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. 2024 May;33(3):e14038.
doi: 10.1111/jsr.14038. Epub 2023 Sep 7.

Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances

Katherine M Rentschler  1 , Snezana Milosavljevic  1 , Annalisa M Baratta  2   3 , Courtney J Wright  1 , Maria V Piroli  1 , Zachary Tentor  4 , Homayoun Valafar  4 , Christian O'Reilly  4   5 , Ana Pocivavsek  1   2
Affiliations

Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances

Katherine M Rentschler et al. J Sleep Res. 2024 May.

Abstract

Patients with neurocognitive disorders often battle sleep disturbances. Kynurenic acid is a tryptophan metabolite of the kynurenine pathway implicated in the pathology of these illnesses. Modest increases in kynurenic acid, an antagonist at glutamatergic and cholinergic receptors, result in cognitive impairments and sleep dysfunction. We explored the hypothesis that inhibition of the kynurenic acid synthesising enzyme, kynurenine aminotransferase II, may alleviate sleep disturbances. At the start of the light phase, adult male and female Wistar rats received systemic injections of either: (i) vehicle; (ii) kynurenine (100 mg kg-1; i.p.); (iii) the kynurenine aminotransferase II inhibitor, PF-04859989 (30 mg kg-1; s.c.); or (iv) PF-04859989 and kynurenine in combination. Kynurenine and kynurenic acid levels were evaluated in the plasma and brain. Separate animals were implanted with electroencephalogram and electromyogram telemetry devices to record polysomnography, and evaluate the vigilance states wake, rapid eye movement sleep and non-rapid eye movement sleep following each treatment. Kynurenine challenge increased brain kynurenic acid and resulted in reduced rapid eye movement sleep duration, non-rapid eye movement sleep delta power and sleep spindles. PF-04859989 reduced brain kynurenic acid formation when given prior to kynurenine, prevented disturbances in rapid eye movement sleep and sleep spindles, and enhanced non-rapid eye movement sleep. Our findings suggest that reducing kynurenic acid in conditions where the kynurenine pathway is activated may serve as a potential strategy for improving sleep dynamics.

Keywords: neuropharmacology; non‐rapid eye movement sleep; rapid eye movement sleep; sleep spindles; tryptophan; ⍺7 nicotinic acetylcholine receptor.

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Conflict of interest statement

Conflict of interest disclosure: The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. KYNA levels in plasma and across brain regions are increased after the acute kynurenine challenge, and reversed after pretreatment with the KAT II inhibitor, PF-04859989.
(A) Schematic representation of truncated kynurenine pathway demonstrating key metabolites and pharmacological tools used in the present study. Adult rats were peripherally injected at Zeitgeber time (ZT) 0 with kynurenine (100 mg/kg) to induce de novo kynurenic acid (KYNA) formation. PF-04859989 (30 mg/kg), systemically active KAT II inhibitor, was given 30 minutes prior at ZT 23.5. Tissues were harvested at ZT 2. KYNA levels were evaluated in the (B) plasma; (C) cerebellum; (D) brainstem; (E) hypothalamus; (F) basal forebrain; (G) hippocampus; (H) cortex; (I) frontal cortex. All data are mean ± SEM. Two-way ANOVA analyses: ^P<0.05, ^^P<0.01, ^^^^P<0.0001; Bonferroni’s post hoc test: *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. N = 9–12 per group.
Figure 2.
Figure 2.. Kynurenine challenge reduces sleep and alters sleep architecture.
Adult rats were treated with vehicle or kynurenine (100 mg/kg) at Zeitgeber time (ZT) 0. Data are mean ± SEM, analyzed by two-way RM ANOVA, with significance shown in graphs as ^P<0.05, ^^P<0.01, ^^^P<0.001 and Bonferroni’s post hoc test **P<0.01, ***P<0.001, ****P<0.0001. (A) 1-hr bins of REMS duration. ZT x treatment: F23,437 = 1.635, P<0.05; treatment: F1,19 = 15.14, P<0.01; ZT: F23,437 = 30.82, P<0.0001. (B) 6-hr bins of REMS duration. ZT x treatment: F3,57 = 4.162, P<0.01; treatment: F1,19 = 15.15, P<0.001; ZT: F3,57 = 99.50, P<0.0001. (C) 6-hr bins of REMS bout number. ZT x treatment: F3,57 = 3.74, P<0.05; treatment: F1,19 = 8.510, P<0.01; ZT: F3,57 = 112.9, P<0.0001. (D) 1-hr bins of NREMS duration. ZT x treatment: F23,437 = 2.032, P<0.01; ZT: F23,437 = 69.02, P<0.0001 (E) 6-hr bins of NREMS duration. ZT: F3,57= 247.3, P<0.0001 (F) NREMS delta spectral power during the entire light phase. Treatment: F1,17 = 4.615, P<0.05; Frequency: F7,119 = 64.15, P<0.0001. N = 20 per group (8 males, 12 females).
Figure 3.
Figure 3.. Kynurenine challenge reduces NREM sleep spindle density.
Adult rats were treated with vehicle or kynurenine (100 mg/kg) at Zeitgeber time (ZT) 0. Sleep spindles were evaluated during the light phase. Data are mean ± SEM, analyzed by two-way RM ANOVA (A) NREMS spindle density (spindles/min NREMS). Treatment x ZT interaction: F2,16= 7.648, P<0.01. ZT: F2,28= 23.43, P<0.0001. (B) Average spindle duration. ZT: F2,28= 133.0, P<0.0001. (C) Spindle peak to peak (p2p) amplitude. ZT: F2,28= 4.023, P<0.05 (D) NREMS spindle power. Frequency: F39,741 = 185.0, P<0.0001. N = 20 per group (8 males, 12 females).
Figure 4.
Figure 4.. PF-04859989 treatment enhances NREM sleep architecture.
Adult rats were treated with vehicle, PF-04859989 (30 mg/kg), or PF-04859989 + kynurenine (100 mg/kg) at the start of the light phase. Data are mean ± SEM, analyzed by two-way RM ANOVA, with significance shown in graphs as ^P<0.05, and Dunnett’s post hoc test *P<0.05 (PF-04859989 + vehicle vs. vehicle), ***P<0.001 (PF-04859989 + kynurenine vs. vehicle). (A) 1-hr bins of REMS duration. ZT: F23,391= 23.98, P<0.0001. (B) 6-hr bins of REMS duration. ZT: F3,51 = 62.44, P<0.0001. (C) 6-hr bins of REMS bout number. ZT: F3,51 = 76.02, P<0.0001. (D) 1-hr bins of NREMS duration. ZT: F23,391= 86.51, P<0.0001 (E) 6-hr bins of NREMS duration. ZT: F3,51= 304.4, P<0.0001 (F) NREMS delta spectral power during the entire light phase. Frequency: F7,91 = 135.0, P<0.0001. N = 18 per group (9 males, 9 females).
Figure 5.
Figure 5.. Pretreatment with PF-04859989 prior to kynurenine challenge restores NREM spindle dynamics.
Adult rats were treated with vehicle, PF-04859989 (30 mg/kg), or PF-04859989 + kynurenine (100 mg/kg) at the start of the light phase. Sleep spindles were evaluated from ZT0–4. Data are mean ± SEM, analyzed by RM ANOVA. (A) NREMS spindle density (spindles/min NREMS). F2,32 = 0.2635, P=0.7700. (B) Average spindle duration. F2,32 = 0.1742, P=0.8409. (C) Spindle peak to peak (p2p) amplitude. F2,32 = 1.953, P=0.1583. (D) NREMS spindle power. Frequency: F39,663 = 840.3, P<0.0001. N = 18 per group (9 males, 9 females).
Figure 6.
Figure 6.. Pretreatment with PF-04859989 attenuates consequences of kynurenine challenge on REM and NREM sleep parameters.
In Sleep Study #1, adult rats were treated with vehicle or kynurenine (100 mg/kg) at Zeitgeber time (ZT) 0. In Sleep Study #2, adult rats were treated with vehicle (ZT 23.5 and ZT 0), PF-04859989 (30 mg/kg; ZT 23.5) + vehicle (ZT 0) or PF-04859989 (30 mg/kg; ZT 23.5) + kynurenine (100 mg/kg; ZT 0). To compare results from the two sleep studies, data were evaluated as percent change from vehicle. (A) REMS duration (ZT 0–12); Student’s T test, t36 = 5.344, ****P<0.0001 (B) NREMS slow wave spectral power (ZT 0–12), two-way ANOVA, F1,144 = 12.31, ***P<0.001 (C) spindle density (ZT 0–4); Student’s T test, t36 = 3.495, **P<0.01. All data are mean ± SEM. Kynurenine: N = 20; PF-04859989 + Kynurenine: N = 18.
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