Mechanisms of cannabidiol neuroprotection in hypoxic–ischemic newborn pigs: Role of 5HT1A and CB2 receptors

Pazos, M. Ruth; Mohammed, Nagat; Lafuente, Héctor; Santos, Martín; Martínez‐Pinilla, Eva; Moreno, Estefanía; Valdizán, Elsa M.; Romero, Julián; Pazos, Ángel; Franco, Rafael; Hillard, Cecilia J.; Álvarez, Francisco J.; Martı́nez-Orgado, José

doi:10.1016/j.neuropharm.2013.03.027

Cited by 197 publications

(255 citation statements)

References 39 publications

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“…However, as there was no bile duct ligation control group treated with the antagonist only, it is not possible to determine if the antagonist was blocking CBD's effects directly, as it could simply be a behavioral effect. Similarly, Pazos et al [197] showed that in a pig model of hypoxic ischemic brain injury, CBD, at a final concentration in brain tissue of~0.2 μM, could be protective when given after the insult. Critically, the protective effects were blocked when a 5-HT 1A antagonist was co-administered with the CBD [197].…”

Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 87%

“…Similarly, Pazos et al [197] showed that in a pig model of hypoxic ischemic brain injury, CBD, at a final concentration in brain tissue of~0.2 μM, could be protective when given after the insult. Critically, the protective effects were blocked when a 5-HT 1A antagonist was co-administered with the CBD [197]. However, since no antagonist-only group was included in the study, a clear demonstration of CBD effects via 5HT1A receptors was achieved.…”

Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 87%

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Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 87%

Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 87%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

View full text Add to dashboard Cite

show abstract

“…These neuroprotective effects were also afforded with CBD, the major nonpsychoactive component of Cannabis sativa, again in animal models of newborn HI encephalopathy [70][71][72][73][74]. CBD administered 15-30 min after an HI insult in newborn pigs reduced the death of neurons and astrocytes, preserved brain activity as measured by amplitude-integrated electroencephalography, prevented the increase in the concentration of H + magnetic resonance spectroscopy biomarkers of brain damage (e.g., lactate/N-acetylaspartate ratio), prevented the appearance of seizures and improved neurobehavioral performance when examined 72 h after HI [70,72,74]. In the case of newborn rats, CBD administered 15 min after an HI insult led to long-lasting neuroprotective effects, reducing brain damage and restoring neurobehavioral function several weeks after the insult [73].…”

Section: Cannabinoids and Brain Damage In The Immature Brain: Neonatamentioning

confidence: 93%

“…The neuroprotective effect of CBD included the prevention of necrotic and apoptotic cell death and was related to the modulation of excitotoxicity, inflammation, and oxidative stress, as demonstrated by in vitro and in vivo studies [71][72][73][74]. It is important to note that this neuroprotective action was associated with no significant side effects and even with some extracerebral benefits (e.g., improved hemodynamic stability and lung dynamics) [70,[72][73][74].…”

Section: Cannabinoids and Brain Damage In The Immature Brain: Neonatamentioning

confidence: 96%

“…In term fetal lambs exposed to HI damage by umbilical cord occlusion, postinsult administration of WIN55212-2 improved cerebral blood flow and reduced astrocytic, as well as apoptotic neuronal, death-those effects relying on the preservation of mitochondrial integrity and functionality [69]. These neuroprotective effects were also afforded with CBD, the major nonpsychoactive component of Cannabis sativa, again in animal models of newborn HI encephalopathy [70][71][72][73][74]. CBD administered 15-30 min after an HI insult in newborn pigs reduced the death of neurons and astrocytes, preserved brain activity as measured by amplitude-integrated electroencephalography, prevented the increase in the concentration of H + magnetic resonance spectroscopy biomarkers of brain damage (e.g., lactate/N-acetylaspartate ratio), prevented the appearance of seizures and improved neurobehavioral performance when examined 72 h after HI [70,72,74].…”

Section: Cannabinoids and Brain Damage In The Immature Brain: Neonatamentioning

confidence: 98%

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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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Looking ahead after 50 years of research on cannabinoids

Mechoulam

2014

Cannabinoids

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My lab has been involved in research on cannabis and endogenous cannabinoids for 50 years. In this overview I first summarise some of our work over these decades. Then, on the basis of previous research, I speculate on a few of the pathways cannabinoid investigations may follow in the future. Two possible research trends are discussed:1. Cannabidiol -effects and mechanisms.2. Fatty acid amides of amino acids and related endogenous molecules -biological roles.

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Mechanisms of cannabidiol neuroprotection in hypoxic–ischemic newborn pigs: Role of 5HT1A and CB2 receptors

Cited by 197 publications

References 39 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

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

Looking ahead after 50 years of research on cannabinoids

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