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Treatment With 2-Pentadecyl-2-Oxazoline Restores Mild Traumatic Brain Injury-Induced Sensorial and Neuropsychiatric Dysfunctions

Traumatic brain injury (TBI) represents an important public health problem and is followed by neuroinflammation and neurological dysfunctions. It has been suggested that brain trauma is often associated to deep behavioral alterations and chronic pain-like syndrome. Despite inducing minimal brain dam...

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Autores principales: Boccella, Serena, Iannotta, Monica, Cristiano, Claudia, Iannotti, Fabio Arturo, Bello, Fabio Del, Guida, Francesca, Belardo, Carmela, Infantino, Rosmara, Ricciardi, Flavia, Giannella, Mario, Calignano, Antonio, Di Marzo, Vincenzo, Maione, Sabatino, Luongo, Livio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052365/
https://www.ncbi.nlm.nih.gov/pubmed/32161542
http://dx.doi.org/10.3389/fphar.2020.00091
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author Boccella, Serena
Iannotta, Monica
Cristiano, Claudia
Iannotti, Fabio Arturo
Bello, Fabio Del
Guida, Francesca
Belardo, Carmela
Infantino, Rosmara
Ricciardi, Flavia
Giannella, Mario
Calignano, Antonio
Di Marzo, Vincenzo
Maione, Sabatino
Luongo, Livio
author_facet Boccella, Serena
Iannotta, Monica
Cristiano, Claudia
Iannotti, Fabio Arturo
Bello, Fabio Del
Guida, Francesca
Belardo, Carmela
Infantino, Rosmara
Ricciardi, Flavia
Giannella, Mario
Calignano, Antonio
Di Marzo, Vincenzo
Maione, Sabatino
Luongo, Livio
author_sort Boccella, Serena
collection PubMed
description Traumatic brain injury (TBI) represents an important public health problem and is followed by neuroinflammation and neurological dysfunctions. It has been suggested that brain trauma is often associated to deep behavioral alterations and chronic pain-like syndrome. Despite inducing minimal brain damage, mild TBI (mTBI) leads to persistent behavioral changes, including anxiety, depression, social interaction impairment, and aggressiveness. The clinical management of these symptoms is still unsatisfactory and new pharmacological treatments are needed, especially for the aggressiveness and depression. In a mouse model of mTBI, we investigated the effect of 2-Pentadecyl-2-Oxazoline (PEA-OXA), a natural compound, that is a secondary metabolite, found in green and roasted coffee beans, on both the pain perception, and neuropsychiatric dysfunctions. We found that the compound acts as a α2 adrenergic antagonist and this mechanism is here described for the first time. Mild TBI mice, starting from 14-d post-trauma, developed anxious and aggressive behavior, whilst depressive-like behavior and impaired social interactions were observed from the 60th d onward. PEA-OXA normalized all the behavioral changes investigated. We also investigated the memory impairments through Morris Water Maze (MWM) test. Both sham and mTBI mice treated with PEA-OXA showed amelioration in the reversal task of the MWM. Nevertheless, the main symptom of the long-term mTBI is represented by the depressive-like behavior, which was completely reversed by PEA-OXA repeated administration. In humans, mTBI-induced depression precedes the appearance of dementias and is characterized by a massive deficit of GABAergic transmission in the cortices. We found that PEA-OXA normalized the GABA changes in the prefrontal cortex. In order to prove the α2-mediated effect of the PEA-OXA we have performed open field test in naïve animals by microinjecting into the medial prefrontal cortex the dexomedetomidine, a selective α2 agonist with or without PEA-OXA co-injection. We found that PEA-OXA antagonized the α2 agonist effect on the locomotor activity. Moreover, PEA-OXA microinjection into the medial prefrontal cortex induced an enhancement of dopamine release. Collectively, these data suggest that this natural compound, through its multi-target activity is able to: i) ameliorate behavioral alterations (i.e. depression), ii) selectively normalize cortical GABA levels, iii) rescue the impaired neuronal activity in the prefrontal cortex.
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spelling pubmed-70523652020-03-11 Treatment With 2-Pentadecyl-2-Oxazoline Restores Mild Traumatic Brain Injury-Induced Sensorial and Neuropsychiatric Dysfunctions Boccella, Serena Iannotta, Monica Cristiano, Claudia Iannotti, Fabio Arturo Bello, Fabio Del Guida, Francesca Belardo, Carmela Infantino, Rosmara Ricciardi, Flavia Giannella, Mario Calignano, Antonio Di Marzo, Vincenzo Maione, Sabatino Luongo, Livio Front Pharmacol Pharmacology Traumatic brain injury (TBI) represents an important public health problem and is followed by neuroinflammation and neurological dysfunctions. It has been suggested that brain trauma is often associated to deep behavioral alterations and chronic pain-like syndrome. Despite inducing minimal brain damage, mild TBI (mTBI) leads to persistent behavioral changes, including anxiety, depression, social interaction impairment, and aggressiveness. The clinical management of these symptoms is still unsatisfactory and new pharmacological treatments are needed, especially for the aggressiveness and depression. In a mouse model of mTBI, we investigated the effect of 2-Pentadecyl-2-Oxazoline (PEA-OXA), a natural compound, that is a secondary metabolite, found in green and roasted coffee beans, on both the pain perception, and neuropsychiatric dysfunctions. We found that the compound acts as a α2 adrenergic antagonist and this mechanism is here described for the first time. Mild TBI mice, starting from 14-d post-trauma, developed anxious and aggressive behavior, whilst depressive-like behavior and impaired social interactions were observed from the 60th d onward. PEA-OXA normalized all the behavioral changes investigated. We also investigated the memory impairments through Morris Water Maze (MWM) test. Both sham and mTBI mice treated with PEA-OXA showed amelioration in the reversal task of the MWM. Nevertheless, the main symptom of the long-term mTBI is represented by the depressive-like behavior, which was completely reversed by PEA-OXA repeated administration. In humans, mTBI-induced depression precedes the appearance of dementias and is characterized by a massive deficit of GABAergic transmission in the cortices. We found that PEA-OXA normalized the GABA changes in the prefrontal cortex. In order to prove the α2-mediated effect of the PEA-OXA we have performed open field test in naïve animals by microinjecting into the medial prefrontal cortex the dexomedetomidine, a selective α2 agonist with or without PEA-OXA co-injection. We found that PEA-OXA antagonized the α2 agonist effect on the locomotor activity. Moreover, PEA-OXA microinjection into the medial prefrontal cortex induced an enhancement of dopamine release. Collectively, these data suggest that this natural compound, through its multi-target activity is able to: i) ameliorate behavioral alterations (i.e. depression), ii) selectively normalize cortical GABA levels, iii) rescue the impaired neuronal activity in the prefrontal cortex. Frontiers Media S.A. 2020-02-25 /pmc/articles/PMC7052365/ /pubmed/32161542 http://dx.doi.org/10.3389/fphar.2020.00091 Text en Copyright © 2020 Boccella, Iannotta, Cristiano, Iannotti, Bello, Guida, Belardo, Infantino, Ricciardi, Giannella, Calignano, Di Marzo, Maione and Luongo http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Boccella, Serena
Iannotta, Monica
Cristiano, Claudia
Iannotti, Fabio Arturo
Bello, Fabio Del
Guida, Francesca
Belardo, Carmela
Infantino, Rosmara
Ricciardi, Flavia
Giannella, Mario
Calignano, Antonio
Di Marzo, Vincenzo
Maione, Sabatino
Luongo, Livio
Treatment With 2-Pentadecyl-2-Oxazoline Restores Mild Traumatic Brain Injury-Induced Sensorial and Neuropsychiatric Dysfunctions
title Treatment With 2-Pentadecyl-2-Oxazoline Restores Mild Traumatic Brain Injury-Induced Sensorial and Neuropsychiatric Dysfunctions
title_full Treatment With 2-Pentadecyl-2-Oxazoline Restores Mild Traumatic Brain Injury-Induced Sensorial and Neuropsychiatric Dysfunctions
title_fullStr Treatment With 2-Pentadecyl-2-Oxazoline Restores Mild Traumatic Brain Injury-Induced Sensorial and Neuropsychiatric Dysfunctions
title_full_unstemmed Treatment With 2-Pentadecyl-2-Oxazoline Restores Mild Traumatic Brain Injury-Induced Sensorial and Neuropsychiatric Dysfunctions
title_short Treatment With 2-Pentadecyl-2-Oxazoline Restores Mild Traumatic Brain Injury-Induced Sensorial and Neuropsychiatric Dysfunctions
title_sort treatment with 2-pentadecyl-2-oxazoline restores mild traumatic brain injury-induced sensorial and neuropsychiatric dysfunctions
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052365/
https://www.ncbi.nlm.nih.gov/pubmed/32161542
http://dx.doi.org/10.3389/fphar.2020.00091
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