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

Serena Boccella,Fabio Del Bello,Vincenzo Di Marzo,Flavia Ricciardi,Sabatino Maione,Monica Iannotta,Livio Luongo,Fabio Arturo Iannotti,Carmela Belardo,Antonio Calignano,Mario Giannella,Rosmara Infantino,Claudia Cristiano,Francesca Guida

doi:10.3389/fphar.2020.00091

Abstract

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.

Highlights

Traumatic brain injury (TBI) is an important public health problem
Mild traumatic brain injury, or, more concussion, is associated with several neuropsychiatric changes that are still neglected from a therapeutic management point of view
Safe pharmacological tools are needed for some of the concussion features related to the behavioral psychiatric changes such as aggressiveness, anxiety, obsessive compulsive like behaviors and depression, which are reported in the DSM-V for post traumatic stress disorders (PTSDs)

Summary

Introduction

Traumatic brain injury (TBI) is an important public health problem. It may be associated to several neurological dysfunctions, inflammatory processes, and cell death (Arciniegas, 2011). Brain trauma is divided into two phases: an early injury and a secondary late reaction. For every 100,000 people in the population, about 500 people per year present to an emergency department with mild traumatic brain injury (mTBI)/ concussion (Bazarian et al, 2005). Several animal models of TBI have been suggested (Shultz et al, 2016) It seems that neuroinflammatory and pro-apoptotic processes occur in the early phase of mTBI (Zetterberg et al, 2013), whereas plastic phenomena, responsible for the change in neuronal activity, become evident in the late phase. The secondary behaviors are associated with changes in brain activity, in particular in the medial prefrontal cortex (mPFC). In our hands PEA failed to counteract repetitive/anxious behaviours and had no effect on neuronal activity during the late phase of mTBI (Guida et al, 2017)

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