoric deficits, and the role of AhR in mediating these effects. Male C57BL/6 mice were fed daily with vehicle, 20 mg/kg 1,4-DHNA, or AhR-inactive isomer 3,7-DHNA, for 3 weeks before administration of 80 mg/kg MPTP or vehicle. Four weeks later, mice were assessed for motoric functions. Both 1,4-DHNA and 3,7-DHNA prevented MPTP-induced deficits in the motor pole test and in the adhesive strip removal test. Additionally, 1,4-DHNA improved balance beam performance and completely prevented MPTP-induced reduction in stride length. In contrast, 3,7-DHNA, an AhR-inactive compound, did not improve balance beam performance and had only a partial effect on stride length. This study suggests that natural metabolites of gut microbiota, such as 1,4-DHNA, could be beneficial to counteract the development of motor deficits observed in PD. Thus, this study further supports the hypothesis that pathological and mitigating processes in the gut could play an essential role in PD development. Moreover, this indicates that 1,4-DHNA’s ability to combat various motor deficits is likely mediated via multiple underlying molecular mechanisms. Specifically, AhR is involved, at least partially, in control of gait and bradykinesia, but it likely does not mediate the effects on fine motor skills.
AB - Parkinson’s disease (PD), characterized by death of dopaminergic neurons in the substantia nigra, is the second most prevalent progressive neurodegenerative disease. However, the etiology of PD is largely elusive. This study employed the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model to examine the effectiveness of 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA), an aryl hydrocarbon receptor (AhR) active gut bacteria-derived metabolite, in mitigating MPTP’s motoric deficits, and the role of AhR in mediating these effects. Male C57BL/6 mice were fed daily with vehicle, 20 mg/kg 1,4-DHNA, or AhR-inactive isomer 3,7-DHNA, for 3 weeks before administration of 80 mg/kg MPTP or vehicle. Four weeks later, mice were assessed for motoric functions. Both 1,4-DHNA and 3,7-DHNA prevented MPTP-induced deficits in the motor pole test and in the adhesive strip removal test. Additionally, 1,4-DHNA improved balance beam performance and completely prevented MPTP-induced reduction in stride length. In contrast, 3,7-DHNA, an AhR-inactive compound, did not improve balance beam performance and had only a partial effect on stride length. This study suggests that natural metabolites of gut microbiota, such as 1,4-DHNA, could be beneficial to counteract the development of motor deficits observed in PD. Thus, this study further supports the hypothesis that pathological and mitigating processes in the gut could play an essential role in PD development. Moreover, this indicates that 1,4-DHNA’s ability to combat various motor deficits is likely mediated via multiple underlying molecular mechanisms. Specifically, AhR is involved, at least partially, in control of gait and bradykinesia, but it likely does not mediate the effects on fine motor skills.
KW - 1,4-dihydroxy-2-naphthoic acid
KW - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
KW - 3,7-dihydroxy-2-naphthoic acid
KW - Parkinson’s disease
KW - aryl hydrocarbon receptor
KW - gut microbiota
KW - motor control
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UR - http://www.scopus.com/inward/citedby.url?scp=85212286694&partnerID=8YFLogxK
U2 - 10.1097/FBP.0000000000000806
DO - 10.1097/FBP.0000000000000806
M3 - Article
C2 - 39660867
AN - SCOPUS:85212286694
SN - 0955-8810
JO - Behavioural Pharmacology
JF - Behavioural Pharmacology
M1 - 10.1097/FBP.0000000000000806
ER -