Palmitoylethanolamide Reduces Neuropsychiatric Behaviors by Restoring Cortical Electrophysiological Activity in a Mouse Model of Mild Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) represents a major public health problem, which is associated with neurological dysfunction. In severe or moderate cases of TBI, in addition to its high mortality rate, subjects may encounter diverse behavioral dysfunctions. Previous reports suggest that an association between TBI and chronic pain syndromes tends to be more common in patients with mild forms of brain injury. Despite causing minimal brain damage, mild TBI (mTBI) often leads to persistent psychologically debilitating symptoms, which can include anxiety, various forms of memory and learning deficits, and depression. At present, no effective treatment options are available for these symptoms, and little is known about the complex cellular activity affecting neuronal activity that occurs in response to TBI during its late phase. Here, we used a mouse model to investigate the effect of Palmitoylethanolamide (PEA) on both the sensorial and neuropsychiatric dysfunctions associated with mTBI through behavioral, electrophysiological, and biomolecular approaches. Fourteen-day mTBI mice developed anxious, aggressive, and reckless behavior, whilst depressive-like behavior and impaired social interactions were observed from the 60th day onward. Altered behavior was associated with changes in interleukin 1 beta (IL-1β) expression levels and neuronal firing activity in the medial prefrontal cortex. Compared with vehicle, PEA restored the behavioral phenotype and partially normalized the biochemical and functional changes occurring at the supraspinal level. In conclusion, our findings reveal some of the supraspinal modifications responsible for the behavioral alterations associated with mTBI and suggest PEA as a pharmacological tool to ameliorate neurological dysfunction induced by the trauma.

Pathophysiological and behavioral deficits in developing mice following rotational acceleration-deceleration traumatic brain injury

“…Evaluation of behavioral outcome at 3-6 months might provide additional value using this model. In order to identify the interdependency of vulnerable neurons and malfunction, the cell types/subpopulations of those degenerated neurons ( Zeisel et al, 2015 ) and more analyses of long-term behavioral changes ( Guida et al, 2017 ; Milman et al, 2005 ), including nociceptive response, depression-like activity and sociability, are worthy of further investigation. The serum and/or CSF concentrations of neuron-specific enolase (NSE; ENO2), S100B, myelin-basic protein (MBP), interleukin 6 (IL-6), vascular cell adhesion protein (VCAM1), and cortisol levels ( Berger et al, 2005 , 2006 , 2002 , 2009 ; Heather et al, 2012 ) were detected in children with AHT.…”

Palmitoylethanolamide Ameliorates Hippocampal Damage and Behavioral Dysfunction After Perinatal Asphyxia in the Immature Rat Brain

“…Palmitoylethanolamide (PEA) is an endogenous lipid compound derived from the reaction between ethanolamine and palmitic acid (Guida et al, 2017a ). PEA is member of the N-acylethanolamides (NAEs) family, characterized for inhibiting mechanisms of secondary injury (Ahmad et al, 2012a ).…”

“…PEA is member of the N-acylethanolamides (NAEs) family, characterized for inhibiting mechanisms of secondary injury (Ahmad et al, 2012a ). This pro-homeostatic mediator (Petrosino et al, 2010 ; Petrosino and Di Marzo, 2017 ) exerted neuroprotective effects when administered exogenously in models of brain injury and neurodegeneration (Herrera et al, 2016 ), including spinal cord injury (Genovese et al, 2008 ; Esposito et al, 2011 ), traumatic brain injury (Ahmad et al, 2012a ; Guida et al, 2017a ), stroke (Ahmad et al, 2012b ), Alzheimer's Disease (D'Agostino et al, 2012 ; Scuderi et al, 2014 ), and Parkinson's Disease (Esposito et al, 2012 ). These effects are apparently mediated by the nuclear Peroxisome Proliferator-Activated Receptor (PPAR)-α (Lo Verme et al, 2005 ).…”

Thrombin as Key Mediator of Seizure Development Following Traumatic Brain Injury

“…Our behavioral experiments were carried a day after the exposure to pilocarpine and two days after mTBI induction. Previous reports indicated that mTBI mice develop long term neuropsychiatric condition of increased anxiety and later depression (Guida et al, 2017;Belardo et al, 2019). In this sense, could a bigger time lag from the seizures restore the hippocampal abilities of the mTBI treated animals?…”