Lack of the Nlrp3 Inflammasome Improves Mice Recovery Following Traumatic Brain Injury.

Natasha Irrera,Alessandra Bitto,Francesco Squadrito,Margherita Calò,Antonio David,Vincenzo Fodale,Giovanni Pallio,Gabriele Pizzino,Federica Mannino,Letteria Minutoli,Emanuela Mazzon,Domenica Altavilla,Vincenzo Arcoraci,Cosentino Francesca,Fausto Famà,Placido Bramanti

doi:10.3389/fphar.2017.00459

Abstract

Treatment for traumatic brain injury (TBI) remains elusive despite compelling evidence from animal models for a variety of therapeutic targets. The activation of the NLRP3 (Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome has been proposed as key point in the brain damage associated with TBI. NLRP3 was tested as potential target for reducing neuronal loss and promoting functional recovery in a mouse model of TBI. Male NLRP3-/- (n = 20) and wild type (n = 27) mice were used. A closed TBI model was performed and inflammatory and apoptotic markers were evaluated. A group of WT mice also received BAY 11-7082, a NLRP3 inhibitor, to further evaluate the role of this pathway. At 24 h following TBI NLRP3-/- animals demonstrated a preserved cognitive function as compared to WT mice, additionally brain damage was less severe and the inflammatory mediators were reduced in brain lysates. The administration of BAY 11-7082 in WT animals subjected to TBI produced overlapping results. At day 7 histology revealed a more conserved brain structure with reduced damage in TBI NLRP3-/- animals compared to WT. Our data indicate that the NLRP3 pathway might be exploited as molecular target for the short-term sequelae of TBI.

Highlights

Traumatic brain injury (TBI) and its sequelae are a common cause of death and disability in young adults all over the world (Maas et al, 2008)
The present study evaluated whether the lack of the NLRP3 inflammasome might ameliorate the course of traumatic brain injury (TBI), reducing inflammation and modulating the apoptotic machinery
Another paper studying the effect of propofol in rats subjected to blast TBI demonstrated a reduced NLRP3 activation and a consequent ameliorated brain damage due to the antioxidant and reactive oxygen species (ROS) scavenger effect of propofol (Ma et al, 2016)

Summary

Introduction

Traumatic brain injury (TBI) and its sequelae are a common cause of death and disability in young adults all over the world (Maas et al, 2008). TBI is a pathologic condition characterized by a direct damage in brain and by harmful secondary pathologic processes such as inflammation, oxidative-nitrosative stress, necrosis and apoptosis (Wang et al, 2007; Brouns and De Deyn, 2009). All these events may be responsible for physical disabilities as well as long-term cognitive, behavioral, psychological, and social deficits that influence lifestyle in TBI patients (Kurth et al, 1994). In particular microglia and astrocytes, are the main source of inflammatory molecules. Glial cells produce neurotoxic molecules, including reactive oxygen species (ROS) and proinflammatory cytokines such as Tumor Necrosis Factor alpha (TNF-α) and interleukins (e.g., IL-6 and IL-1β) (Reale et al, 2009; Yan et al, 2009)

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