Endocannabinoid system and cannabinoids in neurogenesis – new opportunities for neurological treatment? Reports from experimental studies.

Posted on February 11, 2018 by David

“Neurogenesis is one of the most important phenomenona affecting human life. This process consists of proliferation, migration and differentiation of neuroblasts and synaptic integrations of newborn neurons.

Proliferation of new cells continues into old age, also in humans, although the most extensive process of cell formation occurs during the prenatal period. It is possible to distinguish two regions in the brain responsible for neurogenesis: the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ). Hippocampal neurogenesis is very sensitive to various physiological and pathological stimuli.

The functional integration of the newly-born dentate granule cells into hippocampal circuitry, and their ability to mediate long-term potentiation in DG, has led to the hypothesis that neurogenesis in the adult brain may play a key role in learning and memory function, as well as cognitive dysfunction in some diseases.

Brain disorders, such as neurodegenerative diseases or traumatic brain injuries, significantly affect migration, proliferation and differentiation of neural cells. In searching for the best neurological drugs protecting neuronal cells, stimulating neurogenesis, while also developing no side-effects, endocannabinoids proved to be a strong group of substances having many beneficial properties.

Therefore, the latest data is reviewed of the various experimental studies concerning the analysis of the most commonly studied cannabinoids and their impact on neurogenesis.”

http://www.jpccr.eu/Endocannabinoid-system-and-cannabinoids-in-neurogenesis-new-opportunities-for-neurological,74636,0,2.html

http://www.thctotalhealthcare.com/tag/neurogenesis/

Acute ethanol inhibition of adult hippocampal neurogenesis involves CB1 cannabinoid receptor signaling.

Posted on February 10, 2018 by David

Alcoholism: Clinical and Experimental Research

“Chronic ethanol exposure has been found to inhibit adult hippocampal neurogenesis in multiple models of alcohol addiction. Together, these findings suggest that acute CB1R cannabinoid receptor activation and binge ethanol treatment reduce neurogenesis through mechanisms involving CB1R. ” https://www.ncbi.nlm.nih.gov/pubmed/29417597 http://onlinelibrary.wiley.com/doi/10.1111/acer.13608/abstract

“Alcohol-induced neurodegeneration” http://www.diva-portal.org/smash/record.jsf?pid=diva2%3A666727&dswid=174

“Defective Adult Neurogenesis in CB1 Cannabinoid Receptor Knockout Mice. Pharmacological studies suggest a role for CB1 cannabinoid receptors (CB1R) in regulating neurogenesis in the adult brain.” http://molpharm.aspetjournals.org/content/66/2/204.full

“Activation of Type 1 Cannabinoid Receptor (CB1R) Promotes Neurogenesis in Murine Subventricular Zone Cell Cultures” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660454/

“Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases” https://www.ncbi.nlm.nih.gov/pubmed/27364363

“The endocannabinoid system and neurogenesis in health and disease.” https://www.ncbi.nlm.nih.gov/pubmed/17404371

“The role of cannabinoids in adult neurogenesis. Pharmacological targeting of the cannabinoid system as a regulator of neurogenesis may prove a fruitful strategy in the prevention or treatment of mood or memory disorders.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543605/

“Regulation of Adult Neurogenesis by Cannabinoids” https://www.researchgate.net/publication/264424221_Regulation_of_Adult_Neurogenesis_by_Cannabinoids

“Delta-9-Tetrahydrocannabinol (∆9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats. Administration of ∆⁹-THC was observed to enhance the neurogenesis in the brain, especially in hippocampus thus improved the cognitive function of rats.” https://www.ncbi.nlm.nih.gov/pubmed/28933048

“Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement. CBD was observed to stimulate hippocampal neurogenesis.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230631/

“Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. Chronic administration of the major drugs of abuse including opiates, alcohol, nicotine, and cocaine has been reported to suppress hippocampal neurogenesis in adult rats. Plant-derived, or synthetic cannabinoids may promote hippocampal neurogenesis. Cannabinoids appear to be the only illicit drug whose capacity to produce increased hippocampal newborn neurons is positively correlated with its anxiolytic- and antidepressant-like effects. In summary, since adult hippocampal neurogenesis is suppressed following chronic administration of opiates, alcohol, nicotine, and cocaine, the present study suggests that cannabinoids are the only illicit drug that can promote adult hippocampal neurogenesis following chronic administration.” https://www.jci.org/articles/view/25509

Cannabinoid Modulation of the Stressed Hippocampus.

Posted on January 10, 2018 by David

“Exposure to stressful situations is one of the risk factors for the precipitation of several psychiatric disorders, including Major Depressive Disorder, Posttraumatic Stress Disorder and Schizophrenia.

The hippocampal formation is a forebrain structure highly associated with emotional, learning and memory processes; being particularly vulnerable to stress. Exposure to stressful stimuli leads to neuroplastic changes and imbalance between inhibitory/excitatory networks. These changes have been associated with an impaired hippocampal function.

Endocannabinoids (eCB) are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus.

Cannabinoids receptors are highly expressed in the hippocampus, and several lines of evidence suggest that facilitation of cannabinoid signaling within this brain region prevents stress-induced behavioral changes.

Also, chronic stress modulates hippocampal CB₁ receptors expression and endocannabinoid levels.

Moreover, cannabinoids participate in mechanisms related to synaptic plasticity and adult neurogenesis. Here, we discussed the main findings supporting the involvement of hippocampal cannabinoid neurotransmission in stress-induced behavioral and neuroplastic changes.”

https://www.ncbi.nlm.nih.gov/pubmed/29311804

https://www.frontiersin.org/articles/10.3389/fnmol.2017.00411/full

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

Posted on October 6, 2017 by David

Related image

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.”

https://www.ncbi.nlm.nih.gov/pubmed/28978077

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=18871&path[]=60558

Delta-9-Tetrahydrocannabinol (∆9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats.

Posted on September 22, 2017 by David

Neurotoxicity Research

“Neurogenesis is influenced by various external factors such as enriched environments. Some researchers had postulated that neurogenesis has contributed to the hippocampal learning and memory. This project was designed to observe the effect of Delta-9-tetrahydrocannabinol (∆⁹-THC) in cognitive performance that influenced by the neurogenesis.

Different doses of ∆⁹-THC were used for observing the neurogenesis mechanism occurs in the hippocampus of rats. The brains were stained with antibodies, namely BrdU, glial fibrillary acidic protein (GFAP), nestin, doublecortin (DCX) and class III β-tubulin (TuJ-1). The cognitive test was used novel-object discrimination test (NOD) while the proteins involved, DCX and brain-derived neurotrophic factor (BDNF), were measured.

Throughout this study, ∆⁹-THC enhanced the markers involved in all stages of neurogenesis mechanism. Simultaneously, the cognitive behaviour of rat also showed improvement in learning and memory functions observed in behavioural test and molecular perspective.

Administration of ∆⁹-THC was observed to enhance the neurogenesis in the brain, especially in hippocampus thus improved the cognitive function of rats.”

https://www.ncbi.nlm.nih.gov/pubmed/28933048

https://link.springer.com/article/10.1007%2Fs12640-017-9806-x

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

Posted on September 7, 2017 by David

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

Interaction between Cannabinoid Type 1 and Type 2 Receptors in the Modulation of Subventricular Zone and Dentate Gyrus Neurogenesis.

Posted on August 31, 2017 by David

“Neurogenesis in the adult mammalian brain occurs mainly in two neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus (DG). Cannabinoid type 1 and 2 receptors (CB₁R and CB₂R) have been shown to differently modulate neurogenesis. However, low attention has been given to the interaction between CB₁R and CB₂R in modulating postnatal neurogenesis (proliferation, neuronal differentiation and maturation).

We focused on a putative crosstalk between CB₁R and CB₂R to modulate neurogenesis and cultured SVZ and DG stem/progenitor cells from early postnatal (P1-3) Sprague-Dawley rats. Data showed that the non-selective cannabinoid receptor agonist WIN55,212-2 promotes DG cell proliferation (measured by BrdU staining), an effect blocked by either CB₁R or CB₂R selective antagonists. Experiments with selective agonists showed that facilitation of DG cell proliferation requires co-activation of both CB₁R and CB₂R. Cell proliferation in the SVZ was not affected by the non-selective receptor agonist, but it was enhanced by CB₁R selective activation. However, either CB₁R or CB₂R selective antagonists abolished the effect of the CB₁R agonist in SVZ cell proliferation. Neuronal differentiation (measured by immunocytochemistry against neuronal markers of different stages and calcium imaging) was facilitated by WIN55,212-2 at both SVZ and DG. This effect was mimicked by either CB₁R or CB₂R selective agonists and blocked by either CB₁R or CB₂R selective antagonists, cross-antagonism being evident.

In summary, our findings indicate a tight interaction between CB₁R and CB₂R to modulate neurogenesis in the two major neurogenic niches, thus contributing to further unraveling the mechanisms behind the action of endocannabinoids in the brain.”

https://www.ncbi.nlm.nih.gov/pubmed/28848435

http://journal.frontiersin.org/article/10.3389/fphar.2017.00516/full

Role of Endocannabinoids on Neuroinflammation in Autism Spectrum Disorder Prevention

Posted on August 9, 2017 by David

Autism Spectrum Disorder (ASD) disease has become a mounting socio-economical alarm around the world. Neuroinflammtion had been shown in postmortem brain specimens from ASD patients.

The Endocannabinoids System (ES) consists of a family of locally produced, short-lived, endogenous, phospholipid-derived agonists (endocannabinoids) that control energy balance and body composition. The growing number of medical benefits of ES, such as their ability to regulate processes like neuroinflammation, neurogenesis and memory, raise the question of their potential role as a preventive treatment of ASD.

The complex nature of ASD advocates a multimodal drug approach that could protect from the various processes underlying neurodegeneration and thus, at minimum, delay the pathological process. The expected benefit from a chronic treatment aimed at stimulating the endocannabinoid system is a delayed progression of ASD: i.e., reduced inflammation, sustained potential for neurogenesis, and delayed memory impairment. Such results could lead to new therapeutic strategies that target the inflammation and the decline in neurogenesis associated ASD.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535348/

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

Posted on July 24, 2017 by David

Related image

“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.”

https://www.ncbi.nlm.nih.gov/pubmed/28733540

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=18871&path[]=60558

Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders.

Posted on June 8, 2017 by David

Image result for frontiers in pharmacology

“Beneficial effects of cannabidiol (CBD) have been described for a wide range of psychiatric disorders, including anxiety, psychosis, and depression. The mechanisms responsible for these effects, however, are still poorly understood. Similar to clinical antidepressant or atypical antipsychotic drugs, recent findings clearly indicate that CBD, either acutely or repeatedly administered, induces plastic changes. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia. More recently, it was found that CBD modulates cell fate regulatory pathways such as autophagy and others critical pathways for neuronal survival in neurodegenerative experimental models, suggesting the potential benefit of CBD treatment for psychiatric/cognitive symptoms associated with neurodegeneration. These changes and their possible association with CBD beneficial effects in psychiatric disorders are reviewed here.”

https://www.ncbi.nlm.nih.gov/pubmed/28588483

http://journal.frontiersin.org/article/10.3389/fphar.2017.00269/full