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Mar 01 2019
0

Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s Disease and Less Well-Known Diseases

By | Dementia

Authors:

Juan A. Paez, Nuria E. Campillo

Published in Current Medicinal Chemistry

25 February 2018

 

Abstract

The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer’s disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.

 

DOI: 10.2174/0929867325666180226095132

PAYWALL

Citation:

Paez JA, Campillo NE. Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s disease and Less Well-Known Diseases. Current Medicinal Chemistry. February 2018. doi:10.2174/0929867325666180226095132.

Mar 01 2019
0

Cannabis in palliative care: current challenges and practical recommendations

By | Dementia

Authors:

Claude Cyr, Maria Fernanda Arboleda, Sunil Kumar Aggarwal, Lynda G. Balneaves, Paul Daeninck, Andrée Néron, Erin Prosk, Antonio Vigano

Published in Annals of Palliative Medicine

October 2018

 

Abstract

Pain and symptom control challenges are common in palliative care, and the search for other therapeutic strategies is ongoing. Unfortunately, patients and their caregivers are receiving little information or support from healthcare providers regarding the increasingly popular cannabinoid-based medicines (CBM). Clinicians, meanwhile, feel understandably perplexed by the discrepancy between the available evidence and the rapid interest in which patients and their families have demonstrated for CBM. There is an urgent need to address the many challenges that are delaying the appropriate integration of CBM into clinical practice, notwithstanding the obvious need for a solid general knowledge of pharmacology, mechanism of action and available clinical evidence supporting its use. The authors will address these challenges and provide practical recommendations regarding patient assessment for the use of CBM. The authors will also make suggestions regarding patient expectations in order to define clear objectives, review the necessary precautions prior to initiating treatment, aid in selecting the appropriate strain and route of administration as well as establishing proper titration and monitoring protocols. The authors will also discuss the lesser known but potentially therapeutic psychoactive effects of cannabis. As this class of therapeutic agents are likely to play a major role in palliative medicine in the near future, clinicians would benefit from familiarizing themselves with CBM and we can expect that patients and their caregivers will appreciate receiving support in their search for safe and effective therapeutic alternatives.

 

DOI: 10.21037/apm.2018.06.04

FULL TEXT

Citation:

Cyr C, Arboleda MF, Aggarwal SK, et al. Cannabis in palliative care: current challenges and practical recommendations. Annals of Palliative Medicine. 2018;7(4):463-477. doi:10.21037/apm.2018.06.04.

Mar 01 2019
0

Cannabinoids in late‐onset Alzheimer’s disease

By | Cognitive Aging, Dementia

Authors:

AIA Ahmed, MA van der Marck, GAH van den Elsen, MGM Olde Rikkert

Published in Clinical Pharmacology & Therapeutics

8 March 2015

 

Abstract

Given the lack of effective treatments for late-onset Alzheimer’s disease (LOAD) and the substantial burden on patients, families, health care systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety, and pharmacokinetics of cannabinoid-based drugs in older people with dementia.

 

DOI: 10.1002/cpt.117

PAYWALL

Citation:

Ahmed A, Marck MVD, Elsen GVD, Rikkert MO. Cannabinoids in late-onset Alzheimers disease. Clinical Pharmacology & Therapeutics. 2015;97(6):597-606. doi:10.1002/cpt.117.

Mar 01 2019
0

A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice

By | Cognitive Aging, Dementia

Authors:

Andras Bilkei-Gorzo, Onder Albayram, Astrid Draffehn, Kerstin Michel, Anastasia Piyanova, Hannah Oppenheimer, Mona Dvir-Ginzberg, Ildiko Rácz, Thomas Ulas, Sophie Imbeault, Itai Bab, Joachim L Schultze, Andreas Zimmer

Published in Nature Medicine

8 May 2017

 

Abstract

The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.

 

DOI: 10.1038/nm.4311

PAYWALL

Citation:

Bilkei-Gorzo A, Albayram O, Draffehn A, et al. A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nature Medicine. 2017;23(6):782-787. doi:10.1038/nm.4311.

Mar 01 2019
0

The potential therapeutic effects of THC on Alzheimer’s disease

By | Dementia

Authors:

Chuanhai Cao, Yaqiong Li, Hui Liu, Ge Bai, Jonathan Mayl, Xiaoyang Lin, Kyle Sutherland, Neel Nabar, Jianfeng Cai

Published in Journal of Alzheimer’s Disease

16 September 2014

 

Abstract

The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer’s disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin’s enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.

 

DOI: 10.3233/JAD-140093

PAYWALL

Citation:

Cao C, Li Y, Liu H, et al. The Potential Therapeutic Effects of THC on Alzheimers Disease. Journal of Alzheimers Disease. 2014;42(3):973-984. doi:10.3233/jad-140093.

Mar 01 2019
0

Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia

By | Dementia

Authors:

Sebastian Walther, Richard Mahlberg, Uta Eichmann, Dieter Kunz

Published in Psychopharmacology

May 2006

 

Abstract

RATIONALE:
Nighttime agitation occurs frequently in patients with dementia and represents the number one burden on caregivers today. Current treatment options are few and limited due to substantial side effects.

OBJECTIVES:
The aim of the study was to measure the effect of the cannabinoid dronabinol on nocturnal motor activity.

METHODS:
In an open-label pilot study, six consecutive patients in the late stages of dementia and suffering from circadian and behavioral disturbances-five patients with Alzheimer’s disease and one patient with vascular dementia-were treated with 2.5 mg dronabinol daily for 2 weeks. Motor activity was measured objectively using actigraphy.

RESULTS:
Compared to baseline, dronabinol led to a reduction in nocturnal motor activity (P=0.028). These findings were corroborated by improvements in Neuropsychiatric Inventory total score (P=0.027) as well as in subscores for agitation, aberrant motor, and nighttime behaviors (P<0.05). No side effects were observed.

CONCLUSIONS:
The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients. Thus, it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia.

 

DOI: 10.1007/s00213-006-0343-1

FULL TEXT

Citation:

Walther S, Mahlberg R, Eichmann U, Kunz D. Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology. 2006;185(4):524-528. doi:10.1007/s00213-006-0343-1.

Mar 01 2019
0

An update on the advancements in the treatment of agitation in Alzheimer’s disease

By | Dementia

Authors:

Assaf Shelef, Yoram Barak, Uri Berger, Diana Paleacu, Shelly Tadger, Igor Plopsky, Yehuda Baruch

Published in Expert Opinion on Pharmacotherapy

April 2017

 

Abstract

Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks safe and effective long term interventions. Nonpharmacological interventions are suggested as first-line treatment, but aren’t effective for every patient, resulting in pharmacological interventions for some patients, consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; where efficacy doesn’t necessarily outweigh associated risks. Areas covered: Gains in understanding neurobiological mechanisms underlying agitation have fueled several recent clinical trials. This article updates our review published in 2014. Comprehensive literature search for published articles from January 2014 to December 2016 evaluating pharmacologic interventions for agitation in AD was done. A review of several clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, citalopram, escitalopram, pimavanserin, ITI-007, ORM-12741 show promise in treating agitation. Expert opinion: Neurobiological findings, innovative trials designs, statistical approaches, and preliminary paths for regulatory agency acceptance have re-ignited the area of pharmacological treatment of NPS. Though further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to find effective treatments for neuropsychiatric symptoms such as agitation in patients with dementia is well underway.

 

DOI: 10.1080/14656566.2017.1307340

PAYWALL

Citation:

Porsteinsson AP, Antonsdottir IM. An update on the advancements in the treatment of agitation in Alzheimer’s disease. Expert Opinion on Pharmacotherapy. 2017;18(6):611-620. doi:10.1080/14656566.2017.1307340.

Mar 01 2019
0

Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia: An-Open Label, Add-On, Pilot Study

By | Dementia

Authors:

Assaf Shelef, Yoram Barak, Uri Berger, Diana Paleacu, Shelly Tadger, Igor Plopsky, Yehuda Baruch

Published in Journal of Alzheimer’s Disease

27 February 2016

 

Abstract

BACKGROUND:
Tetrahydrocannabinol (THC) is a potential treatment for Alzheimer’s disease (AD).

OBJECTIVE:
To measure efficacy and safety of medical cannabis oil (MCO) containing THC as an add-on to pharmacotherapy, in relieving behavioral and psychological symptoms of dementia (BPSD).

METHODS:
Eleven AD patients were recruited to an open label, 4 weeks, prospective trial.

RESULTS:
Ten patients completed the trial. Significant reduction in CGI severity score (6.5 to 5.7; p <  0.01) and NPI score were recorded (44.4 to 12.8; p <  0.01). NPI domains of significant decrease were: Delusions, agitation/aggression, irritability, apathy, sleep and caregiver distress.

CONCLUSION:
Adding MCO to AD patients’ pharmacotherapy is safe and a promising treatment option.

 

DOI: 10.3233/JAD-150915

PAYWALL

Citation:

Shelef A, Barak Y, Berger U, et al. Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia: An-Open Label, Add-On, Pilot Study. Journal of Alzheimers Disease. 2016;51(1):15-19. doi:10.3233/jad-150915.

Mar 01 2019
0

In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer’s Disease

By | Dementia

Authors:

Georgia Watt, Tim Karl

Published in Frontiers in Pharmacology

3 February 2017

 

Abstract

Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is affecting an increasing number of people. It is characterized by the accumulation of amyloid-β and tau hyperphosphorylation as well as neuroinflammation and oxidative stress. Current AD treatments do not stop or reverse the disease progression, highlighting the need for new, more effective therapeutics. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has demonstrated neuroprotective, anti-inflammatory and antioxidant properties in vitro. Thus, it is investigated as a potential multifunctional treatment option for AD. Here, we summarize the current status quo of in vivo effects of CBD in established pharmacological and transgenic animal models for AD. The studies demonstrate the ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as to promote neurogenesis. Importantly, CBD also reverses and prevents the development of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD and Δ9-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone. The studies provide “proof of principle” that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies. Further investigations should address the long-term potential of CBD and evaluate mechanisms involved in the therapeutic effects described.

 

DOI: 10.3389/fphar.2017.00020

FULL TEXT

Citation:

Watt G, Karl T. In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimers Disease. Frontiers in Pharmacology. 2017;8(20). doi:10.3389/fphar.2017.00020.

Feb 20 2019
0

Cannabidiol Modulates the Expression of Alzheimer’s Disease-Related Genes in Mesenchymal Stem Cells.

By | Alzheimer's Disease

Authors:

Rosaliana Libro, Francesca Diomede, Domenico Scionti, Adriano Piattelli, Gianpaolo Grassi, Federica Pollastro, Placido Bramanti, Emanuela Mazzon, Oriana Trubiani

Published in International Journal of Molecular Sciences

23 December 2016

 

Abstract

Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of several neurodegenerative disorders, including Alzheimer’s disease (AD). The main neuropathological hallmarks of AD are senile plaques, composed of amyloid beta (Aβ), and neurofibrillary tangles, formed by hyperphosphorylated tau. However, current therapies for AD have shown limited efficacy. In this study, we evaluated whether pre-treatment with cannabidiol (CBD), at 5 μM concentration, modulated the transcriptional profile of MSCs derived from gingiva (GMSCs) in order to improve their therapeutic potential, by performing a transcriptomic analysis by the next-generation sequencing (NGS) platform. By comparing the expression profiles between GMSCs treated with CBD (CBD-GMSCs) and control GMSCs (CTR-GMSCs), we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aβ generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3β, a central player in AD pathogenesis, by promoting PI3K/Akt signalling. In order to understand through which receptor CBD exerted these effects, we have performed pre-treatments with receptor antagonists for the cannabinoid receptors (SR141716A and AM630) or for the vanilloid receptor 1 (TRPVI). Here, we have proved that TRPV1 was able to mediate the modulatory effect of CBD on the PI3K/Akt/GSK3β axis. In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aβ production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD.

 

DOI: 10.3390/ijms18010026

Full Text

Citation:

Libro R, Diomede F, Scionti D, et al. Cannabidiol Modulates the Expression of Alzheimer’s Disease-Related Genes in Mesenchymal Stem Cells. International Journal of Molecular Sciences. 2016;18(1):26. doi:10.3390/ijms18010026.