Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-Like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

Zhang, Jian; Teng, Zhao‐Qian; Song, Yunping; Hu, Mei; Chen, Chu

doi:10.1038/jcbfm.2014.247

Cited by 49 publications

(9 citation statements)

References 40 publications

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“…Previous studies have highlighted the anti-inflammatory effects of MAGL inhibition in acute and chronic brain insults and transgenic mouse models [ 10 , 11 , 23 , 24 ]. Additionally, the protective role of 2-AG in preserving BBB integrity after acute brain injury has been described [ 13 ].…”

Section: Resultsmentioning

confidence: 99%

Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury

Piro

Suidan

Quan

et al. 2018

J Neuroinflammation

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BackgroundAcute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae. Preserving or rescuing BBB integrity and homeostasis therefore represents a translational research area of high therapeutic potential.MethodsInduction of general and localized BBB disruption in mice was carried out using systemic administration of LPS and focal photothrombotic ischemic insult, respectively, in the presence and absence of the monoacylglycerol lipase (MAGL) inhibitor, CPD-4645. The effects of CPD-4645 treatment were assessed by gene expression analysis performed on neurovascular-enriched brain fractions, cytokine and inflammatory mediator measurement, and functional assessment of BBB permeability. The mechanism of action of CPD-4645 was studied pharmacologically using inverse agonists/antagonists of the cannabinoid receptors CB1 and CB2.ResultsHere, we demonstrate that the neurovasculature exhibits a unique transcriptional signature following inflammatory insults, and pharmacological inhibition of MAGL using a newly characterized inhibitor rescues the transcriptional profile of brain vasculature and restores its functional homeostasis. This pronounced effect of MAGL inhibition on blood-brain barrier permeability is evident following both systemic inflammatory and localized ischemic insults. Mechanistically, the protective effects of the MAGL inhibitor are partially mediated by cannabinoid receptor signaling in the ischemic brain insult.ConclusionsOur results support considering MAGL inhibitors as potential therapeutics for BBB dysfunction and cerebral edema associated with inflammatory brain insults.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1166-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury

Piro

Suidan

Quan

et al. 2018

J Neuroinflammation

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“…One report showed an increase in neuronal tau immunoreactivity ( 31 ) and another showed elevated amyloid precursor protein (APP) ( 13 ) at a variety of time points post-injury. A final study by Zhang and colleagues showed that monoacylglycerol lipase can lead to behavioral deficits and tauopathy characteristic of a CTE-like phenotype ( 32 ). These findings were further verified in other studies using transgenic models of amyloidosis and tauopathy in which repetitive injury paradigms produced elevated amyloid and tau levels with increased deposition.…”

Section: Implications For Modeling Cte: Results From Prior Cte Modelimentioning

confidence: 99%

Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery

et al. 2015

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Despite the extensive media coverage associated with the diagnosis of chronic traumatic encephalopathy (CTE), our fundamental understanding of the disease pathophysiology remains in its infancy. Only recently have scientific laboratories and personnel begun to explore CTE pathophysiology through the use of preclinical models of neurotrauma. Some studies have shown the ability to recapitulate some aspects of CTE in rodent models, through the use of various neuropathological, biochemical, and/or behavioral assays. Many questions related to CTE development, however, remain unanswered. These include the role of impact severity, the time interval between impacts, the age at which impacts occur, and the total number of impacts sustained. Other important variables such as the location of impacts, character of impacts, and effect of environment/lifestyle and genetics also warrant further study. In this work, we attempt to address some of these questions by exploring work previously completed using single- and repetitive-injury paradigms. Despite some models producing some deficits similar to CTE symptoms, it is clear that further studies are required to understand the development of neuropathological and neurobehavioral features consistent with CTE-like features in rodents. Specifically, acute and chronic studies are needed that characterize the development of tau-based pathology.

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“…For this reason, it has yet to be determined exactly how TDP-43 aggregates coincide and interact with pathological p-Tau accumulation. Overall, few mouse studies have sought to evaluate TDP-43 pathology after closed-head TBI [ 1 , 13 , 73 , 78 ]. Here, we found widespread TDP-43 expression following rTBI with a persistent presence of cytoplasmatic mislocalization by 6 months post rTBI.…”

Section: Discussionmentioning

confidence: 99%

Mouse closed head traumatic brain injury replicates the histological tau pathology pattern of human disease: characterization of a novel model and systematic review of the literature

Kahriman

Bouley

Smith

et al. 2021

acta neuropathol commun

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Traumatic brain injury (TBI) constitutes one of the strongest environmental risk factors for several progressive neurodegenerative disorders of cognitive impairment and dementia that are characterized by the pathological accumulation of hyperphosphorylated tau (p-Tau). It has been questioned whether mouse closed-head TBI models can replicate human TBI-associated tauopathy. We conducted longitudinal histopathological characterization of a mouse closed head TBI model, with a focus on pathological features reported in human TBI-associated tauopathy. Male C57BL/6 J mice were subjected to once daily TBI for 5 consecutive days using a weight drop paradigm. Histological analyses (AT8, TDP-43, pTDP-43, NeuN, GFAP, Iba-1, MBP, SMI-312, Prussian blue, IgG, βAPP, alpha-synuclein) were conducted at 1 week, 4 weeks, and 24 weeks after rTBI and compared to sham operated controls. We conducted a systematic review of the literature for mouse models of closed-head injury focusing on studies referencing tau protein assessment. At 1-week post rTBI, p-Tau accumulation was restricted to the corpus callosum and perivascular spaces adjacent to the superior longitudinal fissure. Progressive p-Tau accumulation was observed in the superficial layers of the cerebral cortex, as well as in mammillary bodies and cortical perivascular, subpial, and periventricular locations at 4 to 24 weeks after rTBI. Associated cortical histopathologies included microvascular injury, neuroaxonal rarefaction, astroglial and microglial activation, and cytoplasmatic localization of TDP-43 and pTDP-43. In our systematic review, less than 1% of mouse studies (25/3756) reported p-Tau using immunostaining, of which only 3 (0.08%) reported perivascular p-Tau, which is considered a defining feature of chronic traumatic encephalopathy. Commonly reported associated pathologies included neuronal loss (23%), axonal loss (43%), microglial activation and astrogliosis (50%, each), and beta amyloid deposition (29%). Our novel model, supported by systematic review of the literature, indicates progressive tau pathology after closed head murine TBI, highlighting the suitability of mouse models to replicate pertinent human histopathology.

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Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-Like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

Cited by 49 publications

References 40 publications

Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury

Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury

Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery

Mouse closed head traumatic brain injury replicates the histological tau pathology pattern of human disease: characterization of a novel model and systematic review of the literature

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