Milnacipran Ameliorates Executive Function Impairments following Frontal Lobe Traumatic Brain Injury in Male Rats: A Multimodal Behavioral Assessment

Craine, Timothy J; Race, Nicholas S.; Kutash, Lindsay A.; Iouchmanov, Anna L.; Moschonas, Eleni H.; O’Neil, Darik A.; Sunleaf, Carlson R; Patel, Aarti; Patel, Neal B.; Grobengieser, Katherine O.; Marshall, Ian P.; Magdelinic, Taylor N; Cheng, Jeffrey P.; Bondi, Corina O.

doi:10.1089/neu.2022.0289

Cited by 6 publications

(4 citation statements)

References 88 publications

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“…Prior to rehabilitation, there was no injury effect on our 3-session version of the AST (Supplemental Fig 4-1), highlighting the importance of task selection for deficit identification. However, an AST variant using withinsession changes (more similar to PbR task) did detect frontal TBI deficits (Craine et al, 2023). In intact rats, reversal learning requires integration of the OFC, PFC, and ventral striatum (Dalton et al, 2014;Dalton et al, 2016;Amodeo et al, 2017).…”

Section: Discussionmentioning

confidence: 94%

Cognitive rehabilitation can improve brain injury-induced deficits in behavioral flexibility and impulsivity linked to impaired reward-feedback activity

Koloski

O'Hearn

Frankot

et al. 2023

Preprint

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Traumatic brain injury (TBI) affects a large population, resulting in severe cognitive impairments. Although cognitive rehabilitation is an accepted treatment for some deficits, studies in patients are limited in ability to probe physiological and behavioral mechanisms. Therefore, animal models are needed to optimize strategies. Frontal TBI in a rat model results in robust and replicable cognitive deficits, making this an ideal candidate for investigating cognitive rehabilitation. In this study, we report three distinct frontal TBI experiments assessing behavior well into the chronic post-injury period using male Long-Evans rats. First, we evaluated the impact of frontal injury on local field potentials recorded simultaneously from 12 brain regions during a probabilistic reversal learning task (PbR). Next, rats were tested on reversal learning (PbR) or impulsivity (differential reinforcement of low-rate behavior: DRL) and half received salient cues associated with reinforcement contingencies as a form of "cognitive rehabilitation". After rehabilitation on the PbR task, brains were stained for markers of activity. On the DRL, cues were devalued to determine if beneficial effects persisted on impulsive behavior. TBI resulted in outcome salience deficits evident in task performance and reward-feedback signals occurring at beta frequencies in orbitofrontal cortex (OFC) and associated frontostriatal regions. Cognitive rehabilitation improved flexibility and increased OFC activity. Rehabilitation also reduced impulsivity, even after cues were degraded, which was partially mediated by improvements in timing behavior. The current study established a robust platform for investigating cognitive rehabilitation in animals and identified a strong role for dysfunctional OFC signaling after frontal TBI.

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Section: Discussionmentioning

confidence: 94%

Cognitive rehabilitation can improve brain injury-induced deficits in behavioral flexibility and impulsivity linked to impaired reward-feedback activity

Koloski

O'Hearn

Frankot

et al. 2023

Preprint

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“…Craine et al studied the role of chronic IP milnacipran treatment (30 mg/kg/day), a serotonin-norepinephrine reuptake inhibitor (SNRI), in improving cognition in male rats subjected to frontal lobe injury. After TBI, rats treated with milnacipran performed significantly better in attentional set-shifting tasks compared to those treated with placebo, and their performance was comparable to that seen in sham rats [111]. In humans, a systematic review conducted by Yue et al demonstrated that the administration of SSRIs was associated with improvements in depressive symptoms following TBI [118,119].…”

Section: Serotoninmentioning

confidence: 97%

“…In the brain, serotonin is produced by neurons originating in the raphe nucleus located in the brainstem. Serotonin works as a neurotransmitter known for its role in regulating mood; however, it has also been shown to be involved in other processes such as neurogenesis and plasticity [107][108][109], cognition [110,111], memory [112], inflammation [113], and gut motility [114,115]. Serotonin and kynurenine, which are upregulated in inflammatory states, are both synthesized from tryptophan and compete for its availability.…”

Section: Serotoninmentioning

confidence: 99%

Dysregulated brain-gut axis in the setting of traumatic brain injury: review of mechanisms and anti-inflammatory pharmacotherapies

El Baassiri,

Raouf,

Badin

et al. 2024

J Neuroinflammation

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Traumatic brain injury (TBI) is a chronic and debilitating disease, associated with a high risk of psychiatric and neurodegenerative diseases. Despite significant advancements in improving outcomes, the lack of effective treatments underscore the urgent need for innovative therapeutic strategies. The brain-gut axis has emerged as a crucial bidirectional pathway connecting the brain and the gastrointestinal (GI) system through an intricate network of neuronal, hormonal, and immunological pathways. Four main pathways are primarily implicated in this crosstalk, including the systemic immune system, autonomic and enteric nervous systems, neuroendocrine system, and microbiome. TBI induces profound changes in the gut, initiating an unrestrained vicious cycle that exacerbates brain injury through the brain-gut axis. Alterations in the gut include mucosal damage associated with the malabsorption of nutrients/electrolytes, disintegration of the intestinal barrier, increased infiltration of systemic immune cells, dysmotility, dysbiosis, enteroendocrine cell (EEC) dysfunction and disruption in the enteric nervous system (ENS) and autonomic nervous system (ANS). Collectively, these changes further contribute to brain neuroinflammation and neurodegeneration via the gut-brain axis. In this review article, we elucidate the roles of various anti-inflammatory pharmacotherapies capable of attenuating the dysregulated inflammatory response along the brain-gut axis in TBI. These agents include hormones such as serotonin, ghrelin, and progesterone, ANS regulators such as beta-blockers, lipid-lowering drugs like statins, and intestinal flora modulators such as probiotics and antibiotics. They attenuate neuroinflammation by targeting distinct inflammatory pathways in both the brain and the gut post-TBI. These therapeutic agents exhibit promising potential in mitigating inflammation along the brain-gut axis and enhancing neurocognitive outcomes for TBI patients.

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“…While milnacipran continues to be an active subject of experimental and clinical studies focusing on chronic pain and major depression [ 9 , 10 , 11 ], it is also being evaluated for other disorders, including cognitive impairment after traumatic brain injury [ 12 ], apnea during Rett syndrome [ 13 ], attention-deficit/hyperactivity disorder [ 14 ] and autism spectrum disorder [ 15 ]. Curiously, there is a paucity of published studies reporting systemic and brain pharmacokinetics of milnacipran in rodents.…”

Section: Introductionmentioning

confidence: 99%

Systemic and Brain Pharmacokinetics of Milnacipran in Mice: Comparison of Intraperitoneal and Intravenous Administration

Bagchi,

Nozohouri,

Ahn

et al. 2023

Pharmaceutics

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Milnacipran is a dual serotonin and norepinephrine reuptake inhibitor, clinically used for the treatment of major depression or fibromyalgia. Currently, there are no studies reporting the pharmacokinetics (PK) of milnacipran after intraperitoneal (IP) injection, despite this being the primary administration route in numerous experimental studies using the drug. Therefore, the present study was designed to investigate the PK profile of IP-administered milnacipran in mice and compare it to the intravenous (IV) route. First a liquid chromatography–mass spectrometry (LC-MS/MS) method was developed and validated to accurately quantify milnacipran in biological samples. The method was used to quantify milnacipran in blood and brain samples collected at various time-points post-administration. Non-compartmental and PK analyses were employed to determine key PK parameters. The maximum concentration (Cmax) of the drug in plasma was at 5 min after IP administration, whereas in the brain, it was at 60 min for both routes of administration. Curiously, the majority of PK parameters were similar irrespective of the administration route, and the bioavailability was 92.5% after the IP injection. These findings provide insight into milnacipran’s absorption, distribution, and elimination characteristics in mice after IP administration for the first time and should be valuable for future pharmacological studies.

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Milnacipran Ameliorates Executive Function Impairments following Frontal Lobe Traumatic Brain Injury in Male Rats: A Multimodal Behavioral Assessment

Cited by 6 publications

References 88 publications

Cognitive rehabilitation can improve brain injury-induced deficits in behavioral flexibility and impulsivity linked to impaired reward-feedback activity

Cognitive rehabilitation can improve brain injury-induced deficits in behavioral flexibility and impulsivity linked to impaired reward-feedback activity

Dysregulated brain-gut axis in the setting of traumatic brain injury: review of mechanisms and anti-inflammatory pharmacotherapies

Systemic and Brain Pharmacokinetics of Milnacipran in Mice: Comparison of Intraperitoneal and Intravenous Administration

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