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

Posted on February 22, 2017 by David Worrell

“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.” https://www.ncbi.nlm.nih.gov/pubmed/28217094

“It is unlikely that any drug acting on a single pathway or target will mitigate the complex pathoetiological cascade leading to AD. Therefore, a multifunctional drug approach targeting a number of AD pathologies simultaneously will provide better, wider-ranging benefits than current therapeutic approaches. Importantly, the endocannabinoid system has recently gained attention in AD research as it is associated with regulating a variety of processes related to AD, including oxidative stress, glial cell activation and clearance of macromolecules. The phytocannabinoid cannabidiol (CBD) is a prime candidate for this new treatment strategy. CBD has been found in vitro to be neuroprotective, to prevent hippocampal and cortical neurodegeneration, to have anti-inflammatory and antioxidant properties, reduce tau hyperphosphorylation and to regulate microglial cell migration. Furthermore, CBD was shown to protect against Aβ mediated neurotoxicity and microglial-activated neurotoxicity, to reduce Aβ production by inducing APP ubiquination and to improve cell viability,. These properties suggest that CBD is perfectly placed to treat a number of pathologies typically found in AD. The studies provide “proof of principle” that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies.” http://journal.frontiersin.org/article/10.3389/fphar.2017.00020/full

http://www.thctotalhealthcare.com/category/alzheimers-disease-ad/

Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target.

Posted on February 19, 2017 by David Worrell

“As a consequence of an increasingly aging population, the number of people affected by neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease, is rapidly increasing. Although the etiology of these diseases has not been completely defined, common molecular mechanisms including neuroinflammation, excitotoxicity and mitochondrial dysfunction have been confirmed and can be targeted therapeutically. Moreover, recent studies have shown that endogenous cannabinoid signaling plays a number of modulatory roles throughout the central nervous system (CNS), including the neuroinflammation and neurogenesis. In particular, the up-regulation of type-2 cannabinoid (CB2) receptors has been found in a number of neurodegenerative disorders. Thus, the modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neuronal degeneration. For these reasons this review will focus on the CB2 receptor as a promising pharmacological target in a number of neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pubmed/28210207

“Targeting Cannabinoid CB2 Receptors in the Central Nervous System. Medicinal Chemistry Approaches with Focus on Neurodegenerative Disorders” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020102/

“The influence of cannabinoids on generic traits of neurodegeneration. Modulation of the endogenous cannabinoid system is emerging as a potentially viable option in the treatment of neurodegeneration. Endocannabinoid signalling has been found to be altered in many neurodegenerative disorders. To this end, pharmacological manipulation of the endogenous cannabinoid system, as well as application of phytocannabinoids and synthetic cannabinoids have been investigated. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders. This review details the mechanisms of neurodegeneration and highlights the beneficial effects of cannabinoid treatment.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954477/

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Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer's disease.

Posted on February 14, 2017 by David Worrell

“Despite efforts to understand the mechanism of neuronal cell death, finding effective therapies for neurodegenerative diseases is still a challenge. Cognitive deficits are often associated with neurodegenerative diseases. Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer’s still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer’s disease may be addressed from two different points of view, neuroprotection or cognitive enhancement. Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising. In fact, G-protein-coupled receptors (GPCRs) remain the most common ‘druggable’ targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways. Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer’s disease. GPCR-mediated modulation of mTOR may take advantage of different GPRCs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.” https://www.ncbi.nlm.nih.gov/pubmed/28189739]]>

Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer’s disease.

Posted on February 14, 2017 by David Worrell

Image result for Progress in Neurobiology

Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer’s still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer’s disease may be addressed from two different points of view, neuroprotection or cognitive enhancement.

Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising.

In fact, G-protein-coupled receptors (GPCRs) remain the most common ‘druggable’ targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways.

Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer’s disease. GPCR-mediated modulation of mTOR may take advantage of different GPRCs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.”

https://www.ncbi.nlm.nih.gov/pubmed/28189739

Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation.

Posted on January 26, 2017 by David Worrell

“Microglial cells are important mediators of the immune response in the CNS. The phytocannabinoid, cannabidiol (CBD), has been shown to have central anti-inflammatory properties, and the purpose of the present study was to investigate the effects of CBD and other phytocannabinoids on microglial phagocytosis.

CONCLUSIONS AND IMPLICATIONS:

The TRPV-dependent phagocytosis-enhancing effect of CBD suggests that pharmacological modification of TRPV channel activity could be a rational approach to treating neuroinflammatory disorders involving changes in microglial function and that CBD is a potential starting point for future development of novel therapeutics acting on the TRPV receptor family.” https://www.ncbi.nlm.nih.gov/pubmed/24641282]]>

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

Posted on December 28, 2016 by David Worrell

“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.”

https://www.ncbi.nlm.nih.gov/pubmed/28025562

Δ9-THC-Caused Synaptic and Memory Impairments Are Mediated through COX-2 Signaling

Posted on December 4, 2016 by David Worrell

Image result for cell journal

“Marijuana has been used for thousands of years as a treatment for medical conditions.

However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ⁹-tetrahydrocannabinol (Δ⁹-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in the brain. COX-2 induction by Δ⁹-THC is mediated via CB1 receptor-coupled G protein βγ subunits.

Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ⁹-THC exposures. Ablation of COX-2 also eliminates Δ⁹-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories.

Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ⁹-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition.

These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.”

http://www.cell.com/cell/abstract/S0092-8674(13)01360-3

“Cannabidiolic acid as a selective cyclooxygenase-2 inhibitory component in cannabis.” https://www.ncbi.nlm.nih.gov/pubmed/18556441

Cannabinoids prevent the amyloid β-induced activation of astroglial hemichannels: A neuroprotective mechanism.

Posted on October 23, 2016 by David Worrell

Image result for glia journal

“The mechanisms involved in Alzheimer’s disease are not completely understood and how astrocytes and their gliotransmission contribute to this neurodegenerative disease remains to be fully elucidated.

Previous studies have shown that amyloid-β peptide (Aβ) induces neuronal death by a mechanism that involves the excitotoxic release of ATP and glutamate associated to astroglial hemichannel opening.

We have demonstrated that synthetic and endogenous cannabinoids (CBs) reduce the opening of astrocyte Cx43 hemichannels evoked by activated microglia or inflammatory mediators.

Nevertheless, whether CBs could prevent the astroglial hemichannel-dependent death of neurons evoked by Aβ is unknown.

We report that CBs fully prevented the hemichannel activity and inflammatory profile evoked by Aβ in astrocytes.

Moreover, CBs fully abolished the Aβ-induced release of excitotoxic glutamate and ATP associated to astrocyte Cx43 hemichannel activity, as well as neuronal damage in hippocampal slices exposed to Aβ.

Consequently, this work opens novel avenues for alternative treatments that target astrocytes to maintain neuronal function and survival during AD.”

https://www.ncbi.nlm.nih.gov/pubmed/27757991

Cannabinoids and Dementia: A Review of Clinical and Preclinical Data.

Posted on October 9, 2016 by David Worrell

“The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia.

We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD).

Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro.

However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce.

While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia.

Further research is needed, including in vivo models of dementia and human studies.”

https://www.ncbi.nlm.nih.gov/pubmed/27713372

Vascular Dysfunction in a Transgenic Model of Alzheimer’s Disease: Effects of CB1R and CB2R Cannabinoid Agonists.

Posted on October 5, 2016 by David Worrell

Image result for Front Neurosci.

“There is evidence of altered vascular function, including cerebrovascular, in Alzheimer’s disease (AD) and transgenic models of the disease.

Indeed vasoconstrictor responses are increased, while vasodilation is reduced in both conditions. β-Amyloid (Aβ) appears to be responsible, at least in part, of alterations in vascular function.

Cannabinoids, neuroprotective and anti-inflammatory agents, induce vasodilation both in vivo and in vitro.

We have demonstrated a beneficial effect of cannabinoids in models of AD by preventing glial activation.

In this work we have studied the effects of these compounds on vessel density in amyloid precursor protein (APP) transgenic mice, line 2576, and on altered vascular responses in aortae isolated ring.

In summary, we have confirmed and extended the existence of altered vascular responses in Tg APP mice.

Moreover, our results suggest that treatment with cannabinoids may ameliorate the vascular responses in AD-type pathology.”

https://www.ncbi.nlm.nih.gov/pubmed/27695396

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Category Archives: Alzheimer’s Disease (AD)