Adrenalectomy exacerbates stress-induced impairment in fear discrimination: A causal role for kynurenic acid?

Impaired activity of the hypothalamic-pituitary axis and reduced blood levels of glucocorticoids (GCs) are signature features of stress-related maladies. Recent evidence suggests a possible role of the tryptophan metabolite kynurenic acid (KYNA) in this context. Here we investigated possible causal relationships in adult male rats, using stress-induced fear discrimination as a translationally relevant behavioral outcome measure. One week following adrenalectomy (ADX) or sham surgery, animals were for 2 h either physically restrained or exposed to a predator odor, which caused a much milder stress response. Extracellular KYNA levels were determined before, during and after stress by in vivo microdialysis in the prefrontal cortex. Separate cohorts underwent a fear discrimination procedure starting immediately after stress termination. Different auditory conditioned stimuli (CS) were either paired with a foot shock (CS+) or non-reinforced (CS-). One week later, fear was assessed by re-exposing the animals to each CS. Separate groups of rats were treated with the KYNA synthesis inhibitor BFF-816 prior to stress initiation to test a causal role of KYNA in fear discrimination. Restraint stress raised extracellular KYNA levels by ∼85 % in ADX rats for several hours, and these animals were unable to discriminate between CS+ and CS-. Both effects were prevented by BFF-816 and were not observed after exposure to predator odor or in sham-operated rats. These findings suggest that a causal connection exists between adrenal function, stress-induced KYNA increases, and behavioral deficits. Pharmacological inhibition of KYNA synthesis may therefore be an attractive, novel option for the treatment of stress-related disorders.

Stress-induced impairment in fear discrimination is causally related to increased kynurenic acid formation in the prefrontal cortex.

RATIONALE: Stress is related to cognitive impairments which are observed in most major brain diseases. Prior studies showed that the brain concentration of the tryptophan metabolite kynurenic acid (KYNA) is modulated by stress, and that changes in cerebral KYNA levels impact cognition. However, the link between these phenomena has not been tested directly so far. OBJECTIVES: To investigate a possible causal relationship between acute stress, KYNA, and fear discrimination. METHODS: Adult rats were exposed to one of three acute stressors-predator odor, restraint, or inescapable foot shocks (ISS)-and KYNA in the prefrontal cortex was measured using microdialysis. Corticosterone was analyzed in a subset of rats. Another cohort underwent a fear discrimination procedure immediately after experiencing stress. Different auditory conditioned stimuli (CSs) were either paired with foot shock (CS+) or were non-reinforced (CS-). One week later, fear was assessed by re-exposing rats to each CS. Finally, to test whether stress-induced changes in KYNA causally impacted fear discrimination, a group of rats that received ISS were pre-treated with the selective KYNA synthesis inhibitor PF-04859989. RESULTS: ISS caused the greatest increase in circulating corticosterone levels and raised extracellular KYNA levels by ~ 85%. The two other stressors affected KYNA much less (< 25% increase). Moreover, only rats that received ISS were unable to discriminate between CS+ and CS-. PF-04859989 abolished the stress-induced KYNA increase and also prevented the impairment in fear discrimination in animals that experienced ISS. CONCLUSIONS: These findings demonstrate a causal connection between stress-induced KYNA increases and cognitive deficits. Pharmacological manipulation of KYNA synthesis therefore offers a novel approach to modulate cognitive processes in stress-related disorders.

A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites.

Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these (1) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood-brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer's disease, and Parkinson's disease.