Microglia activation states and cannabinoid system: Therapeutic implications

Mecha, Míriam; Carrillo‐Salinas, Francisco; Feliú, Ana; Mestre, Leyre; Guaza, Carmen

doi:10.1016/j.pharmthera.2016.06.011

Cited by 136 publications

(116 citation statements)

References 259 publications

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“…In multiple sclerosis and Huntington's disease, the overexpression of CB 2 receptors occurs in both activated astrocytes and reactive microglia (Benito et al, 2007; Sagredo et al, 2009). The increase in CB 2 receptors in activated glial elements may be related to the influence of these cells on neuronal homeostasis, for example, by enhancing metabolic support and glutamate reuptake activity exerted by astrocytes (Fernández-Ruiz et al, 2015 for review), by facilitating the transfer of microglial cells from M1 to M2 phenotypes (Mecha et al, 2016 for review) or by attenuating the generation of proinflammatory cytokines, chemokines, nitric oxide and reactive oxygen species by either astrocytes or microglial cells when they become activated (Fernández-Ruiz et al, 2015 for review). These possibilities place the receptor in a promising position for the development of novel therapies.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis

Fernández-Trapero

Espejo-Porras

Rodríguez‐Cueto

et al. 2017

Disease Models &Amp; Mechanisms

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Targeting of the CB2 receptor results in neuroprotection in the SOD1G93A mutant mouse model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB2 receptors are facilitated by their upregulation in the spinal cord of the mutant mice. Here, we investigated whether similar CB2 receptor upregulation, as well as parallel changes in other endocannabinoid elements, is evident in the spinal cord of dogs with degenerative myelopathy (DM), caused by mutations in the superoxide dismutase 1 gene (SOD1). We used well-characterized post-mortem spinal cords from unaffected and DM-affected dogs. Tissues were used first to confirm the loss of motor neurons using Nissl staining, which was accompanied by glial reactivity (elevated GFAP and Iba-1 immunoreactivity). Next, we investigated possible differences in the expression of endocannabinoid genes measured by qPCR between DM-affected and control dogs. We found no changes in expression of the CB1 receptor (confirmed with CB1 receptor immunostaining) or NAPE-PLD, DAGL, FAAH and MAGL enzymes. In contrast, CB2 receptor levels were significantly elevated in DM-affected dogs determined by qPCR and western blotting, which was confirmed in the grey matter using CB2 receptor immunostaining. Using double-labelling immunofluorescence, CB2 receptor immunolabelling colocalized with GFAP but not Iba-1, indicating upregulation of CB2 receptors on astrocytes in DM-affected dogs. Our results demonstrate a marked upregulation of CB2 receptors in the spinal cord in canine DM, which is concentrated in activated astrocytes. Such receptors could be used as a potential target to enhance the neuroprotective effects exerted by these glial cells.

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Section: Discussionmentioning

confidence: 99%

Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis

Fernández-Trapero

Espejo-Porras

Rodríguez‐Cueto

et al. 2017

Disease Models &Amp; Mechanisms

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“…Conflicting reports on the effects of eCB during inflammation abound in the literature, with some studies arguing that eCB display an anti‐inflammatory response in the CNS, whereas others suggest that the eCB rather enhance the pro‐inflammatory effects of LPS . Roche et al .…”

Section: Discussionmentioning

confidence: 99%

Participation of hypothalamic CB1 receptors in reproductive axis disruption during immune challenge

Surkin

Rosso

Correa

et al. 2017

J Neuroendocrinology

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Immune challenge inhibits reproductive function and endocannabinoids (eCB) modulate sexual hormones. However, no studies have been performed to assess whether the eCB system mediates the inhibition of hormones that control reproduction as a result of immune system activation during systemic infections. For that reason, we evaluated the participation of the hypothalamic cannabinoid receptor CB1 on the hypothalamic-pituitary-gonadal (HPG) axis activity in rats submitted to immune challenge. Male adult rats were treated i.c.v. administration with a CB1 antagonist/inverse agonist (AM251) (500 ng/5 μL), followed by an i.p. injection of lipopolysaccharide (LPS) (5 mg/kg) 15 minutes later. Plasmatic, hypothalamic and adenohypophyseal pro-inflammatory cytokines, hormones and neuropeptides were assessed 90 or 180 minutes post-LPS. The plasma concentration of tumour necrosis factor α and adenohypophyseal mRNA expression of Tnfα and Il1β increased 90 and 180 minutes post i.p. administration of LPS. However, cytokine mRNA expression in the hypothalamus increased only 180 minutes post-LPS, suggesting an inflammatory delay in this organ. CB1 receptor blockade with AM251 increased LPS inflammatory effects, particularly in the hypothalamus. LPS also inhibited the HPG axis by decreasing gonadotrophin-releasing hormone hypothalamic content and plasma levels of luteinising hormone and testosterone. These disruptor effects were accompanied by decreased hypothalamic Kiss1 mRNA expression and prostaglandin E2 content, as well as by increased gonadotrophin-inhibitory hormone (Rfrp3) mRNA expression. All these disruptive effects were prevented by the presence of AM251. In summary, our results suggest that, in male rats, eCB mediate immune challenge-inhibitory effects on reproductive axis at least partially via hypothalamic CB1 activation. In addition, this receptor also participates in homeostasis recovery by modulating the inflammatory process taking place after LPS administration.

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“…Similar to macrophages in the periphery and other organs, microglia exhibit differential activation states generally associated with pro‐inflammatory or immunoregulatory functions (Mecha, Carrillo‐Salinas, Feliu, Mestre, & Guaza, ). The former contribute to neuroinflammation and neuronal injury through secretion of pro‐inflammatory and neurotoxic mediators, whereas the latter exert crucial influences on tissue repair through production of anti‐inflammatory cytokines (Tang & Le, ).…”

Section: Subsets Of Microglia: More Than Pro‐inflammatory and Immunormentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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Microglia activation states and cannabinoid system: Therapeutic implications

Cited by 136 publications

References 259 publications

Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis

Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis

Participation of hypothalamic CB1 receptors in reproductive axis disruption during immune challenge

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

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