Endocannabinoids regulate the activity of astrocytic hemichannels and the microglial response against an injury: In vivo studies

Vázquez, Carmen M.; Tolón, Rosa M.; Pazos, M. Ruth; Fernández, Marta; Koester, Erin C.; Cravatt, Benjamin F.; Hillard, Cecilia J.; Romero, Julián

doi:10.1016/j.nbd.2015.04.005

Cited by 33 publications

(27 citation statements)

References 51 publications

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“…As previously reported for astrocytes in culture (Benito et al, 2012), as well as in vivo (Vázquez et al, 2015), this divergence is suggestive of long-term adaptations in the FAAH -/-mouse that are not obtained with a short-term pharmacological blockade of the enzyme.…”

Section: Discussionsupporting

confidence: 77%

“…We have recently reported that astrocytes lacking FAAH activity exhibited an M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 exacerbated inflammatory response that was especially evident when challenged with a proinflammatory stimulus, such as beta-amyloid (Benito et al, 2012). Furthermore, recent data have corroborated that FAAH deletion leads to a pro-inflammatory phenotype also in vivo, particularly involving microglial cells (Ativie et al, 2014;Vázquez et al, 2015). On the other hand, a deficit in AEA production has also been linked to the cognitive dysfunction in AD (Jung et al, 2011).…”

Section: Introductionmentioning

confidence: 96%

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Endocannabinoid regulation of amyloid-induced neuroinflammation

Vázquez

Tolón

Grande

et al. 2015

Neurobiology of Aging

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The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer's disease (AD). We aimed to evaluate the effect of the pharmacologic and genetic inhibition of anandamide-degrading enzyme in a mouse model of AD (5xFAD). Pharmacologic inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines and also on the cognitive impairment, plaque deposition, and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1 mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques, and gliosis. These data reinforce the notion of a role for the EC system in neuroinflammation and open new perspectives on the relevance of modulating EC levels in the inflamed brain.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 96%

Endocannabinoid regulation of amyloid-induced neuroinflammation

Vázquez

Tolón

Grande

et al. 2015

Neurobiology of Aging

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“…In the situation of trauma, the astrocytes are the first to sense injury, and the activation of microglia is triggered by astrocytic ATP release. Lack of Cx43 hemichannels causes reduced leakage of ATP and thus inhibits the activation of microglia [25][26][27] . The release of TNF-α and IL-1β from LPS-activated microglia targets astrocytes mainly through Cx43 hemichannels [28,29] .…”

Section: Resultsmentioning

confidence: 99%

Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis

et al. 2015

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“…The selective activation of either cannabinoid receptor type is beneficial at preserving neuronal cells or preventing microglial activation induced by ␤-amyloid peptides (22,717). The beneficial effects of genetic or pharmacological inactivation of endocannabinoid degradative enzymes were also investigated (61,139,685,878). However, in agreement with the hypothesis that activation of CB1, particularly by 2-AG, might also contribute to some of the cognitive impairments in late stages of the disease, because of maladaptive neuromodulatory effects (603), also CB1 antagonists can produce beneficial effects (546), and a FAAH inhibitor capable of elevating 2-AG levels was shown to ameliorate memory retention loss caused by ␤-amyloid only when administered early after the insult (869).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

363

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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Endocannabinoids regulate the activity of astrocytic hemichannels and the microglial response against an injury: In vivo studies

Cited by 33 publications

References 51 publications

Endocannabinoid regulation of amyloid-induced neuroinflammation

Endocannabinoid regulation of amyloid-induced neuroinflammation

Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

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