Cannabidiol exerts protective effects in an in vitro model of Parkinson’s disease activating AKT/mTOR pathway.

Fitoterapia“Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the degeneration of the nigrostriatal dopaminergic pathway with loss of substantia nigra pars compacta neurons and dopamine depletion. Various natural compounds showed protective actions against PD.

In this work, the protective effects of cannabidiol (CBD), obtained from Cannabis sativa, were evaluated in retinoic acid differentiated SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+), an in vitro PD model.

CBD counteracted the loss of cell viability caused by MPP+, reducing apoptosis as demonstrated by the reduction of Bax and caspase 3. Moreover, CBD reduced the nuclear levels of PARP-1. The protective effects of CBD seem to be mediated by the activation of ERK and AKT/mTOR pathways.

These data suggested the involvement of ERK in the modulation of autophagy. However, beclin 1 levels were not modified neither by MPP+ nor by CBD. These results indicated that CBD may exert preventive and protective actions in PD.”

https://www.ncbi.nlm.nih.gov/pubmed/32184097

https://www.sciencedirect.com/science/article/abs/pii/S0367326X20301350?via%3Dihub

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Cannabinoids, Blood-Brain Barrier, and Brain Disposition.

Image result for pharmaceutics“Potential therapeutic actions of the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are based on their activity as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds.

THC and CBD lipophilicity and their neurological actions makes them candidates as new medicinal approaches to treat central nervous system (CNS) diseases. However, they show differences about penetrability and disposition in the brain.

The present article is an overview about THC and CBD crossing the blood-brain barrier (BBB) and their brain disposition. Several findings indicate that CBD can modify the deleterious effects on BBB caused by inflammatory cytokines and may play a pivotal role in ameliorating BBB dysfunction consequent to ischemia. Thus supporting the therapeutic potential of CBD for the treatment of ischemic and inflammatory diseases of CNS.

Cannabinoids positive effects on cognitive function could be also considered through the aspect of protection of BBB cerebrovascular structure and function, indicating that they may purchase substantial benefits through the protection of BBB integrity. Delivery of these cannabinoids in the brain following different routes of administration (subcutaneous, oral, and pulmonary) is illustrated and commented. Finally, the potential role of cannabinoids in drug-resistance in the clinical management of neurological or psychiatric diseases such as epilepsy and schizophrenia is discussed on the light of their crossing the BBB.”

https://www.ncbi.nlm.nih.gov/pubmed/32183416

 

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The role of the cannabinoid system in opioid analgesia and tolerance.

“Opioid receptor agonist drugs, such as morphine, are very effective for treating chronic and severe pain; but, tolerance can develop with long-term use. Although there is a lot of information about the pathophysiological mechanisms of opioid tolerance, it is still not fully clarified. Suggested mechanisms for opioid tolerance include opioid receptor desensitisation, reduction of sensitivity G-proteins, activation of mitogen-activated protein kinase (MAPK), altered intracellular signaling pathway including nitric oxide, and activation of mammalian target of rapamycin (mTOR).

One way to reduce opioid tolerance and increase the analgesic potential is to use low doses. Combination of cannabinoids with opioids has been shown to manifest reduce the opioid dose. Experimental studies revealed an interaction of the endocannabinoid system and opioid antinociception.

Cannabinoid and opioid receptor systems use common pathways in the formation of analgesic effect and demonstrate their activity via G protein coupled receptors (GPCR). Cannabinoid drugs modulate opioid analgesic activity at a number of distinct levels within the cell, ranging from direct receptor associations, to post-receptor interactions through shared signal transduction pathways.

This review summarizes the data indicating that with combining cannabinoids and opioids drugs may be able to produce long-term analgesic effects, while preventing the opioid analgesic tolerance.”

https://www.ncbi.nlm.nih.gov/pubmed/32167427

http://www.eurekaselect.com/180186/article

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Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study.

 SpringerLink“Excessive fear and anxiety, coupled with corticolimbic dysfunction, are core features of stress- and trauma-related psychopathology, such as posttraumatic stress disorder (PTSD).

Interestingly, low doses of ∆9-tetrahydrocannabinol (THC) can produce anxiolytic effects, reduce threat-related amygdala activation, and enhance functional coupling between the amygdala and medial prefrontal cortex and adjacent rostral cingulate cortex (mPFC/rACC) during threat processing in healthy adults.

Together, these findings suggest the cannabinoid system as a potential pharmacological target in the treatment of excess fear and anxiety. However, the effects of THC on corticolimbic functioning in response to threat have not be investigated in adults with trauma-related psychopathology.

OBJECTIVE:

To address this gap, the present study tests the effects of an acute low dose of THC on corticolimbic responses to threat in three groups of adults: (1) non-trauma-exposed healthy controls (HC; n = 25), (2) trauma-exposed adults without PTSD (TEC; n = 27), and (3) trauma-exposed adults with PTSD (n = 19).

METHODS:

Using a randomized, double-blind, placebo-controlled, between-subjects design, 71 participants were randomly assigned to receive either THC or placebo (PBO) and subsequently completed a well-established threat processing paradigm during functional magnetic resonance imaging.

RESULTS:

In adults with PTSD, THC lowered threat-related amygdala reactivity, increased mPFC activation during threat, and increased mPFC-amygdala functional coupling.

CONCLUSIONS:

These preliminary data suggest that THC modulates threat-related processing in trauma-exposed individuals with PTSD, which may prove advantageous as a pharmacological approach to treating stress- and trauma-related psychopathology.”

https://www.ncbi.nlm.nih.gov/pubmed/32162103

https://link.springer.com/article/10.1007%2Fs00213-020-05499-8

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Cannabis and the Cornea.

Publication Cover

“While cannabis has the potential to reduce corneal pain, cannabinoids might induce side effects. This review article examines the effects of cannabinoids on the cornea. As more states and countries consider the legalization of adult cannabis use, health-care providers will need to identify ocular effects of cannabis consumption.

Methods: Studies included in this review examined the connection between cannabis and the cornea, more specifically anti-nociceptive and anti-inflammatory actions of cannabinoids. NCBI Databases from 1781 up to December 2019 were consulted.

Conclusion: More than half of the studies examined the therapeutic effects of cannabinoids on the cornea. As the field is still young, more studies should be conducted to develop safe cannabinoid treatments for corneal diseases.

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Influence of cannabinoids upon nerve-evoked skeletal muscle contraction.

Neuroscience Letters“Endocannabinoids play important roles in regulating CNS synaptic function and peripheral metabolism, but cannabinoids can also act acutely to modulate contraction strength in skeletal muscle.

Nerve terminals and the skeletal muscle sarcolemma express components of the cannabinoid signaling system.

Endocannabinoids, N-arachidonylethanolamine (anandamide, AEA) and 2-arachidonoyl-glycerol (2-AG), are produced by skeletal muscle. They may be involved in the acute regulation of neuromuscular transmission, by adjusting the parameters for quantal acetylcholine release from the motor nerve terminal. Downstream of neuromuscular transmission, cannabinoids may also act to limit the efficiency of excitation-contraction coupling.

Improved understanding of the distinct signaling actions of particular cannabinoid compounds and their receptor/transduction systems will help advance our understanding of the role of endocannabinoids in skeletal muscle physiology.

Cannabinoids might also offer the potential to develop new pharmacotherapeutics to treat neuromuscular disorders that affect muscle strength.”

https://www.ncbi.nlm.nih.gov/pubmed/32156612

https://www.sciencedirect.com/science/article/abs/pii/S0304394020301701?via%3Dihub

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Antinociceptive and Immune Effects of Delta-9-tetrahydrocannabinol or Cannabidiol in Male Versus Female Rats with Persistent Inflammatory Pain.

Journal of Pharmacology and Experimental Therapeutics: 373 (1)

“Chronic pain is the most common reason reported for using medical cannabis.

The goal of this research was to determine if the two primary phytocannabinoids, THC and CBD, are effective treatments for persistent inflammatory pain.

These results suggest that THC may be more beneficial than CBD for reducing inflammatory pain, in that THC maintains its efficacy with short-term treatment in both sexes, and does not induce immune activation.

SIGNIFICANCE STATEMENT: CBDs and THCs pain-relieving effects are examined in male and female rats with persistent inflammatory pain to determine if individual phytocannabinoids could be a viable treatment for men and women with chronic inflammatory pain. Additionally, sex differences in the immune response to an adjuvant and to THC and CBD are characterized to provided preliminary insight into immune-related effects of cannabinoid-based therapy for pain.”

https://www.ncbi.nlm.nih.gov/pubmed/32179573

http://jpet.aspetjournals.org/content/early/2020/03/16/jpet.119.263319

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Cannabidiol attenuates behavioral changes in a rodent model of schizophrenia through 5-HT1A, but not CB1 and CB2 receptors.

Pharmacological Research“Preclinical and clinical data indicate that cannabidiol (CBD), a non-psychotomimetic compound from the Cannabis sativa plant, can induce antipsychotic-like effects.

These data suggest that CBD induces antipsychotic-like effects by activating 5-HT1A receptors and indicate that this compound could be an interesting alternative for the treatment of negative and cognitive symptoms of schizophrenia.”

https://www.ncbi.nlm.nih.gov/pubmed/32151683

https://www.sciencedirect.com/science/article/abs/pii/S1043661819315439?via%3Dihub

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The effects of cannabinoids on glioblastoma growth: A systematic review with meta-analysis of animal model studies.

European Journal of Pharmacology“Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant brain tumour, with a poor prognosis despite available surgical and radio-chemotherapy, rising the necessity for searching alternative therapies. Several preclinical studies evaluating the efficacy of cannabinoids in animal models of GBM have been described, but the diversity of experimental conditions and of outcomes hindered definitive conclusions about cannabinoids efficacy.

A search in different databases (Pubmed, Web of Science, Scopus and SciELO) was conducted during June 2019 to systematically identify publications evaluating the effects of cannabinoids in murine xenografts models of GBM. The tumour volume and number of animals were extracted, being a random effects meta-analysis of these results performed to estimate the efficacy of cannabinoids. The impact of different experimental factors and publication bias on the efficacy of cannabinoids was also assessed. Nine publications, which satisfied the inclusion criteria, were identified and subdivided in 22 studies involving 301 animals.

Overall, cannabinoid therapy reduced the fold of increase in tumour volume in animal models of GBM, when compared with untreated controls. The overall weighted standardized difference in means (WSDM) for the effect of cannabinoids was -1.399 (95% CI: -1.900 to -0.898; P-value<0.0001). Furthermore, treatment efficacy was observed for different types of cannabinoids, alone or in combination, and for different treatment durations.

Cannabinoid therapy was still effective after correcting for publication bias. The results indicate that cannabinoids reduce the tumour growth in animal models of GBM, even after accounting for publication bias.”

https://www.ncbi.nlm.nih.gov/pubmed/32145324

https://www.sciencedirect.com/science/article/abs/pii/S0014299920301473?via%3Dihub

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Stimulation of brain cannabinoid CB1 receptors can ameliorate hypertension in spontaneously hypertensive rats.

Clinical and Experimental Pharmacology and Physiology“Excessive activation of the sympatho-adrenomedullary system plays a pathogenic role in triggering and sustaining essential hypertension. We previously reported that, in normotensive rats, intracerebroventricularly (i.c.v.) administered neuropeptides, corticotropin-releasing factor and bombesin induced activation of the sympatho-adrenomedullary system, and that brain cannabinoid CB1 receptors negatively regulated this activation.

In this study, we investigated the effects of brain CB1 receptor stimulation on blood pressure and the sympatho-adrenomedullary outflow in spontaneously hypertensive rats (SHRs), commonly used animal models of essential hypertension, and in Wistar-Kyoto (WKY) rats, normotensive controls of SHRs.

These results suggest that stimulation of brain CB1 receptors can ameliorate hypertension accompanied by enhanced sympathetic outflow without affecting blood pressure under normotensive conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/32141630

https://onlinelibrary.wiley.com/doi/abs/10.1111/1440-1681.13297

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