Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke

Bravo-Ferrer, Isabel; Cuartero, María Isabel; Zarruk, Juan G.; Pradillo, Jesús M.; Hurtado, Olivia; Romera, Víctor G.; Díaz-Alonso, Javier; García‐Segura, Juan M.; Guzmán, Manuel; Lizasoaín, Ignacio; Galve‐Roperh, Ismael; Moro, Marı́a A.

doi:10.1161/strokeaha.116.014793

Cited by 60 publications

(45 citation statements)

References 50 publications

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“…These inconsistencies may be due to differences in study design, including seizure induction paradigm, species, and the specific agonist tested. [49][50][51][52] The inclusion of Cnr2 −/− mice in our study also served as a control for drug specificity, as drugs acting at CB2Rs would not be expected to have any effect on mice lacking functional receptors. A, Male Cnr2 −/− /R1648H (RH; teal stripe) and Cnr2 +/− /RH (gray stripe) mutants exhibit decreased latency to myoclonic jerk (MJ) when compared to wild-type (WT; black; ## P < .01, ### P < .001).…”

Section: Discussionmentioning

confidence: 99%

“…[46][47][48] The doses of JWH-133 and SR144528 used in this study were selected because they had been previously shown to elicit effects in the brain in other models of neurological disorders. [49][50][51][52] The inclusion of Cnr2 −/− mice in our study also served as a control for drug specificity, as drugs acting at CB2Rs would not be expected to have any effect on mice lacking functional receptors.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

2019

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“…LPS-injected models have been used to represent a pro-inflammatory rather than anti-inflammatory state. Thus, they might not be the most suitable for evaluating of CB 2 R. CB 2 R imaging in an animal model of stroke Ischemic stroke involves a cascade of hemodynamic, vascular, structural, and inflammatory responses in a time-dependent manner [54][55][56]. Inflammation is implicated in the initial neuronal loss and consists mainly of pro-inflammatory responses and the extension of the lesion in the penumbra; the subsequent [43] was reported in an SD rat model of photothrombotic stroke at 24 h after surgery.…”

Section: Cb 2 Imaging In Animal Modelsmentioning

confidence: 99%

Positron emission tomography of type 2 cannabinoid receptors for detecting inflammation in the central nervous system

Ametamey

2018

Acta Pharmacol Sin

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Cannabinoid receptor CB (CBR) is upregulated on activated microglia and astrocytes in the brain under inflammatory conditions and plays important roles in many neurological diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. The advent of positron emission tomography (PET) using CBR radiotracers has enabled the visualization of CBR distribution in vivo in animal models of central nervous system inflammation, however translation to humans has been less successful. Several novel CBR radiotracers have been developed and evaluated to quantify microglial activation. In this review, we summarize the recent preclinical and clinical imaging results of CBR PET tracers and discuss the prospects of CBR imaging using PET.

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“…Researchers have shown that newly generated neuroblasts from the subventricular zone (SVZ) can migrate into the infarct area and promote neurologic recovery after stroke by differentiating into mature neurons and modulating local immunoreactions (Parent et al, 2002, Tobin et al, 2014). Neurogenesis has been widely regarded as a prognostic indicator in stroke research, and its promotion has been shown to be neuroprotective (Bravo-Ferrer et al, 2017, Song et al, 2017). Conversely, inhibition of SVZ neurogenesis can aggravate neurologic damage and worsen stroke outcomes (Wang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Effects of crenolanib, a nonselective inhibitor of PDGFR, in a mouse model of transient middle cerebral artery occlusion

Wang

Zhang

et al. 2017

Neuroscience

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Neurogenesis in the subventricular zone (SVZ) plays a vital role in neurologic recovery after stroke. However, only a small fraction of newly generated neuroblasts from the SVZ will survive long-term. Successful migration and survival of neuroblasts requires angiogenesis, lesion-derived chemo-attractants, and appropriate local microenvironments, which are partly regulated by the platelet-derived growth factor receptor (PDGFR) signaling pathway. In this study, we investigated the effects of PDGFR inhibition in a mouse model of transient middle cerebral artery occlusion (MCAO). We blocked the pathway using a selective pan-PDGFR inhibitor, crenolanib, during the acute post-MCAO phase (days 1–3) or during the sub-acute phase (days 7–9). Downregulating the PDGFR signaling pathway with crenolanib from day 1 to day 3 after MCAO significantly decreased the migration of neuroblasts from the SVZ to the peri-infarct region, decreased angiogenesis, and lowered expression of vascular endothelial growth factor, stromal cell-derived factor-1, and monocyte chemotactic protein-1. Downregulation of the PDGFR signaling pathway on days 7 to 9 with crenolanib significantly increased apoptosis of the neuroblasts that had migrated to the peri-infarct region, increased the number of activated microglia, and decreased the expression of brain-derived neurotrophic factor, neurotrophin-3, and interleukin-10. Crenolanib treatment increased the apoptosis of pericytes and decreased the pericyte/vascular coverage, but had no effects on apoptosis of astrocytes. We conclude that PDGFR signaling pathway plays a vital role in the SVZ neurogenesis after stroke, it can also affect angiogenesis, lesion-derived chemo-attractants and local microenvironment, which are of importance in the stroke-induced neurogenesis.

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Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke

Cited by 60 publications

References 50 publications

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

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

Positron emission tomography of type 2 cannabinoid receptors for detecting inflammation in the central nervous system

Effects of crenolanib, a nonselective inhibitor of PDGFR, in a mouse model of transient middle cerebral artery occlusion

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