Cannabinoids, Blood–Brain Barrier, and Brain Disposition

Calapai, Fabrizio; Cardia, Luigi; Sorbara, Emanuela Elisa; Navarra, Michele; Gangemi, Sebastiano; Calapai, Gioacchino; Mannucci, Carmen

doi:10.3390/pharmaceutics12030265

Cited by 71 publications

(43 citation statements)

References 96 publications

(107 reference statements)

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“…CBD was demonstrated as effective in preventing disruption of an in vitro BBB model under hypoxic and glucose deprivation conditions (Hind et al, 2016). Altogether, these results suggest that activating TRPV2 might be a relevant strategy to positively modulate the BBB in the context of brain disorders including ischemic stroke (Calapai et al, 2020). Here, we looked at interspecies differences in the expression and activity of TRPV in rat and human BBB.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Study of Transient Receptor Potential Vanilloid 1-4 at the Rat and Human Blood–Brain Barrier Reveals Interspecies Differences

Luo

Saubaméa

Chasseigneaux

et al. 2020

Front. Cell Dev. Biol.

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Transient receptor potential vanilloid 1-4 (TRPV1-4) expression and functionality were investigated in brain microvessel endothelial cells (BMEC) forming the blood–brain barrier (BBB) from rat and human origins. In rat, Trpv1-4 were detected by qRT-PCR in the brain cortex, brain microvessels, and in primary cultures of brain microvessel endothelial cells [rat brain microvessel endothelial cells (rPBMEC)]. A similar Trpv1-4 expression profile in isolated brain microvessels and rPBMEC was found with the following order: Trpv4 > Trpv2 > Trpv3 > Trpv1 . In human, TRPV1-4 were detected in the BBB cell line human cerebral microvessel endothelial cells D3 cells (hCMEC/D3) and in primary cultures of BMEC isolated from human adult and children brain resections [human brain microvascular endothelial cells (hPBMEC)], showing a similar TRPV1-4 expression profile in both hCMEC/D3 cells and hPBMECs as follow: TRPV2 > > TRPV4 > TRPV1 > TRPV3 . Western blotting and immunofluorescence experiments confirmed that TRPV2 and TRPV4 are the most expressed TRPV isoforms in hCMEC/D3 cells with a clear staining at the plasma membrane. A fluorescent dye Fluo-4 AM ester was applied to record intracellular Ca 2+ levels. TRPV4 functional activity was demonstrated in mediating Ca 2+ influx under stimulation with the specific agonist GSK1016790A (ranging from 3 to 1000 nM, EC 50 of 16.2 ± 4.5 nM), which was inhibited by the specific TRPV4 antagonist, RN1734 (30 μM). In contrast, TRPV1 was slightly activated in hCMEC/D3 cells as shown by the weak Ca 2+ influx induced by capsaicin at a high concentration (3 μM), a highly potent and specific TRPV1 agonist. Heat-induced Ca 2+ influx was not altered by co-treatment with a selective potent TRPV1 antagonist capsazepine (20 μM), in agreement with the low expression of TRPV1 as assessed by qRT-PCR. Our present study reveals an interspecies difference between Rat and Human. Functional contributions of TRPV1-4 subtype expression were not identical in rat and human tissues reflective of BBB integrity. TRPV2 was predominant in the human whereas TRPV4 had a larger role in the rat. This interspecies difference from a gene expression point of view should be taken into consideration when modulators of TRPV2 or TRPV4 are investigated in rat models of brain disorders.

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Section: Discussionmentioning

confidence: 99%

Molecular and Functional Study of Transient Receptor Potential Vanilloid 1-4 at the Rat and Human Blood–Brain Barrier Reveals Interspecies Differences

Luo

Saubaméa

Chasseigneaux

et al. 2020

Front. Cell Dev. Biol.

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“…The endocannainoid system has been implicated in the modulation of the blood-brain barrier [178], and may likely be a potential target for the treatment and/or clinical management of neurological or psychiatric diseases such as schizophrenia and epilepsy [179]. Both AEA and 2-AG have been shown to regulate (decrease) the permeability in in vivo and in vitro models of ischaemia/reperfusion, chronic head injury, and multiple sclerosis [178,180,181].…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

Lowe

Toyang²,

Steele

et al. 2021

IJMS

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The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems. In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development. The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development. The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases. This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.

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“…In addition, a meta-analysis that reviewed 34 publications of cannabidiol-mediated ischemic stroke indicated that cannabidiol markedly reduced cerebral I/R-induced infarction [ 282 ]. Most importantly, cannabidiol was highly lipophilic and could easily cross BBB, reaching a relatively high concentration quickly after administration [ 283 ]. Notably, more than 100 clinical trials related to the therapeutic application of cannabidiol are being conducted or are completed at present, with several trials for CNS disorders.…”

Section: Phytochemicals That Exert Neuroprotection In Experimental Ischemic Strokementioning

confidence: 99%

Neuroprotective Phytochemicals in Experimental Ischemic Stroke: Mechanisms and Potential Clinical Applications

Wang

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ischemic stroke is a challenging disease with high mortality and disability rates, causing a great economic and social burden worldwide. During ischemic stroke, ionic imbalance and excitotoxicity, oxidative stress, and inflammation are developed in a relatively certain order, which then activate the cell death pathways directly or indirectly via the promotion of organelle dysfunction. Neuroprotection, a therapy that is aimed at inhibiting this damaging cascade, is therefore an important therapeutic strategy for ischemic stroke. Notably, phytochemicals showed great neuroprotective potential in preclinical research via various strategies including modulation of calcium levels and antiexcitotoxicity, antioxidation, anti-inflammation and BBB protection, mitochondrial protection and antiapoptosis, autophagy/mitophagy regulation, and regulation of neurotrophin release. In this review, we summarize the research works that report the neuroprotective activity of phytochemicals in the past 10 years and discuss the neuroprotective mechanisms and potential clinical applications of 148 phytochemicals that belong to the categories of flavonoids, stilbenoids, other phenols, terpenoids, and alkaloids. Among them, scutellarin, pinocembrin, puerarin, hydroxysafflor yellow A, salvianolic acids, rosmarinic acid, borneol, bilobalide, ginkgolides, ginsenoside Rd, and vinpocetine show great potential in clinical ischemic stroke treatment. This review will serve as a powerful reference for the screening of phytochemicals with potential clinical applications in ischemic stroke or the synthesis of new neuroprotective agents that take phytochemicals as leading compounds.

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Cannabinoids, Blood–Brain Barrier, and Brain Disposition

Cited by 71 publications

References 96 publications

Molecular and Functional Study of Transient Receptor Potential Vanilloid 1-4 at the Rat and Human Blood–Brain Barrier Reveals Interspecies Differences

Molecular and Functional Study of Transient Receptor Potential Vanilloid 1-4 at the Rat and Human Blood–Brain Barrier Reveals Interspecies Differences

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

Neuroprotective Phytochemicals in Experimental Ischemic Stroke: Mechanisms and Potential Clinical Applications

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