The Acute Activation of the CB1 Receptor in the Hippocampus Decreases Neurotoxicity and Prevents Spatial Memory Impairment in Rats Lesioned with β-Amyloid 25-35.

Neuroscience“Given their anti-inflammatory properties, cannabinoids have been shown to be neuroprotective agents and to reduce excitotoxicity, through the activation of the Cannabinoid receptor type 1 (CB1r).

These properties have led to CB1r being proposed as pharmacological targets for the treatment of various neurodegenerative diseases.

This study aimed to evaluate the neuroprotective effect of an acute activation of CB1r on spatial memory and its impact on iNOS protein expression, NO● levels, gliosis and the neurodegenerative process induced by the injection of Aβ(25-35) into the CA1 subfield of the hippocampus.

The data obtained in the present research suggest that the acute early activation of CB1r is crucial for neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/31400487

https://www.sciencedirect.com/science/article/abs/pii/S0306452219305433?via%3Dihub

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Intraperitoneal cannabidiol attenuates neonatal germinal matrix hemorrhage-induced neuroinflamtion and perilesional apoptosis.

Publication Cover“As the survival of preterm infants has increased significantly, germinal matrix hemorrhage (GMH) has become an important public health issue. Nevertheless, treatment strategies for the direct neuronal injury are still scarce. The present study aims to analyze the neuroprotective properties of cannabidiol in germinal matrix hemorrhage.

Results. Reduction of reactive astrocytosis was observed both in the perilesional area 24 hours and 14 days after the hemorrhage lesion (p < 0.001) and in the Stratum oriens of the ipsilateral hippocampal CA1 14 days after the hemorrhage lesion (p < 0.05) in the treated groups. Similarly, there was a reduction in the number of Caspase 3-positive astrocytes in the perilesional area in the treated groups 24 hours after the hemorrhage lesion (p < 0.001). Finally, we found a significant increase in the weight of the rats treated with cannabidiol.

Conclusion. The treatment of GMH with cannabidiol significantly reduced the number of apoptotic cells and reactive astrocytes in the perilesional area and the ipsilateral hippocampus. In addition, this response was sustained 14 days after the hemorrhage. These results corroborate our hypothesis that cannabidiol is a potential neuroprotective agent in the treatment of germinal matrix hemorrhage.”

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Endogenous and synthetic cannabinoids induce the downregulation of cannabinoid CB1 receptor in retina.

Experimental Eye Research

“Endogenous and synthetic cannabinoids have been shown to provide neuroprotection to retinal neurons in acute animal models of retinopathy.

Chronic exposure to cannabinoid receptor (CB1R) agonists has been reported to induce downregulation of the CB1R in brain and behavioral tolerance.

The aim of this study was to investigate the effect of subchronic/chronic cannabinoid administration on CB1R downregulation in normal rat retina, its downstream prosurvival signaling and subsequent effect on retinal neuroprotection against AMPA excitotoxicity.

This study provides novel information regarding agonist-induced CB1R downregulation in rat retina after subchronic/chronic cannabinoid treatment, and its effect on downstream prosurvival signaling and neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/31199905

https://www.sciencedirect.com/science/article/pii/S0014483519301216?via%3Dihub

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Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’s Disease.

“Finding a therapy for Alzheimer’s disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates.

Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain.

This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive.

Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal.

Pairwise combinations of THC and CBN lead to a synergistic neuroprotective interaction.

Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potential lead drug candidates for AD and other neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/31104297

https://link.springer.com/article/10.1007%2Fs12035-019-1637-8

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Endocannabinoid System in Spinocerebellar Ataxia Type-3 and Other Autosomal-Dominant Cerebellar Ataxias: Potential Role in Pathogenesis and Expected Relevance as Neuroprotective Targets.

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“Spinocerebellar ataxias (SCAs) are a group of hereditary and progressive neurological disorders characterized by a loss of balance and motor coordination. SCAs have no cure and effective symptom-alleviating and disease-modifying therapies are not currently available. However, based on results obtained in studies conducted in murine models and information derived from analyses in post-mortem tissue samples from patients, which show notably higher levels of CB1 receptors found in different cerebellar neuronal subpopulations, the blockade of these receptors has been proposed for acutely modulating motor incoordination in cerebellar ataxias, whereas their chronic activation has been proposed for preserving specific neuronal losses. Additional studies in post-mortem tissues from SCA patients have also demonstrated elevated levels of CB2 receptors in Purkinje neurons as well as in glial elements in the granular layer and in the cerebellar white matter, with a similar profile found for endocannabinoid hydrolyzing enzymes, then suggesting that activating CB2 receptors and/or inhibiting these enzymes may also serve to develop cannabinoid-based neuroprotective therapies.”
“Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3.” https://www.ncbi.nlm.nih.gov/pubmed/27717809
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Pre- and post-conditioning treatment with an ultra-low dose of Δ9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage.

Behavioural Brain Research

“Preconditioning, a phenomenon where a minor noxious stimulus protects from a subsequent more severe insult, and post-conditioning, where the protective intervention is applied following the insult, offer new insight into the neuronal mechanism(s) of neuroprotection and may provide new strategies for the prevention and treatment of brain damage. We have previously reported that a single administration of an extremely low dose of Δ(9)-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) to mice induced minor long-lasting cognitive deficits.

In the present study we examined the possibility that such a low dose of THC will protect the mice from more severe cognitive deficits induced by the epileptogenic drug pentylenetetrazole (PTZ). THC (0.002 mg/kg, a dose that is 3-4 orders of magnitude lower than the doses that induce the conventional effects of THC) was administered 1-7 days before, or 1-3 days after the injection of PTZ (60 mg/kg). The consequences of this treatment were studied 3-7 weeks later by various behavioral tests that evaluated different aspects of memory and learning.

We found that a single administration of THC either before or after PTZ abolished the PTZ-induced long-lasting cognitive deficits.

Biochemical studies indicated a concomitant reduction in phosphorylated-ERK (extracellular signal-regulated kinase) in the cerebella of mice 7 weeks following the injection of THC.

Our results suggest that a pre- or post-conditioning treatment with extremely low doses of THC, several days before or after brain injury, may provide safe and effective long-term neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/21315768

https://www.sciencedirect.com/science/article/pii/S0166432811001094?via%3Dihub

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Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons.

Neuropharmacology

“Cannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington’s disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoidsystem in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-α in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8 mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGLfloxed/floxed;GFAP-Cre/+ mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration.”

https://www.ncbi.nlm.nih.gov/pubmed/30914306

https://www.sciencedirect.com/science/article/pii/S0028390819301066?via%3Dihub

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Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration.

 “The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids.

METHODS:

We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro.

RESULTS:

Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis.

CONCLUSIONS:

The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.”

https://www.ncbi.nlm.nih.gov/pubmed/30899454

https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-019-0148-x

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miRNA expression profiles and molecular networks in resting and LPS-activated BV-2 microglia-Effect of cannabinoids.

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“Mammalian microRNAs (miRNAs) play a critical role in modulating the response of immune cells to stimuli.

Cannabinoids are known to exert beneficial actions such as neuroprotection and immunosuppressive activities. However, the underlying mechanisms which contribute to these effects are not fully understood.

We previously reported that the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) differ in their anti-inflammatory signaling pathways.

Using lipopolysaccharide (LPS) to stimulate BV-2 microglial cells, we examined the role of cannabinoids on the expression of miRNAs. Expression was analyzed by performing deep sequencing, followed by Ingenuity Pathway Analysis to describe networks and intracellular pathways.

miRNA sequencing analysis revealed that 31 miRNAs were differentially modulated by LPS and by cannabinoids treatments. In addition, we found that at the concentration tested, CBD has a greater effect than THC on the expression of most of the studied miRNAs.

The results clearly link the effects of both LPS and cannabinoids to inflammatory signaling pathways. LPS upregulated the expression of pro-inflammatory miRNAs associated to Toll-like receptor (TLR) and NF-κB signaling, including miR-21, miR-146a and miR-155, whereas CBD inhibited LPS-stimulated expression of miR-146a and miR-155. In addition, CBD upregulated miR-34a, known to be involved in several pathways including Rb/E2f cell cycle and Notch-Dll1 signaling.

Our results show that both CBD and THC reduced the LPS-upregulated Notch ligand Dll1 expression. MiR-155 and miR-34a are considered to be redox sensitive miRNAs, which regulate Nrf2-driven gene expression. Accordingly, we found that Nrf2-mediated expression of redox-dependent genes defines a Mox-like phenotype in CBD treated BV-2 cells.

In summary, we have identified a specific repertoire of miRNAs that are regulated by cannabinoids, in resting (surveillant) and in LPS-activated microglia. The modulated miRNAs and their target genes are controlled by TLR, Nrf2 and Notch cross-talk signaling and are involved in immune response, cell cycle regulation as well as cellular stress and redox homeostasis.”

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[Endogenous Cannabinoid System of the Brain as the Target for Influences at Neurodegenerate Diseases]

“The review represents the analysis of works about role of endogenous cannabinoid (EC) system in the neuro- degenerate diseases (ND), in which the cellular death and disturbances of neuronal functions of the hippo- campus, neocortex and striatum are observed. Here, the diseases.ofAlzheimer, of Parkinson, of Hangtington, and the temporal lobe epilepsy are considered. In recent years the fundamental role of EC system in regu- lation of neuroexcitability, energy metabolism, inflammatory and many other processes has been opened in ND pathogenesis. It points to possibility of development of therapeutic approaches which use the prepara- tions for activation of EC system. In the review various mechanisms of cellular survival and their reparations provided to EC system during action of pathological factors are stated.”

https://www.ncbi.nlm.nih.gov/pubmed/30695519

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