A Controlled Cortical Impact Mouse Model for Mild Traumatic Brain Injury

Febinger, Heidi Y; Thomasy, Hannah E.; Gemma, Carmelina

doi:10.21769/bioprotoc.1901

Cited by 3 publications

(2 citation statements)

References 5 publications

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“…The composite Neuroscore was used to assess motor ability and reflexes. This test has previously demonstrated motor deficits for up to one-month post-TBI (McIntosh et al, 1989; Maegele et al, 2005; Zhang et al, 2005; Febinger et al, 2016). There were seven main parameters that contributed to the composite Neuroscore: right and left forelimb flexion, right and left hindlimb flexion, right and left resistance to lateral pulsion, and performance on the angle board.…”

Section: Methodsmentioning

confidence: 99%

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

Sadek,

Stover,

Liu

et al. 2023

Preprint

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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 three days post-injury (DPI), which normalized by seven 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.Significance StatementThe kynurenine pathway and its rate-limiting enzyme indoleamine 2,3 dioxygenase 1 (IDO1) have been implicated in a variety of neurological disorders, including traumatic brain injury. We have demonstrated increased IDO1 activity in male rats after fluid percussion injury, a widely used model of traumatic brain injury. Pharmacological IDO1 inhibition after fluid percussion injury improved performance on tests of memory and anxiety-like behaviors, demonstrating a role for IDO1 in traumatic brain injury outcomes and supporting further investigation into its potential as a therapeutic target.

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Section: Methodsmentioning

confidence: 99%

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

Sadek,

Stover,

Liu

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The composite Neuroscore was used to assess motor ability and reflexes. This test has previously demonstrated motor deficits for up to 1 month post-TBI (Febinger et al, 2016;Maegele et al, 2005;McIntosh et al, 1989;Zhang et al, 2005). There were seven main parameters that contributed to the composite Neuroscore: right and left forelimb flexion, right and left hindlimb flexion, right and left resistance to lateral pulsion, and performance on the angle board.…”

Section: Composite Neuroscorementioning

confidence: 99%

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

Sadek,

Stover,

Liu

et al. 2024

J of Neuroscience Research

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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.

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