IDO‐1 inhibition improves outcome after fluid percussion injury in adult male rats

• Published in: Journal of neuroscience research 2024-05, Vol.102 (5), p.e25338-n/a
• Main Authors: Sadek, Marawan, Stover, Kurt R., Liu, Xiaojing, Reed, Mark A., Weaver, Donald F., Reid, Aylin Y.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; anxiety; Brain Injuries, Traumatic - drug therapy; Brain Injuries, Traumatic - enzymology; Cerebral cortex; Cognitive ability; Dioxygenase; Disease Models, Animal; Head injuries; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Indoles - administration & dosage; Inflammation; Inhibitors; kynurenine; Kynurenine - metabolism; learning and memory; Male; Males; Metabolites; Neocortex; Neurological complications; Neuroprotection; Neurotoxicity; Open-field behavior; Oral administration; Percussion; Rats, Sprague-Dawley; Recovery; Succinimides - administration & dosage; Therapeutic targets; Traumatic brain injury; Tryptophan
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.25338

The enzyme indoleamine 2,3 dioxygenase 1 (IDO1) catalyzes the rate‐limiting step in the kynurenine pathway (KP) which produces both neuroprotective and neurotoxic metabolites. Neuroinflammatory signals produced as a result of pathological conditions can increase production of IDO1 and boost its enzymatic capacity. IDO1 and the KP have been implicated in behavioral recovery after human traumatic brain injury (TBI), but their roles in experimental models of TBI are for the most part unknown. We hypothesized there is an increase in KP activity in the fluid percussion injury (FPI) model of TBI, and that administration of an IDO1 inhibitor will improve neurological recovery. In this study, adult male Sprague Dawley rats were subjected to FPI or sham injury and received twice‐daily oral administration of the IDO1 inhibitor PF‐06840003 (100 mg/kg) or vehicle control. FPI resulted in a significant increase in KP activity, as demonstrated by an increased ratio of kynurenine: tryptophan, in the perilesional neocortex and ipsilateral hippocampus 3 days postinjury (DPI), which normalized by 7 DPI. The increase in KP activity was prevented by PF‐06840003. IDO1 inhibition also improved memory performance as assessed in the Barnes maze and anxiety behaviors as assessed in open field testing in the first 28 DPI. These results suggest increased KP activity after FPI may mediate neurological dysfunction, and IDO1 inhibition should be further investigated as a potential therapeutic target to improve recovery. Pharmacological IDO1 inhibition was administered following the fluid percussion injury model of traumatic brain injury in young adult male rats. IDO1 inhibition prevented the increase in kynurenine pathway activity that was seen in the brain of the vehicle‐treated group at 3 days postinjury, as demonstrated by the ratio of kynurenine to tryptophan (A). IDO1 inhibition also resulted in improved outcomes in spatial memory tasks, with treated rats spending more time in the target quadrant of the Barnes maze compared to vehicle controls at 28 days postinjury (B). In addition, IDO1 inhibition resulted in less anxiety‐like behaviors, with rats spending a larger percentage of time in the inner field of the open field test compared to vehicle controls at 25 days postinjury (C). These results suggest increased KP activity after FPI may mediate neurological dysfunction, and IDO1 inhibition should be further investigated as a potential therapeutic target to improve recovery.