Upregulation of the cannabinoid CB2 receptor in environmental and viral inflammation-driven rat models of Parkinson's disease

Concannon, Ruth M.; Okine, Bright N.; Finn, David P.; Dowd, Eilís

doi:10.1016/j.expneurol.2016.06.014

Cited by 48 publications

(39 citation statements)

References 56 publications

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“…In recent study, up‐regulation of the CB2R was shown in inflammation‐driven PD rat model (Concannon et al . ). Although more studies are necessary, these findings suggest that CB2Rs function in the pathophysiology of PD.…”

Section: Changes In the Endocannabinoid System In Neurodegenerative Dmentioning

confidence: 97%

Endocannabinoid system in neurodegenerative disorders

Basavarajappa

Shivakumar

Joshi

et al. 2017

Journal of Neurochemistry

154

140

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Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid (EC) system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs.

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Section: Changes In the Endocannabinoid System In Neurodegenerative Dmentioning

confidence: 97%

Endocannabinoid system in neurodegenerative disorders

Basavarajappa

Shivakumar

Joshi

et al. 2017

Journal of Neurochemistry

154

140

View full text Add to dashboard Cite

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“…Since microglial activation leads to upregulation of CB 2 and A 2A receptor expression (Carlisle, Marciano‐Cabral, Staab, Ludwick, & Cabral, ; Concannon, Okine, Finn, & Dowd, , ; Correa et al, ; Gyoneva et al, ; Madeira, Rashid, Ambrósio, Santiago, & Langmann, ; Maresz, Carrier, Ponomarev, Hillard, & Dittel, ; Mecha, Carrillo‐Salinas, Feliú, Mestre, & Guaza, ; van der Putten et al, ), our next aim was to identify the heteromer in microglia and any differential expression of A 2A ‐CB 2 Hets in resting versus activated microglial cells. In resting microglia the different signal transduction read‐outs led to results that were similar to those found in cotransfected HEK‐293T cells.…”

Section: Resultsmentioning

confidence: 99%

“…Resting microglia express more CB 1 R than CB 2 R and cannabinoids help to impede cell activation. Interestingly, A 2A and CB 2 receptors have in common that they are upregulated upon microglial activation (Aires et al, 2019;Benito et al, 2005;Concannon et al, 2015Concannon et al, , 2016Fishman et al, 2009;Maresz et al, 2005;van der Putten et al, 2009). Evidence comes from in vitro assays, for instance in primary cultures of microglia from rodent brain, and also from data obtained using brain samples from patients suffering from CNS diseases coursing with neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

Franco

Reyes‐Resina

Aguinaga

et al. 2019

Glia

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Neuroprotective M2‐skewed microglia appear as promising to alter the course of neurodegenerative diseases and G protein‐coupled receptors (GPCRs) are potential targets to achieve such microglial polarization. A common feature of adenosine A2A (A2AR) and cannabinoid CB2 (CB2R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB2R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases. A2AR antagonists reduce amyloid burden and improve cognitive performance and memory in AD animal models. We here show a close interrelationship between these two receptors in microglia; they are able to physically interact and affect the signaling of each other, likely due to conformational changes within the A2A‐CB2 receptor heteromer (A2A‐CB2Het). Particularly relevant is the upregulation of A2A‐CB2Het expression in samples from the APPSw,Ind AD transgenic mice model. The most relevant finding, confirmed in both heterologous cells and in primary cultures of microglia, was that blockade of A2A receptors results in increased CB2R‐mediated signaling. This heteromer‐specific feature suggests that A2AR antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.

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“…[14][15][16][17][18] In contrast, cannabinoid 2 receptors (CB2Rs) have received less attention for their role in the central nervous system. 20,[23][24][25] Furthermore, CB2Rs are highly upregulated in response to brain injury in several mouse models, 26,27 including a rat model of epilepsy in which CB2R expression was upregulated on hippocampal neurons following status epilepticus, suggesting that CB2Rs may play a protective role following injury. [19][20][21][22] Although the cell-specific pattern of CB2R expression in the brain remains controversial, both microglial and neuronal expression have been described.…”

Section: Introductionmentioning

confidence: 99%

Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice

2019

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Objective: The endocannabinoid system (ECS) is comprised of cannabinoid receptors 1 and 2 (CB1R and CB2R), endogenous ligands, and regulatory enzymes, and serves to regulate several important physiological functions throughout the brain and body. Recent evidence suggests that the ECS may be a promising target for the treatment of epilepsy, including epilepsy subtypes that arise from mutations in the voltage-gated sodium channel SCN1A. The objective of this study was to explore the effects of modulating CB2R activity on seizure susceptibility. Methods: We examined susceptibility to induced seizures using a number of paradigms in CB2R knockout mice (Cnr2 −/− ), and determined the effects of the CB2R agonist, JWH-133, and the CB2R antagonist, SR144528, on seizure susceptibility in wild-type mice. We also examined seizure susceptibility in Cnr2 mutants harboring the human SCN1A R1648H (RH) epilepsy mutation and performed Electroencephalography (EEG) analysis to determine whether the loss of CB2Rs would increase spontaneous seizure frequency in Scn1a RH mutant mice. Results: Both heterozygous (Cnr2 +/− ) and homozygous (Cnr2 −/− ) knockout mice exhibited increased susceptibility to pentylenetetrazole (PTZ)-induced seizures. The CB2R agonist JWH-133 did not significantly alter seizure susceptibility in wildtype mice; however, administration of the CB2R antagonist SR144528 resulted in increased susceptibility to PTZ-induced seizures. In offspring from a cross between the Cnr2 × RH lines, both Cnr2 and RH mutants were susceptible to PTZ-induced seizures; however, seizure susceptibility was not significantly increased in mutants expressing both mutations. No spontaneous seizures were observed in either RH or Cnr2/RH mutants during 336-504 hours of continuous EEG recordings. Significance: Our results demonstrate that reduced CB2R activity is associated with increased seizure susceptibility. CB2Rs might therefore provide a therapeutic target for the treatment of some forms of epilepsy. K E Y W O R D Scannabinoid 2 receptor, CB2R agonist, CB2R antagonist, SCN1A, seizure susceptibility 2360 | SHAPIRO et Al.

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Upregulation of the cannabinoid CB2 receptor in environmental and viral inflammation-driven rat models of Parkinson's disease

Cited by 48 publications

References 56 publications

Endocannabinoid system in neurodegenerative disorders

Endocannabinoid system in neurodegenerative disorders

Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice

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Upregulation of the cannabinoid CB2 receptor in environmental and viral inflammation-driven rat models of Parkinson's disease

Cited by 48 publications

References 56 publications

Endocannabinoid system in neurodegenerative disorders

Endocannabinoid system in neurodegenerative disorders

Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists

Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice

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Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists