Cannabinoid Receptor Type 1 Agonist ACEA Protects Neurons from Death and Attenuates Endoplasmic Reticulum Stress-Related Apoptotic Pathway Signaling.

Neurotoxicity Research

“Neurodegeneration is the result of progressive destruction of neurons in the central nervous system, with unknown causes and pathological mechanisms not yet fully elucidated. Several factors contribute to neurodegenerative processes, including neuroinflammation, accumulation of neurotoxic factors, and misfolded proteins in the lumen of the endoplasmic reticulum (ER).

Endocannabinoid signaling has been pointed out as an important modulatory system in several neurodegeneration-related processes, inhibiting the inflammatory response and increasing neuronal survival. Thus, we investigated the presumptive protective effect of the selective cannabinoid type 1 (CB1) receptor agonist) against inflammatory (lipopolysaccharide, LPS) and ER stress (tunicamycin) stimuli in an in vitro neuronal model (Neuro-2a neuroblastoma cells). Cell viability analysis revealed that ACEA was able to protect against cell death induced by LPS and tunicamycin.

This neuroprotective effect occurs via the CB1 receptor in the inflammation process and via the transient receptor potential of vanilloid type-1 (TRPV1) channel in ER stress. Furthermore, the immunoblotting analyses indicated that the neuroprotective effect of ACEA seems to involve the modulation of eukaryotic initiation factor 2 (eIF2α), transcription factor C/EBP homologous protein (CHOP), and caspase 12, as well as the survival/death p44/42 MAPK, ERK1/2-related signaling pathways.

Together, these data suggest that the endocannabinoid system is a potential therapeutic target in neurodegenerative processes, especially in ER-related neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/29134561

https://link.springer.com/article/10.1007%2Fs12640-017-9839-1

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Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol.

Neurobiology of Aging

“This study was designed to test our hypothesis that an ultra-low dose of delta-9 tetrahydrocannabinol (THC) reverses age-dependent cognitive impairments in old mice and to examine the possible biological mechanisms that underlie this behavioral effect. These findings suggest that extremely low doses of THC that are devoid of any psychotropic effect and do not induce desensitization may provide a safe and effective treatment for cognitive decline in aging humans.”  https://www.ncbi.nlm.nih.gov/pubmed/29107185

“Cognitive decline is an integral aspect of aging. The idea that age-related cognitive decline can be reversed and that the old brain can be revitalized is not new. It has been previously suggested that the endocannabinoid system is part of an antiaging homeostatic defense system.  In previous studies, we have shown that ultra-low doses of tetrahydrocannabinol (THC, the main psychotropic ingredient in cannabis) protected young mice from cognitive impairments that were evoked by various insults. In the present study, we tested our hypothesis that a single ultra-low dose of THC can reverse age-dependent cognitive decline in mice. Here, we show that a single extremely low dose of THC devoid of any psychotropic activity can trigger an endogenous compensatory mechanism that improves cognitive functioning in old mice and that this effect lasts for at least several weeks. Since THC in high doses (dronabinol, 1–10 mg) is already approved for medical treatments in humans, and since its safety profile is well characterized, we believe that the initiation of clinical trials with ultra-low doses of THC designed to reverse cognitive decline in elderly patients should be straightforward.”  http://www.sciencedirect.com/science/article/pii/S0197458017303214

“Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol. These findings suggest that extremely low doses of THC that are devoid of any psychotropic effect and do not induce desensitization may provide a safe and effective treatment for cognitive decline in aging humans.”   http://www.neurobiologyofaging.org/article/S0197-4580(17)30321-4/fulltext

Neurobiology of Aging Home

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AM1241 alleviates MPTP-induced Parkinson’s disease and promotes the regeneration of DA neurons in PD mice.

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“The main pathological feature of Parkinson’s disease (PD) is the loss of dopaminergic neurons in the substantia nigra. In this study, we investigated the role of cannabinoid receptor 2 (CB2R) agonist AM1241 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a mouse model of PD.

Upon treatment with AM1241, the decreased CB2R level in the PD mouse brain was reversed and the behavior score markedly elevated, accompanied with a dose-dependent increase of dopamine and serotonin. In addition, western blot assay and immunostaining results suggested that AM1241 significantly activated PI3K/Akt/MEK phosphorylation and increased the expression of Parkin and PINK1, both in the substantia nigra and hippocampus. The mRNA expression analysis further demonstrated that AM1241 increased expression of the CB2R and activated Parkin/PINK1 signaling pathways. Furthermore, the increased number of TH-positive cells in the substantia nigra indicated that AM1241 regenerated DA neurons in PD mice, and could therefore be a potential candidate for PD treatment. The clear co-localization of CB2R and DA neurons suggested that AM1241 targeted CB2R, thus also identifying a novel target for PD treatment.

In conclusion, the selective CB2 agonist AM1241 has a significant therapeutic effect on PD mice and resulted in regeneration of DA neurons following MPTP-induced neurotoxicity. The possible mechanisms underlying the neurogenesis effect of AM1241 might be the induction of CB2R expression and an increase in phosphorylation of the PI3K/AKT signaling pathway.”

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Intra-cerebral cannabidiol infusion-induced neuroprotection is partly associated with the TNF-α/TNFR1/NF-кB pathway in transient focal cerebral ischaemia.

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“Stroke is a neurological disease, which, in addition to high mortality, imposes many financial and mental burdens on families and the society.

The main objective of this study was to investigate the effect of cannabidiol (CBD) on one of the major inflammatory pathways in cerebral ischaemia.

RESULTS:

Administration of CBD (100 and 200 ng/rat) caused a significant reduction in infarction, brain oedema, and BBB permeability compared with the vehicle-received group. Down-regulation of TNF-α, TNFR1, and NF-кB expression was also observed by CBD.

CONCLUSION:

The results achieved in this study support the idea that CBD has a cerebroprotective effect (partly through suppression of TNF-α, TNFR1, and NF-кB) on ischaemic injury.”

https://www.ncbi.nlm.nih.gov/pubmed/28872345

http://www.tandfonline.com/doi/abs/10.1080/02699052.2017.1358397?journalCode=ibij20

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Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair.

 Lipids

“The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids.

The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids.

Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.”

https://www.ncbi.nlm.nih.gov/pubmed/28875399

https://link.springer.com/article/10.1007%2Fs11745-017-4292-8

“The seed of Cannabis sativa L. has been an important source of nutrition for thousands of years in Old World cultures. Technically a nut, hempseed typically contains over 30% oil and about 25% protein, with considerable amounts of dietary fiber, vitamins and minerals. Hempseed oil is over 80% in polyunsaturated fatty acids (PUFAs), and is an exceptionally rich source of the two essential fatty acids (EFAs) linoleic acid (18:2 omega-6) and alpha-linolenic acid (18:3 omega-3). The omega-6 to omega-3 ratio (n6/n3) in hempseed oil is normally between 2:1 and 3:1, which is considered to be optimal for human health. Hempseed has been used to treat various disorders for thousands of years in traditional oriental medicine.”  http://link.springer.com/article/10.1007%2Fs10681-004-4811-6

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Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity.

British Journal of Pharmacology

“Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing, and storage. While the biological effects of decarboxylated cannabinoids such as Δ9 -tetrahydrocannabinol (Δ9 -THC) have been extensively investigated, the bioactivity of Δ9 -THCA is largely unknown, despite its occurrence in different Cannabis preparations. The aim of this study was to determine whether Δ9 -THCA modulates the PPARγ pathway and has neuroprotective activity.

The effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of Δ9 -THCA on mitochondrial biogenesis and PGC-1α expression was investigated in N2a cells. The neuroprotective effect was analysed in STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein, and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt-q94). In vivo neuroprotective activity of Δ9 -THCA was investigated in mice intoxicated with the mitochondrial toxin 3-nitropropionic acid (3-NP).

KEY RESULTS:

Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. Δ9 -THCA increases mitochondrial mass in neuroblastoma N2a cells, and prevents cytotoxicity induced by serum deprivation in STHdhQ111/Q111cells and by mutHtt-q94 in N2a cells. Δ9 -THCA, through a PPARγ-dependent pathway, was neuroprotectant in mice intoxicated with 3-NP, improving motor deficits and preventing striatal degeneration. In addition, Δ9 -THCA attenuated microgliosis, astrogliosis and the upregulation of proinflammatory markers induced by 3-NP.

CONCLUSION AND IMPLICATIONS:

Δ9 -THCA shows potent neuroprotective activity, worth consideration for the treatment of Huntington´s Disease and possibly other neurodegenerative and neuroinflammatory diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28853159

http://onlinelibrary.wiley.com/doi/10.1111/bph.14019/abstract

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Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia.

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“Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB1 and CB2 receptors, which may form heteromeric complexes (CB1-CB2Hets) with unknown function in microglia.

We aimed at establishing the expression and signaling properties of cannabinoidreceptors in resting and LPS/IFN-γ-activated microglia. Unlike CB1, CB2 receptors and CB1-CB2Hets were upregulated in activated microglia. Resting cell refractory CB2 receptors became robustly coupled to Gi in activated cells, in which CB1-CB2Hets mediated a positive cross-talk. Resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß1-42). Activation microglial markers were detected in the striatum of a Parkinson’s disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APPSw,Ind) mice, a transgenic Alzheimer’s disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APPSw,Ind and in cells from control animals activated using LPS plus IFN- γ. Expression of CB1-CB2Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment.

In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB1-CB2Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB1-CB2 heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28843453

http://www.sciencedirect.com/science/article/pii/S0889159117304038

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Is the Cannabinoid CB2 Receptor a Major Regulator of the Neuroinflammatory Axis of the Neurovascular Unit in Humans?

Elsevier

“The central nervous system (CNS) is an immune privileged site where the neurovascular unit (NVU) and the blood-brain barrier (BBB) act as a selectively permeable interface to control the passage of nutrients and inflammatory cells into the brain parenchyma. However, in response to injury, infection, or disease, CNS cells become activated, and release inflammatory mediators to recruit immune cells to the site of inflammation.

Increasing evidence suggests that cannabinoids may have a neuroprotective role in CNS inflammatory conditions.

For many years, it was widely accepted that cannabinoid receptor type 1 (CB1) modulates neurological function centrally, while peripheral cannabinoid receptor type 2 (CB2) modulates immune function.

As knowledge about the physiology and pharmacology of the endocannabinoid system advances, there is increasing interest in targeting CB2 as a potential treatment for inflammation-dependent CNS diseases (Ashton & Glass, 2007), where recent rodent and human studies have implicated intervention at the level of the NVU and BBB.

These are incredibly important in brain health and disease. Therefore, this review begins by explaining the cellular and molecular components of these systems, highlighting important molecules potentially regulated by cannabinoid ligands and then takes an unbiased look at the evidence in support (or otherwise) of cannabinoid receptor expression and control of the NVU and BBB function in humans.”

https://www.ncbi.nlm.nih.gov/pubmed/28826541

http://www.sciencedirect.com/science/article/pii/S1054358917300376?via%3Dihub

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Neuroprotective activity of cannabinoid receptor-2 against oxidative stress and apoptosis in rat pups having experimentally-induced congenital hypothyroidism.

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“In this study, it was aimed to show the cannabinoid receptor-2 (CB2) role, which is a part of neuroprotective endocannabinoidal system, against increasing nitric oxide synthetase (iNOS, eNOS) levels and the apoptotic activity (caspase-3, caspase-9 and DNA in situ fragmentation) within the postnatal critical period in pups of pregnant rats with artificially induced maternal thyroid hormone (TH) deficiency.

In conclusion, apoptosis was triggered via oxidative stress in hypothyroid pups. Accordingly, neuroprotective activity of CB2 receptors were motivated spontaneously to resist to CNS lesions during the first 3 weeks of postnatal period.”

https://www.ncbi.nlm.nih.gov/pubmed/28799288

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Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid.

ijms-logo

“The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection.

The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis. CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies.

The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes.”

https://www.ncbi.nlm.nih.gov/pubmed/28788104

http://www.mdpi.com/1422-0067/18/8/1669

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