Cannabinoid receptor subtypes 1 and 2 mediate long-lasting neuroprotection and improve motor behavior deficits after transient focal cerebral ischemia

Schmidt, Werner; Schäfer, Florian; Striggow, V.; Fröhlich, Katja; Striggow, Frank

doi:10.1016/j.neuroscience.2012.09.080

Cited by 38 publications

(43 citation statements)

References 77 publications

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“…Similar elevations of anandamide, 2-AG, and Nacylethanolamines have been detected in experimental cerebral ischemia [47][48][49][50]. As far as the cannabinoid receptors are concerned, most studies showed an upregulated expression of both CB 1 R and, in particular, CB 2 R in stroke, with neurons (for CB 1 R) and microglial/macrophages, astrocytes, and neutrophils (for CB 2 R) being the most common cellular substrates for these responses [33,[51][52][53][54]. However, some studies described downregulatory responses of both receptors at very early times after induction of ischemia [33,55].…”

Section: Cannabinoids and Acute Brain Damage: Stroke And Brain Traumamentioning

confidence: 66%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

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Cannabinoids form a singular family of plantderived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

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Section: Cannabinoids and Acute Brain Damage: Stroke And Brain Traumamentioning

confidence: 66%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

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“…More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9-14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20). The specificities of the detected CB 2 R protein and CB 2 -mRNA remain questionable, however, owing to a lack of controls using CB 1 −/− and CB 2 −/− mice in most previous studies (21).…”

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confidence: 99%

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Zhang

Gao

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

310

353

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Cannabinoid CB 2 receptors (CB 2 Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB 2 Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB 2 mRNA and CB 2 R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB 2 Rs by JWH133 or other CB 2 R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB 1 −/− mice are blocked by CB 2 R antagonist and absent in CB 2 −/− mice. These data suggest that CB 2 R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.T he presence of functional cannabinoid CB 2 receptors (CB 2 Rs) in the brain has been controversial. When CB 2 Rs were first cloned, in situ hybridization (ISH) failed to detect CB 2 mRNA in brain (1). Similarly, Northern blot and polymerase chain reaction (PCR) assays failed to detect CB 2 mRNA in brain (2-5). Therefore, CB 2 Rs were considered "peripheral cannabinoid receptors" (1, 6).In contrast, other studies using ISH and radioligand binding assays detected CB 2 mRNA and receptor binding in rat retina (7), mouse cerebral cortex (8), and hippocampus and striatum of nonhuman primates (9). More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9-14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20). The specificities of the detected CB 2 R protein and CB 2 -mRNA remain questionable, however, owing to a lack of controls using CB 1 −/− and CB 2 −/− mice in most previous studies (21). A currently accepted view is that brain CB 2 Rs are expressed predominantly in activated microglia during neuroinflammation, whereas brain neurons, except for a very small number in the brainstem, lack CB 2 R expression (21).On the other hand, we recently reported that brain CB 2 Rs modulate cocaine self-administration and cocaine-induced increases in locomotion and extracellular dopamine (DA) in the nucleus accumbens in mice (22). This finding is supported by recent studies demonstrating that systemic administration of the CB 2 R agonist O-1966 inhibited cocaine-induced conditioned place preference in WT mice, but not in CB 2 −/− mice (23), and that increased CB 2 R expression in mouse brain attenuates cocaine self-administration and cocaine-enhanced locomotion (19). In addition, brain CB 2 Rs may be involved in several DA-related CNS disorders, such as Parkinson's disease (24), schizophrenia (25), anxiety (26), and depression (27). The cellular mechanisms underlying CB 2 R modulation of DA-related behav...

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“…У взрослых людей нейрогенез является малоактивным процессом [14], и усиление этого эндогенного процесса может служить в качестве терапевтической стратегии для улучшения функциональных исходов у выживших после инсульта. В этом смысле эндоканнабиноидная система может быть перспективным кандидатом, учитывая ее четко установленную защитную роль при различной патологии головного мозга [15][16][17][18][19] и данные о ее способ-ности модулировать пролиферацию нейральных стволо-вых клеток [20,21], а также миграцию нейробластов in vitro и ex vivo [22] в физиологических условиях. Наиболее значимыми каннабиноидными рецепторами являются каннабиноидный рецептор 1-го типа (CB1R), в основном экспрессируемый нейронами [23], и каннабиноидный рецептор 2-го типа (CB2R), главным образом, располо-женный на клетках микроглии и, что более интересно, в нейрогенных нишах головного мозга в эмбриональном и постнатальном периодах [24][25][26].…”

Section: ключевые слова: хронический период (Chronic Phase) нейрогенunclassified

“…Consistently, mice on this pharmacological treatment, like mice with CB2R genetic deletion, displayed a lower number of new neurons (NeuN neurogenesis a limited process in humans, 14 enhancement of this endogenous process might serve as a therapeutic strategy to improve functional outcome of stroke survivors. In this sense, the endocannabinoid system could be a promising candidate, given its well-established protective role in different brain pathologies [15][16][17][18][19] and its reported capacity to modulate neural stem cell proliferation 20,21 as well as in vitro and ex vivo neuroblast migration 22 in physiological conditions. The most relevant cannabinoid receptors are cannabinoid type-1 receptor(CB1R), mainly expressed by neurons, 23 and cannabinoid type-2 receptor (CB2R), mostly located in microglia and, interestingly, in neurogenic niches of both embryonic and postnatal brain.…”

mentioning

confidence: 99%

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

Bravo-Ferrer¹,

Cuartero²,

Zarruk³

et al. 2017

Stroke

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+ /BrdU+ cells) in peri-infarct cortex 28 days after stroke when compared with vehicle-treated group, an effect accompanied by a worse sensorimotor performance in behavioral tests. The CB2R agonist did not affect neurogenesis or outcome in vivo, but increased the migration of neural progenitor cells in vitro; the CB2R antagonist alone did not affect in vitro migration. Conclusions-Our data support that CB2R is fundamental for driving neuroblast migration and suggest that an endocannabinoid tone is required for poststroke neurogenesis by promoting neuroblast migration toward the injured brain tissue, increasing the number of new cortical neurons and, conceivably, enhancing motor functional recovery after stroke.

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Cannabinoid receptor subtypes 1 and 2 mediate long-lasting neuroprotection and improve motor behavior deficits after transient focal cerebral ischemia

Cited by 38 publications

References 77 publications

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

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

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Cannabinoid receptor subtypes 1 and 2 mediate long-lasting neuroprotection and improve motor behavior deficits after transient focal cerebral ischemia

Cited by 38 publications

References 77 publications

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

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

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Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice